Digital Health Professions Education in the Field of Pediatrics: Systematic Review and Meta-Analysis by the Digital Health Education Collaboration.
Reducing childhood morbidity and mortality is challenging, particularly in countries with a shortage of qualified health care workers. Lack of trainers makes it difficult to provide the necessary continuing education in pediatrics for postregistration health professionals. Digital education, teaching and learning by means of digital technologies, has the potential to deliver medical education to a large audience while limiting the number of trainers needed. The goal of the research was to evaluate whether digital education can replace traditional learning to improve postregistration health professionals' knowledge, skills, attitudes, and satisfaction and foster behavior change in the field of pediatrics. We completed a systematic review of the literature by following the Cochrane methodology. We searched 7 major electronic databases for articles published from January 1990 to August 2017. No language restrictions were applied. We independently selected studies, extracted data, and assessed risk of bias, and pairs of authors compared information. We contacted authors of studies for additional information if necessary. All pooled analyses were based on random effects models. We included individually or cluster randomized controlled trials that compared digital education with traditional learning, no intervention, or other forms of digital education. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. Twenty studies (1382 participants) were included. Participants included pediatricians, physicians, nurses, and midwives. Digital education technologies were assessed including high-fidelity mannequins (6 studies), computer-based education (12 studies), mobile learning (1 study), and virtual reality (1 study). Most studies reported that digital education was either as effective as or more effective than the control intervention for outcomes including skill, knowledge, attitude, and satisfaction. High-fidelity mannequins were associated with higher postintervention skill scores compared with low-fidelity mannequins (standardized mean difference 0.62; 95% CI 0.17-1.06; moderate effect size, low-quality evidence). One study reported physician change in practicing behavior and found similar effects between offline plus online digital education and no intervention. The only study that assessed impact on patient outcome found no difference between intervention and control groups. None of the included studies reported adverse or untoward effects or economic outcomes of the digital education interventions. The risk of bias was mainly unclear or high. The quality of evidence was low due to study inconsistencies, limitations, or imprecision across the studies. Digital education for postregistration health professions education in pediatrics is at least as effective as traditional learning and more effective than no learning. High-fidelity mannequins were found to be more effective at improving skills than traditional learning with low-fidelity mannequins. Computer-based offline/online digital education was better than no intervention for knowledge and skill outcomes and as good as traditional face-to-face learning. This review highlights evidence gaps calling for more methodologically rigorous randomized controlled trials on the topic. PROSPERO CRD42017057793; https://tinyurl.com/y5q9q5o6.


Astrocytes release prostaglandin E2 to modify respiratory network activity.
Previously (Forsberg et al., 2016), we revealed that prostaglandin E2 (PGE2), released during hypercapnic challenge, increases calcium oscillations in the chemosensitive parafacial respiratory group (pFRG/RTN). Here, we demonstrate that pFRG/RTN astrocytes are the PGE2 source. Two distinct astrocyte subtypes were found using transgenic mice expressing GFP and MrgA1 receptors in astrocytes. Although most astrocytes appeared dormant during time-lapse calcium imaging, a subgroup displayed persistent, rhythmic oscillating calcium activity. These active astrocytes formed a subnetwork within the respiratory network distinct from the neuronal network. Activation of exogenous MrgA1Rs expressed in astrocytes tripled astrocytic calcium oscillation frequency in both the preBötzinger complex and pFRG/RTN. However, neurons in the preBötC were unaffected, whereas neuronal calcium oscillatory frequency in pFRG/RTN doubled. Notably, astrocyte activation in pFRG/RTN triggered local PGE2 release and blunted the hypercapnic response. Thus, astrocytes play an active role in respiratory rhythm modulation, modifying respiratory-related behavior through PGE2 release in the pFRG/RTN.


A Comparative Study of Conservative versus Surgical Treatment Protocols for 77 Patients with Idiopathic Granulomatous Mastitis.
The purpose of this study was to analyze the clinical features and demographic data of patients with idiopathic granulomatous mastitis (IGM) and to compare the results of conservative versus surgical treatment protocols. The demographic data, clinical findings, microbiological and pathologic features, scanning and treatment methods, recurrence, and recovery rates of 77 patients were analyzed retrospectively. The patients were divided into two groups based on the type of treatment received. Core biopsies were used to diagnose 37 patients: 26 using incisional biopsies and 14 using excisional biopsies. Of the patient population with IGM, 31 were treated with surgical excision, one with a simple mastectomy, and one with a subcutaneous mastectomy combined with a breast implant, whereas 44 were treated with steroids. The recovery rates of the 44 patients who were treated conservatively were 6 (1-15) months while for the 33 patients who were treated surgically, it was 1 (1-5) month (p = 0.001). Nine patients from the conservative treatment group experienced a recurrence while there were no recurrences in the surgically treated group (p = 0.009). Among all patients, the recurrence rate was 11.7% (9/77) while the average follow-up period was 16.57 ± 18.57 months. As a comparative study between conservative treatment protocols and surgical ones for patients with idiopathic granulomatous mastitis (IGM), this study is the largest to date. A wide surgical excision is the preferred approach for treating patients with IGM because of the low recurrence rate.


Physiology in microgravity.
Studies of physiology in microgravity are remarkably recent, with almost all the data being obtained in the past 40 years. The first human spaceflight did not take place until 1961. Physiological measurements in connection with the early flights were crude, but, in the past 10 years, an enormous amount of new information has been obtained from experiments on Spacelab. The United States and Soviet/Russian programs have pursued different routes. The US has mainly concentrated on relatively short flights but with highly sophisticated equipment such as is available in Spacelab. In contrast, the Soviet/Russian program concentrated on first the Salyut and then the Mir space stations. These had the advantage of providing information about long-term exposure to microgravity, but the degree of sophistication of the measurements in space was less. It is hoped that the International Space Station will combine the best of both approaches. The most important physiological changes caused by microgravity include bone demineralization, skeletal muscle atrophy, vestibular problems causing space motion sickness, cardiovascular problems resulting in postflight orthostatic intolerance, and reductions in plasma volume and red cell mass. Pulmonary function is greatly altered but apparently not seriously impaired. Space exploration is a new frontier with long-term missions to the moon and Mars not far away. Understanding the physiological changes caused by long-duration microgravity remains a daunting challenge.


The effects of mirtazapine on plasma lipid profiles in healthy subjects.
The novel antidepressant mirtazapine has been linked to elevated random plasma total cholesterol (TC) levels. The purpose of this study was to evaluate in a more controlled and precise approach the putative effects of mirtazapine on plasma lipids. In a double-blind design, 50 healthy subjects (30 women and 20 men) were randomized to receive either mirtazapine (N = 28) or placebo (N = 22) for a 4-week period. The study was conducted from June 1997 to September 1998. The initial dose for the mirtazapine group was 15 mg daily, which was increased to 30 mg daily at the beginning of the second week. Body weight and plasma lipoprotein profiles, including TC, low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triglycerides, were determined at baseline and at weekly intervals throughout the study period. At baseline, there were no group differences in any of the measures. There was a statistically significant increase of 2.5% in mean body weight over the course of the study in the mirtazapine group that appeared to reach a plateau at 3 weeks, while no increase was observed in the placebo group. Mirtazapine subjects also showed significantly increased TC at week 4 (p =.016) and a transient rise in triglycerides that normalized by week 4. No significant changes in any of the other lipid parameters, including HDL, LDL, and TC/HDL ratios, were observed within either group. Changes in TC were significantly and positively correlated with changes in weight (p <.01). These results suggest that while mirtazapine may be associated with increased TC, it does not increase LDL levels or affect the ratio of TC to HDL.


Novel Algorithm for the Differential Diagnosis of Hyponatraemia in Anuric Patients Undergoing Maintenance Haemodialysis.
Hyponatraemia is associated with increased mortality in patients undergoing maintenance haemodialysis. In anuric patients, hyponatraemia development depends on the water-sodium ratio in retained fluid within the interdialysis interval (IDI). This study aimed to calculate the retained sodium-retained water ratio in patients on maintenance haemodialysis and make a differential diagnosis of hyponatraemia according to these data. The amount of retained water was determined as body weight gain (ΔBW) within the IDI. Sodium retention was calculated using our formula: eRNa+ = ΔBW × (SNa+)t2 - total body water (TBW)t1 × ([SNa+]t1 - [SNa+]t2), where TBW represents the calculated volume of the total body water and (SNa+)t1 and (SNa+)t2 represent the sodium concentration at the beginning and at the end of the IDI, respectively. We performed 89 measurements in 32 anuric patients on maintenance haemodialysis. Hyponatraemia was detected in 13 measurements at the end of the IDI. The ΔBW had no statistically significant difference between normonatraemic and hyponatraemic patients. Hyponatraemic patients had significantly lower levels of retained sodium. The retained water--retained sodium ratio facilitated in differentiating dilution hyponatraemia, nutritional hyponatraemia, depletion hyponatraemia, and dilution hyponatraemia associated with sodium wasting or malnutrition. The composition of retained fluid during the IDI may be hypotonic, hypertonic, or isotonic in relation to the extracellular fluid. Most of the hyponatraemic patients had hypotonic fluid retained during the IDI because of dilution as well as gastrointestinal sodium loss and/or malnutrition.


The role of imaging in determining prognosis for primary sclerosing cholangitis: A systematic review.
Primary sclerosing cholangitis (PSC) is a chronic, progressive, fibrotic bile duct disease. Resultant complications include infection, progressive liver disease and cancer. While diagnosis relies extensively on imaging, the role of imaging in determining prognosis is unclear. The aim of this study was to systematically review existing imaging indices and features that predict PSC progression. We performed a systematic review of imaging features that predict PSC progression. PubMed, EMBASE, MEDLINE, Clinicaltrials.gov and the Cochrane Library were searched from inception to November 2018 for relevant studies. Pertinent data were extracted and assessed. Study quality was evaluated using the Newcastle-Ottawa scale (NOS). The search returned 2504 results. Nine studies were included in the final review. Four studies evaluated the prognostic value of imaging features and five evaluated prognostic algorithms. The mean NOS score was 4.44 ± 0.98 on a scale of 0 to 9. Imaging features that were of prognostic value were degree of intrahepatic duct narrowing, the presence of a dominant biliary duct stricture and percentage of narrowed intraheptic ducts. Three imaging indices (one endoscopic retrograde cholangiopancreatography (ERCP)-based and two magnetic resonance-based) had been derived. The ERCP index was validated in a second cohort and subsequently updated to improve its predictive ability. The magnetic resonance cholangiopancreatography (MRCP) index was validated in two studies and was found to be predicative of transplant-free survival. A modified MRCP index (MRCP-risk score) was evaluated in a prospective multicenter study and was found to be predicative of PSC-related disease progression. In conclusion, ERCP and MRCP-based indices have short-term prognostic value in PSC. However, more studies are required to validate their predictability of disease-related progression, such as liver decompensation, ascending cholangitis, cholangiocarcinoma and liver transplantation.


Powder exfoliated MoS2 nanosheets with highly monolayer-rich structures as high-performance lithium-/sodium-ion-battery electrodes.
Due to their low yield and easy aggregation during the electrode preparation process, exfoliated MoS2 monolayers cannot fulfill the requirements of alkali-metal-ion battery tests. Hence, we have developed a facile process to fabricate powder exfoliated MoS2 nanosheets capable of large-scale production and having highly monolayer-rich structures. This process contains two steps: liquid-phase exfoliation of the edge-rich MoS2 precursor and a freeze-drying procedure. The proposed MoS2 precursors contain rich edge fractions that are easily exfoliated by this method, and the freeze-drying procedure can maintain the unique monolayer-rich structure of MoS2 in the powder phase. The electrochemical evaluations of both lithium- and sodium-ion batteries reveal that the proposed powder exfoliated monolayer-rich MoS2 electrode exhibits remarkable specific capacities and stable cyclic performances. In particular, the monolayer-rich MoS2 nanosheet electrode delivers a superior lithium-storage capacity of ∼1400 mA h g-1. The exfoliated MoS2 nanosheet electrode can withstand over 1000 cycles even at 1 A g-1. The mechanism reveals that these unique MoS2 nanosheets not only have a large surface area but also their inclusive monolayer structures exhibit much higher charge mobility than those of bulk MoS2.


[Modern taxonomy, classification, and nomenclature of streptococci].
Comparative analysis of main trends of taxonomy, classification, and nomenclature of prokaryotic organisms and streptococci was performed. Phylogenetic classification of streptococci was thoroughly considered. Original classification of streptococci based on pathogenicity and ecological-epidemiological criteria was proposed for medical purposes. Allocation of groups of pathogenic and opportunistic streptococci, which are recommended to place in III and IV groups of pathogenicity, was substantiated. It was shown that according to ecological-epidemiological criterion streptococci can be referred to agents of anthroponoses, zoonoses, and sapronoses.


Comparison of an adaptive local thresholding method on CBCT and µCT endodontic images.
Root canal segmentation on cone beam computed tomography (CBCT) images is difficult because of the noise level, resolution limitations, beam hardening and dental morphological variations. An image processing framework, based on an adaptive local threshold method, was evaluated on CBCT images acquired on extracted teeth. A comparison with high quality segmented endodontic images on micro computed tomography (µCT) images acquired from the same teeth was carried out using a dedicated registration process. Each segmented tooth was evaluated according to volume and root canal sections through the area and the Feret's diameter. The proposed method is shown to overcome the limitations of CBCT and to provide an automated and adaptive complete endodontic segmentation. Despite a slight underestimation (-4, 08%), the local threshold segmentation method based on edge-detection was shown to be fast and accurate. Strong correlations between CBCT and µCT segmentations were found both for the root canal area and diameter (respectively 0.98 and 0.88). Our findings suggest that combining CBCT imaging with this image processing framework may benefit experimental endodontology, teaching and could represent a first development step towards the clinical use of endodontic CBCT segmentation during pulp cavity treatment.


Emergency medical services capacities in the developing world: preliminary evaluation and training in Addis Ababa, Ethiopia.
In December 1999, a group of emergency physicians from the United States, Israel, and Ethiopia met for the Second Annual Symposium on Emergency Medicine and to perform an initial evaluation of the prehospital care system in Addis Ababa. The symposium was structured into a workshop on prehospital care and a clinical seminar for emergency medicine providers. This article describes the current prehospital infrastructure in Addis Ababa, Ethiopia. This serves as the basis for more specific needs assessments and training interventions, which are ongoing. The authors present a list of priorities for the development of an emergency medical services (EMS) system for Addis Ababa that was generated in partnership with local government and the World Health Organization. The article contrasts these initial recommendations with those found in the literature on the development of EMS systems in developing nations.


[Changes in immunologic reactivity in patients with gastrointestinal bleeding].
The disorders in immunologic reactivity in acute gastrointestinal bleeding were studied in dynamics in 160 patients. Pronouncement of disorders in the T-system of immunity, activation of the reactions of specific sensibilization and autoallergic phenomena depend on severity of the blood loss. In ulcer location in the duodenum, the performance of an organ-preserving operation with vagotomy and elimination of the ulcer which is a source of antigen stimulation is preferable.


A comparison of different rigid contact lenses: edge thicknesses and contours.
The edge thickness and contour of rigid lenses is an important factor in lens comfort and acceptance. In this study the edges of two CAB lenses, a PMMA-silicone combination lens, a pure silicone lens had standard PMMA lenses are evaluated by molding the lenses. Considerable variation in thickness and contour of the peripheral portion of the lenses were found.


Protective immunity against feline immunodeficiency virus induced by inoculation with vif-deleted proviral DNA.
To determine whether live-attenuated feline immunodeficiency virus (FIV) proviral DNA will induce protective immunity, a plasmid clone constructed with a FIV provirus containing a deletion in the viral accessory gene vif (FIV-pPPR-Deltavif) was inoculated as proviral DNA into four cats by the intramuscular route. After 43 weeks, these cats were boosted with the same proviral plasmid. Analysis of peripheral blood mononuclear cells at several time points after the primary and booster inoculations revealed no detectable virus or proviral DNA. At 6 weeks after the booster, immunized cats and additional naive control cats were challenged with a cell-free preparation of the infectious biological isolate FIV-PPR by the intraperitoneal route. Virus was detected after challenge in unvaccinated control cats but not in any of the FIV-pPPR-Deltavif-immunized cats. Both FIV Gag- and Env-specific cytotoxic T lymphocyte (CTL) activities were detected in peripheral blood cells of control cats after challenge infection, whereas only one of four cats immunized with FIV-pPPR-Deltavif DNA exhibited a measurable CTL response to Env following challenge. Although anti-Gag antibodies were not detected after both proviral DNA inoculation and challenge, anti-Env antibodies were found in FIV-pPPR-Deltavif-immunized cats after vaccination as well as after challenge. These findings indicate that inoculation with FIV-pPPR-Deltavif proviral DNA induced resistance to challenge with infectious FIV and that a vif deletion mutant may provide a relatively safe attenuated lentiviral vaccine.


A Nearly Neutral Model of Molecular Signatures of Natural Selection after Change in Population Size.
The nearly neutral theory is a common framework to describe natural selection at the molecular level. This theory emphasizes the importance of slightly deleterious mutations by recognizing their ability to segregate and eventually get fixed due to genetic drift in spite of the presence of purifying selection. As genetic drift is stronger in smaller than in larger populations, a correlation between population size and molecular measures of natural selection is expected within the nearly neutral theory. However, this hypothesis was originally formulated under equilibrium conditions. As most natural populations are not in equilibrium, testing the relationship empirically may lead to confounded outcomes. Demographic nonequilibria, for instance following a change in population size, are common scenarios that are expected to push the selection-drift relationship off equilibrium. By explicitly modeling the effects of a change in population size on allele frequency trajectories in the Poisson random field framework, we obtain analytical solutions of the nonstationary allele frequency spectrum. This enables us to derive exact results of measures of natural selection and effective population size in a demographic nonequilibrium. The study of their time-dependent relationship reveals a substantial deviation from the equilibrium selection-drift balance after a change in population size. Moreover, we show that the deviation is sensitive to the combination of different measures. These results therefore constitute relevant tools for empirical studies to choose suitable measures for investigating the selection-drift relationship in natural populations. Additionally, our new modeling approach extends existing population genetics theory and can serve as foundation for methodological developments.


Concentration-dependent effects of fullerenol on cultured hippocampal neuron viability.
Recent studies have shown that the biological actions and toxicity of the water-soluble compound, polyhydroxyfullerene (fullerenol), are related to the concentrations present at a particular site of action. This study investigated the effects of different concentrations of fullerenol on cultured rat hippocampal neurons. Fullerenol at low concentrations significantly enhanced hippocampal neuron viability as tested by MTT assay and Hoechst 33342/propidium iodide double stain detection. At high concentrations, fullerenol induced apoptosis confirmed by Comet assay and assessment of caspase proteins. These findings suggest that fullerenol promotes cell death and protects against cell damage, depending on the concentration present. The concentration-dependent effects of fullerenol were mainly due to its influence on the reduction-oxidation pathway.


Relationship between walking performance and types of community-based activities in people with stroke: an observational study.
To examine the relationship between clinical walking performance and amount and type of community activity in people after stroke. A cross-sectional observational study of 14 people with stroke living in Sydney and able to walk was carried out. Demographics (such as age, gender, side of stroke, time since stroke, presence of spouse) and aspects of walking performance (such as speed, capacity, automaticity, and stairs ability) were measured. People with stroke were observed for at least five hours while they carried out activities in the community. These activities were then categorized into four types: domestic intrinsic, domestic extrinsic, leisure without contact, and leisure with contact activity. No relationship was found between walking performance and the amount of community activity. There was no relationship between walking performance and total time spent on domestic intrinsic activity. Walking speed and stairs ability were significantly correlated with leisure with contact activity (r=0.56, p=0.04, and r=0.57, p=0.03 respectively) and inversely correlated with leisure without contact (r=-0.72, p<0.01, and r=-0.66, p=0.01 respectively). Walking capacity was also inversely correlated with leisure without contact (r=-0.77, p<0.01). Only stairs ability was significantly correlated with domestic extrinsic activity (r=0.77, p<0.01). Findings suggest that if walking performance is poor after stroke, activities at home and in the community will be limited, so that people may become housebound and isolated from society.


Programming permanent and transient molecular protection via mechanical stoppering.
Chemical protection is an essential tool in synthetic chemistry, which involves blocking reactive sites on a molecule through covalent bonds. Physical approaches, such as encapsulation and host-mediated protection, have emerged as interesting alternatives that use steric bulk to inhibit reactivity. Here, we report the protection of a redox-active viologen through its incorporation into mechanically interlocked molecules (MIMs), namely hetero[4]rotaxanes. The viologen was confined inside a host cavity and flanked by two mechanical stoppers, which allowed for permanent and transient protection. Deprotection occurred on-demand via an unstoppering process, triggered by a proton transfer, polarity effect, or a thermal stimulus. We anticipate that permanent and transient mechanical stoppering could be incorporated into devices to function as molecular probes, transport/delivery systems, or stimuli-controlled degradable materials.


DNA repair and recombination functions in Arabidopsis telomere maintenance.
In this review, we discuss recent advances in the knowledge of plant telomere maintenance, focusing on the model plant Arabidopsis thaliana and, in particular, on the roles of proteins involved in DNA repair and recombination. The question of the interrelationships between DNA repair and recombination pathways and proteins with telomere function and maintenance is of increasing interest and has been the subject of a number of recent reviews (Cech 2004, d'Adda di Fagagna et al. 2004, Hande 2004, Harrington 2004, Maser and DePinho 2004). Understanding of telomere biology, DNA repair and recombination in plants has rapidly progressed over the last decade, substantially due to genetic approaches in Arabidopsis, and we feel that this is an appropriate time to review current knowledge in this field. A number of recent reviews have dealt more generally with the subject of plant telomere structure and evolution (Riha et al. 2001, McKnight et al. 2002, Riha and Shippen 2003b, McKnight and Shippen 2004, Fajkus et al. 2005) and we thus focus specifically on plant telomere biology in the context of DNA repair and recombination in Arabidopsis.


[Residual choledocholithiasis: modern realities].
In 748 patients, ageing 28-80 yrs, residual calculi of common biliary duct were removed, using various methods. Transfistular removing of biliary calculi was the method of choice in presence of external drain and endoscopic papillosphincterotomy (EPST) - in its absence. Efficacy of the first variant have had constituted 95.2% and of the second--88%. In 9.5% patients the reoperations were performed--open or laparoscopic. Late results in majority of patients were studied in terms not less than 3 years. Good late results of transdrainage nonoperative elimination of calculi in the first 3 years have had constituted 90% and in the next 6-10 years--99%; while in EPST--accordingly, 85 and 88%. In spite of constantly widening possibilities of the residual choledocholithiasis elimination the main task for modern biliary surgery--the prophylaxis of this not rare complication of cholelithic disease--persist.


TMC1 is an essential component of a leak channel that modulates tonotopy and excitability of auditory hair cells in mice.
Hearing sensation relies on the mechano-electrical transducer (MET) channel of cochlear hair cells, in which transmembrane channel-like 1 (TMC1) and transmembrane channel-like 2 (TMC2) have been proposed to be the pore-forming subunits in mammals. TMCs were also found to regulate biological processes other than MET in invertebrates, ranging from sensations to motor function. However, whether TMCs have a non-MET role remains elusive in mammals. Here, we report that in mouse hair cells, TMC1, but not TMC2, provides a background leak conductance, with properties distinct from those of the MET channels. By cysteine substitutions in TMC1, we characterized four amino acids that are required for the leak conductance. The leak conductance is graded in a frequency-dependent manner along the length of the cochlea and is indispensable for action potential firing. Taken together, our results show that TMC1 confers a background leak conductance in cochlear hair cells, which may be critical for the acquisition of sound-frequency and -intensity.


Do Arterial Hemodynamic Parameters Predict Cognitive Decline Over a Period of 2 Years in Individuals Older Than 80 Years Living in Nursing Homes? The PARTAGE Study.
Several studies have highlighted a link between vascular alterations and cognitive decline. The PARTAGE study showed that arterial stiffness as evaluated by carotid-femoral pulse wave velocity (cfPWV) was associated with a more pronounced cognitive decline over a 1-year period in very old frail institutionalized individuals. The aim of the present analysis was to assess the role of hemodynamic parameters, such as blood pressure (BP), heart rate (HR), cfPWV, and central/peripheral pulse pressure amplification (PPA) on cognitive decline over 2 years in very old frail individuals. A total of 682 individuals from the PARTAGE study cohort, aged older than 80 years (mean age at inclusion: 87.5 ± 5.0 years) and living in French and Italian nursing homes, were analyzed. Mini-Mental State Examination (MMSE) score was assessed at baseline (BL) and at the end of the first and second year of follow-up (2y-FU). Those with a decrease in MMSE of 3 or more points between BL and 2y-FU were considered as "decliners." The cfPWV and PPA at baseline were assessed with an arterial tonometer. After adjustment for baseline MMSE, HR, body mass index, age, education level, and activities of daily living (ADLs), cfPWV was higher and PPA lower in "decliners" compared with "nondecliners," whereas BP did not differ between the 2 groups. Logistic multivariate analysis also revealed that high cfPWV, low PPA, high HR, and low ADLs were all determinants of MMSE decline. This 2-year longitudinal study in very old institutionalized individuals shows that arterial stiffness and high HR enabled us to identify subjects at higher risk of cognitive decline, whereas BP alone did not appear to have a significant predictive value. These findings highlight the contribution of vascular determinants in cognitive decline even in this very old population.


Expression of tissue factor pathway inhibitor in vascular smooth muscle cells and its regulation by growth factors.
Tissue factor pathway inhibitor (TFPI) in vivo is thought to be synthesized mainly by endothelial cells. To date, no significant regulator of TFPI synthesis has been described. Vascular smooth muscle cells (VSMC) express tissue factor in vitro and in vivo, which may contribute to vascular thrombosis. We hypothesized that VSMC might also express TFPI. To determine this, we examined growth-arrested coronary VSMC in culture and found that VSMC secreted an amount of TFPI similar to that seen in endothelial cells. Immunohistochemistry of normal human coronary arteries showed TFPI staining throughout the media and intima of the vessel with localization to VSMC and endothelial cells. To determine regulation of TFPI expression in VSMC, we examined the effects of serum stimulation on TFPI secretion and found that FBS induced a 5-fold increase in TFPI antigen and activity levels in conditioned medium at 48 hours (P<0.001) when compared with serum-free conditions. A similar stimulatory effect was seen with 10% pooled human serum. Moreover, epidermal growth factor and platelet-derived growth factor-B increased TFPI secretion by 4- to 5-fold and 2- to 3-fold, respectively (P<0.05), and these growth factors accounted for approximately 50% of the TFPI secretion effects of human serum. The serum effect was associated with a 3-fold increase in TFPI mRNA 24 hours after release from growth arrest and a 50% decrease in TFPI secretion after treatment with actinomycin D. Taken together, this study suggests that there is significant TFPI expression in VSMC in culture and in VSMC within the intima and media of the normal coronary artery wall. We present the first evidence for TFPI regulation by serum in VSMC and more specifically by its constituent growth factors, epidermal growth factor and platelet-derived growth factor-B.


Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects.
We have studied the effect of prolonged hyperinsulinemia and hyperglycemia on serum leptin levels in young nonobese males during 72-h euglycemic-hyperinsulinemic and hyperglycemic ( approximately 8.5 and 12.6 mM) clamps. Hyperinsulinemia increased serum leptin concentrations (by RIA) dose-dependently. An increase in serum insulin concentration of > 200 pM for > 24 h was needed to significantly increase serum leptin. An increase of approximately 800 pM increased serum leptin by approximately 70% over 72 h. Changes in plasma glucose concentrations (from approximately 5.0 to approximately 12.6 mM) or changes in plasma FFA concentrations (from < 100 to > 1,000 microM) had no effect on serum leptin. Serum leptin concentrations changed with circadian rhythmicity. The cycle length was approximately 24 h, and the cycle amplitude (peak to trough) was approximately 50%. The circadian leptin cycles and the circadian cycles of total body insulin sensitivity (i.e., GIR, the glucose infusion rates needed to maintain euglycemia during hyperinsulinemic clamping) changed in a mirror image fashion. Moreover, GIR decreased between Days 2 and 3 (from 11.4+/-0.2 to 9. 8+/-0.2 mg/kg min, P< 0.05) when mean 24-h leptin levels reached a peak. In summary, we found (a) that 72 h of hyperinsulinemia increased serum leptin levels dose-dependently; (b) that hyperglycemia or high plasma FFA levels did not affect leptin release; (c) that leptin was released with circadian rhythmicity, and (d) that 24-h leptin cycles correlated inversely with 24-h cycles of insulin sensitivity. We speculate that the close positive correlation between body fat and leptin is mediated, at least in part, by insulin.


The human CD5L/AIM-CD36 axis: A novel autophagy inducer in macrophages that modulates inflammatory responses.
CD5L (CD5 molecule-like) is a secreted glycoprotein that participates in host response to bacterial infection. CD5L influences the monocyte inflammatory response to the bacterial surface molecules lipopolysaccharide (LPS) and lipoteichoic acid (LTA) by inhibiting TNF secretion. Here we studied the intracellular events that lead to macrophage TNF inhibition by human CD5L. To accomplish this goal, we performed functional analyses with human monocytic THP1 macrophages, as well as with peripheral blood monocytes. Inhibition of phosphatidylinositol 3-kinase (PtdIns3K) reversed the inhibitory effect of CD5L on TNF secretion. Among the various PtdIns3K isoforms, our results indicated that CD5L activates PtdIns3K (whose catalytic subunit is termed PIK3C3), a key modulator involved in autophagy. Further analysis revealed a concomitant enhancement of autophagy markers such as cellular LC3-II content, increased LC3 puncta, as well as LC3-LysoTracker Red colocalization. Moreover, electron microscopy showed an increased presence of cytosolic autophagosomes in THP1 macrophages overexpressing CD5L. Besides preventing TNF secretion, CD5L also inhibited IL1B and enhanced IL10 secretion. This macrophage anti-inflammatory pattern of CD5L was reverted upon silencing of autophagy protein ATG7 by siRNA transfection. Additional siRNA experiments in THP1 macrophages indicated that the induction of autophagy mechanisms by CD5L was achieved through cell-surface scavenger receptor CD36, a multiligand receptor expressed in a wide variety of cell types. Our data represent the first evidence that CD36 is involved in autophagy and point to a significant contribution of the CD5L-CD36 axis to the induction of macrophage autophagy.


Low-intensity agricultural landscapes in Transylvania support high butterfly diversity: implications for conservation.
European farmland biodiversity is declining due to land use changes towards agricultural intensification or abandonment. Some Eastern European farming systems have sustained traditional forms of use, resulting in high levels of biodiversity. However, global markets and international policies now imply rapid and major changes to these systems. To effectively protect farmland biodiversity, understanding landscape features which underpin species diversity is crucial. Focusing on butterflies, we addressed this question for a cultural-historic landscape in Southern Transylvania, Romania. Following a natural experiment, we randomly selected 120 survey sites in farmland, 60 each in grassland and arable land. We surveyed butterfly species richness and abundance by walking transects with four repeats in summer 2012. We analysed species composition using Detrended Correspondence Analysis. We modelled species richness, richness of functional groups, and abundance of selected species in response to topography, woody vegetation cover and heterogeneity at three spatial scales, using generalised linear mixed effects models. Species composition widely overlapped in grassland and arable land. Composition changed along gradients of heterogeneity at local and context scales, and of woody vegetation cover at context and landscape scales. The effect of local heterogeneity on species richness was positive in arable land, but negative in grassland. Plant species richness, and structural and topographic conditions at multiple scales explained species richness, richness of functional groups and species abundances. Our study revealed high conservation value of both grassland and arable land in low-intensity Eastern European farmland. Besides grassland, also heterogeneous arable land provides important habitat for butterflies. While butterfly diversity in arable land benefits from heterogeneity by small-scale structures, grasslands should be protected from fragmentation to provide sufficiently large areas for butterflies. These findings have important implications for EU agricultural and conservation policy. Most importantly, conservation management needs to consider entire landscapes, and implement appropriate measures at multiple spatial scales.


The landscape of somatic mutation in sporadic Chinese colorectal cancer.
Colorectal cancer is the fifth prevalent cancer in China. Nevertheless, a large-scale characterization of Chinese colorectal cancer mutation spectrum has not been carried out. In this study, we have performed whole exome-sequencing analysis of 98 patients' tumor samples with matched pairs of normal colon tissues using Illumina and Complete Genomics high-throughput sequencing platforms. Canonical CRC somatic gene mutations with high prevalence (>10%) have been verified, including TP53, APC, KRAS, SMAD4, FBXW7 and PIK3CA. PEG3 is identified as a novel frequently mutated gene (10.6%). APC and Wnt signaling exhibit significantly lower mutation frequencies than those in TCGA data. Analysis with clinical characteristics indicates that APC gene and Wnt signaling display lower mutation rate in lymph node positive cancer than negative ones, which are not observed in TCGA data. APC gene and Wnt signaling are considered as the key molecule and pathway for colorectal cancer initiation, and these findings greatly undermine their importance in tumor progression for Chinese patients. Taken together, the application of next-generation sequencing has led to the determination of novel somatic mutations and alternative disease mechanisms in colorectal cancer progression, which may be useful for understanding disease mechanism and personalizing treatment for Chinese patients.


Colorectal cancer expression of peroxisome proliferator-activated receptor gamma (PPARG, PPARgamma) is associated with good prognosis.
The peroxisome proliferator-activated receptor gamma (PPARG, PPARgamma) is a nuclear receptor that regulates expression of mediators of lipid metabolism and the inflammatory response. There is controversy over the pro-oncogenic or antioncogenic effects of PPARG, and little is known about its prognostic significance in colon cancer. Among 470 patients with colorectal cancer (stages I-IV) identified in 2 independent prospective cohorts, PPARG expression was detected in 102 tumors (22%) by immunohistochemistry. Cox proportional hazards models were used to compute hazard ratios (HRs) of colorectal cancer-specific and overall mortalities, adjusted for patient characteristics and molecular features including cyclooxygenase 2, fatty acid synthase, KRAS, BRAF, PIK3CA, p53, p21, beta-catenin, LINE-1 hypomethylation, microsatellite instability (MSI), and the CpG island methylation phenotype (CIMP). Compared with patients with PPARG-negative tumors, patients with PPARG-positive tumors had significantly lower overall mortality, determined by Kaplan-Meier analysis (P=.0047), univariate Cox regression (HR, 0.55; 95% confidence interval [CI], 0.37-0.84; P=.0053), and multivariate analysis (adjusted HR, 0.43; 95% CI, 0.27-0.69; P=.0004). Patients with PPARG-positive tumors experienced lower colorectal cancer-specific mortality (adjusted HR, 0.44; 95% CI, 0.25-0.79; P=.0054). The relationship between PPARG and lower mortality did not appear to be significantly modified by MSI, CIMP, LINE-1, or the other clinical and molecular variables examined (all P(interaction)>.05). Tumor expression of PPARG is independently associated with longer survival of patients. PPARG expression appears to mark an indolent subset of colorectal cancers.


Traumatic posterior hip subluxation in American football.
Traumatic posterior hip subluxation is a potentially devastating injury that is often misdiagnosed as a simple hip sprain or strain. The purpose of the present study was to outline the injury mechanism, pathoanatomy, clinical and radiographic findings, and treatment of traumatic hip subluxation in an athletic population. Over a nine-year period, eight participants in American football who had sustained a traumatic posterior hip subluxation were evaluated and treated. The injury mechanism, clinical findings, and radiographic findings were reviewed. The mean duration of follow-up was thirty-four months. The most common mechanism of injury was a fall on a flexed, adducted hip. Physical examination revealed painful limitation of hip motion. Initial radiographs demonstrated a characteristic posterior acetabular lip fracture. Initial magnetic resonance images revealed disruption of the iliofemoral ligament, hemarthrosis, and a viable femoral head. Two players were treated acutely with hip aspiration, and all eight players were treated with a six-week regimen of toe-touch weight-bearing with use of crutches. Six players recovered and returned to the previous level of competition. Two players had development of severe osteonecrosis and ultimately required total hip arthroplasty. The pathognomonic radiographic and magnetic resonance imaging triad of posterior acetabular lip fracture, iliofemoral ligament disruption, and hemarthrosis defines traumatic posterior hip subluxation. Patients in whom large hemarthroses are diagnosed on magnetic resonance images should undergo acute aspiration, and all players should be treated with a six-week regimen of toe-touch weight-bearing with use of crutches. Patients who have no sign of osteonecrosis on magnetic resonance imaging at six weeks can safely return to sports activity. Patients in whom osteonecrosis is diagnosed at six weeks are at risk for collapse and joint degeneration, and they should be advised against returning to sports.


First documented rhythm and clinical outcome in children who undergo extracorporeal cardiopulmonary resuscitation for in-hospital cardiac arrest: A report from the american heart association get with the guidelines® - resuscitation registry (GWTG-R).
Outcomes of conventional cardiopulmonary resuscitation are improved when the initial rhythm is shockable (ventricular fibrillation or pulseless ventricular tachycardia). In children, the first documented rhythm is typically asystole or pulseless electrical activity. We evaluate the role the initial rhythm plays in outcomes for children undergoing extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital cardiac arrest. Consecutive patients < 18 years with in-hospital ECPR events ≥ 10 minutes reported to the American Heart Association Get With The Guidelines® - Resuscitation registry from 2014 to 2019 were included. Primary outcome was survival to hospital discharge. Logistic regression modeling was used to compute propensity score matching based on patient, cardiac arrest event and hospital characteristics; patients with initial shockable rhythm were matched to patients with initial non-shockable rhythm. The final cohort included 466 patients, of which 82 (18%) had a shockable, and 384 (82%) had a non-shockable initial rhythm. After propensity score matching of 287 (62%) patients, there was no difference in survival to hospital discharge (risk ratio [RR] 1.2, 95% CI, 0.95-1.53, p = 0.13) or favorable neurologic outcome, defined as Pediatric Cerebral Performance Category (PCPC) of 1 or 2, or no decline from baseline (RR 1.28, 95% CI, 0.84-1.96, p = 0.25) between patients with and without shockable initial rhythm. In children with in-hospital cardiac arrest undergoing ECPR, there was no significant difference in survival or favorable neurologic outcome between those with initial shockable rhythm compared to non-shockable rhythm. Further investigation to evaluate ECPR patient characteristics and outcomes is warranted to help guide eligibility and ECMO deployment practices.


Renewable energy homes for marine life: Habitat potential of a tidal energy project for benthic megafauna.
An increasing number of offshore structures are being deployed worldwide to meet the growing demand for renewable energy. Besides energy production, these structures can also provide new artificial habitats to a diversity of fish and crustacean species. This study characterises how concrete mattresses that stabilise the submarine power cable of a tidal energy test site can increase habitat capacity for benthic megafauna. A five-year monitoring, which relied on both visual counts and video-based surveys by divers, revealed that these mattresses provide a suitable habitat for 5 taxa of large crustaceans and fish. In particular, two commercially valuable species, i.e. the edible crab Cancer pagurus and the European lobster Homarus gammarus, showed a constant occupancy of these artificial habitats throughout the course of the project. The shape and the number of shelters available below individual mattresses largely determine potential for colonisation by mobile megafauna. Local physical characteristics of the implantation site (e.g. substratum type, topography, exposition to current etc.) significantly impact amount and type of shelters provided by the concrete mattresses. Thus, to characterise habitat potential of artificial structures, it is not only essential to consider (i) the design of the structures, but also to (ii) account for their interactions with local environmental conditions when deployed on the seafloor.


Amyloid fibril systems reduce, stabilize and deliver bioavailable nanosized iron.
Iron-deficiency anaemia (IDA) is a major global public health problem. A sustainable and cost-effective strategy to reduce IDA is iron fortification of foods, but the most bioavailable fortificants cause adverse organoleptic changes in foods. Iron nanoparticles are a promising solution in food matrices, although their tendency to oxidize and rapidly aggregate in solution severely limits their use in fortification. Amyloid fibrils are protein aggregates initially known for their association with neurodegenerative disorders, but recently described in the context of biological functions in living organisms and emerging as unique biomaterial building blocks. Here, we show an original application for these protein fibrils as efficient carriers for iron fortification. We use biodegradable amyloid fibrils from β-lactoglobulin, an inexpensive milk protein with natural reducing effects, as anti-oxidizing nanocarriers and colloidal stabilizers for iron nanoparticles. The resulting hybrid material forms a stable protein-iron colloidal dispersion that undergoes rapid dissolution and releases iron ions during acidic and enzymatic in vitro digestion. Importantly, this hybrid shows high in vivo iron bioavailability, equivalent to ferrous sulfate in haemoglobin-repletion and stable-isotope studies in rats, but with reduced organoleptic changes in foods. Feeding the rats with these hybrid materials did not result in abnormal iron accumulation in any organs, or changes in whole blood glutathione concentrations, inferring their primary safety. Therefore, these iron-amyloid fibril hybrids emerge as novel, highly effective delivery systems for iron in both solid and liquid matrices.


[Breast tissue: estrogen receptors. Immunohistochemical and biochemical analysis of normal and hyperplastic tissue and carcinoma in situ. Apropos of 86 cases].
Estrogen receptors (ER) were investigated using immunohistochemical techniques in 54 cases and biochemical techniques in 38 cases on a series of biopsy specimens of normal, hyperplasic and malignant mammary tissue (intraductal carcinoma). Immunohistochemical data were submitted to quantitative and semi-quantitative analysis (SAMBA 200, TITN). On normal tissue, immunostaining is bright and evenly distributed in galactophores and ductulo-lobular junctions; it is unevenly distributed but consistently present in lobules and increasing after menopause. On hyperplasic tissue, immunostaining of papillary cystadenomas and epitheliosis and fibroadenosis zones was similar to normal tissue with respect to the intensity and heterogeneity. Conversely, their immunohistochemical features are close to blunt duct adenosis and atypical lobular hyperplasia of ductulo-lobular junctions. On malignant tissue, immunostaining is unpredictable, it can be evenly distributed, unevenly distributed in patches or gradients, or totally absent. Immunohistochemical techniques can only be used to assess the intensity and distribution of ER in function of cell type in normal tissue and during a cancerous process. Thus strong receptivity of ductulo-lobular junctions may reinforce the claim that these structures are the targets for estrogen co-carcinogenic substances. The heterogeneity of ER at the onset of carcinoma suggests the possibility of several pathway of development. The fact that myoepithelial cell never seem to display estrogen type receptivity makes it logical to seek a special sensitivity for them.


The effect of the source and the concentration of polymers on the release of chlorhexidine from mucoadhesive buccal tablets.
In the current work, two groups of chlorhexidine mucoadhesive buccal tablets were prepared, using either rod or irregularly-shaped spherical particles of hydroxypropyl methylcellulose and different ratios of poloxamer 407 (P407). The tablets were designed to release the drug over two hours. Their physicochemical properties and drug release profiles were investigated. The impact on dry granulation, the ex-vivo mucoadhesion, the swelling index, the morphology of swollen tablets and the drug release kinetic were investigated. Drug-polymers chemical interaction was studied using Fourier Transforms Infrared Spectroscopy (FTIR) and differential scanning calorimetry (DSC). Due to different particle shapes, the preparation of dry granules required a 40 KN force for rod-shaped particles compared to 10 KN for the irregularly-shaped spherical particles. All formulations showed at least two-hours residence time using ex-vivo mucoadhesion. Statistically, there was no significant difference in the swelling index, drug release nor its kinetic for both groups. However, the microscopical morphology of the swollen tablet and the size of the pores were affected by particle shape. Increasing the ratio of P407 to 62.5% resulted in a pronounced increase in drug release from around 60% to >90% after two hours. Following the FTIR and DSC analyses, no chemical interaction was noted apart from the steric hindrance effect of P407, which was observed even with the physical mixtures.


Trapping H- bound to the nitrogenase FeMo-cofactor active site during H2 evolution: characterization by ENDOR spectroscopy.
We here show that the iron-molybdenum (FeMo)-cofactor of the nitrogenase alpha-70(Ile) molybdenum-iron (MoFe) protein variant accumulates a novel S = (1)/(2) state that can be trapped during the reduction of protons to H(2). (1,2)H-ENDOR measurements disclose the presence of two protons/hydrides (H(+/)(-)) whose hyperfine tensors have been determined from two-dimensional field-frequency (1)H ENDOR plots. The two H(+/)(-) have large isotropic hyperfine couplings, A(iso)( )() approximately 23 MHz, which shows they are bound to the cofactor. The favored analysis for these plots indicates that the two H(+/)(-) have the same principal values, which indicates that they are chemically equivalent. The tensors are further related to each other by a permutation of the tensor components, which indicates an underlying symmetry of binding relative to the cofactor. At present, no model for the structure of the iron-molybdenum (FeMo)-cofactor in the S = (1)/(2) state trapped during the reduction of H(+) can be shown unequivocally to satisfy all of the constraints generated by the ENDOR analysis. The data disfavors any model that involves protonation of sulfides, and thus suggests that the intermediate instead contains two chemically equivalent bound hydrides; it appears unlikely that these are terminal monohydrides.


Effects of laser irradiation on hematoporphyrin-treated normal and transformed thyroid cells in culture.
Laser irradiation of tissues treated in vivo with the hematoporphyrin derivative (HPD) is known to result in a cytocidal effect, reportedly more pronounced in the tumor than in the surrounding normal tissues. In order to ascertain if this phenomenon had a clear cellular basis, it has been now reproduced in vitro in a model system consisting of normal and transformed cell lines. Epithelial rat thyroid cells were infected and transformed with a RNA oncogenic virus. Both the original (normal) and the viral-transformed (tumorigenic) cells were incubated with HPD and exposed to two types of laser irradiation: 631 nm, continuous wave; and 337.1 nm, pulsed. Under the conditions tested, the percentage survival of the transformed cells was found to be lower (up to approximately 3 times) than that of the normal cells. The cytocidal effect was greater using the pulsed than using the continuous-wave irradiation. The difference between normal and tumor cells was more evident at 30 micrograms than at 50 micrograms of HPD per ml. The HPD not followed by laser irradiation had no effect on the cell growth rate. The findings of a significant difference in the sensitivity to photoactivated HPD between normal and tumor cells under strictly controlled and highly comparable conditions opens new possibilities to the study of the cellular and molecular mechanisms involved in the phototherapy of tumors. Furthermore, studies in vitro on the active components of the photosensitizer and on their selectivity towards the tumor cells, explained at a cellular level, will lead to better approaches to photochemotherapy in vivo.


Efficient Reconstitution of Basidiomycota Diterpene Erinacine Gene Cluster in Ascomycota Host Aspergillus oryzae Based on Genomic DNA Sequences.
To develop the versatile methodology for genome mining of mushroom metabolites, we examined the production of bioactive diterpenes erinacines using genomic DNA sequences. In this report, we initially identified high expression loci (hot spots) in Aspergillus oryzae by sequencing the genomic DNAs from highly yielding transformants which were obtained in our previous biosynthetic studies. Genome editing knock-in of all erinacine biosynthetic genes directly to the hot spot showed that A. oryzae correctly spliced more than 90% of the introns in the mushroom genomic DNA gene sequences. Then, we reconstituted the erinacine biosynthetic gene cluster using two rounds of knock-in of the cDNAs and newly developed repeatable genetic engineering by plasmid recycling. At 100% transformation rate, we obtained a transformant that successfully produced erinacine Q and its intermediates. In this study, we elucidated a biosynthetic pathway of erinacines involving functionally unique hydroxylation supported by dehydrogenase EriH and xylose-specific glycosylation by introducing plant genes for supplying UDP-xylose. Our newly developed hot spot knock-in and plasmid recycling allowed us to avoid a time-consuming screening process and to use unlimited introduction of biosynthetic genes due to marker-free genome editing.


Randomized Trial of a "Dynamic Choice" Patient-Centered Care Intervention for Mobile Persons With HIV in East Africa.
Persons with HIV (PWH) with high mobility face obstacles to HIV care engagement and viral suppression. We sought to understand whether a patient-centered intervention for mobile PWH would improve viral suppression and retention in care, and if so, which subgroups would benefit most. In a randomized trial, we evaluated the effect of an intervention designed to address barriers to care among mobile (≥2 weeks out of community in previous year) PWH with viral nonsuppression or recent missed visits in Kenya and Uganda (NCT04810650). The intervention included dynamic choice of a "travel pack" (emergency antiretroviral therapy [ART] supply, discrete ART packaging, and travel checklist), multimonth and offsite refills, facilitated transfer to out-of-community clinics, and hotline access to a mobility coordinator. The primary outcome was viral suppression (<400 copies/mL) at 48 weeks. Secondary outcomes included retention in care and ART possession. From April 2021 to July 2022, 201 participants were enrolled and randomized (102 intervention, 99 control): 109 (54%) were female participants and 101 (50%) from Kenya; median age was 37 years (interquartile range: 29-43). At 48 weeks, there was no significant difference in viral suppression in intervention (85%) vs. control (86%). The intervention improved retention in care (risk ratio: 1.06[1.02-1.1]; P < 0.001) and ART possession (risk ratio: 1.07[1.03-1.11]; P < 0.001), with larger effect sizes among persons with baseline nonsuppression and high mobility (≥2 weeks out of community in previous 3 months). Mobile PWH-centered care should be considered for high-risk mobile populations, including nonsuppressed and highly mobile PWH, to improve retention in care and sustain viral suppression over time. NCT04810650.


Evaluation of alternative respiratory syndromes for specific syndromic surveillance of influenza and respiratory syncytial virus: a time series analysis.
Syndromic surveillance is increasingly being evaluated for its potential for early warning of increased disease activity in the population. However, interpretation is hampered by the difficulty of attributing a causative pathogen. We described the temporal relationship between laboratory counts of influenza and respiratory syncytial virus (RSV) detection and alternative groupings of Emergency Department (ED) respiratory diagnoses. ED and laboratory data were obtained for the south-eastern area of Sydney, NSW for the period 1 June 2001 - 1 December 2006. Counts of ED visits and laboratory confirmed positive RSV and influenza cases were aggregated by week. Semi-parametric generalized additive models (GAM) were used to determine the association between the incidence of RSV and influenza and the incidence of respiratory syndrome ED presentations while controlling for temporal confounders. For every additional RSV laboratory count, ED diagnoses of bronchiolitis increased by 3.1% (95%CI: 2.7%-3.5%) in the same week. For every additional influenza laboratory count, ED diagnoses of influenza-like illness increased by 4.7% (95%CI: 4.2%-5.2%) one week earlier. In this study, large increases in ED diagnoses of bronchiolitis and influenza-like illness were independent and proxy indicators for RSV and influenza activity, respectively.


Soluble Epoxide Hydrolase Inhibition by t-TUCB Promotes Brown Adipogenesis and Reduces Serum Triglycerides in Diet-Induced Obesity.
Brown adipose tissue (BAT) is an important target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH) converts bioactive epoxy fatty acids (EpFAs) into less active diols. sEH inhibitors (sEHI) are beneficial in many chronic diseases by stabilizing EpFAs. However, roles of sEH and sEHI in brown adipogenesis and BAT activity in treating diet-induced obesity (DIO) have not been reported. sEH expression was studied in in vitro models of brown adipogenesis and the fat tissues of DIO mice. The effects of the sEHI, trans-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy-benzoic acid (t-TUCB), were studied in vitro and in the obese mice via mini osmotic pump delivery. sEH expression was increased in brown adipogenesis and the BAT of the DIO mice. t-TUCB promoted brown adipogenesis in vitro. Although t-TCUB did not change body weight, fat pad weight, or glucose and insulin tolerance in the obese mice, it decreased serum triglycerides and increased protein expression of genes important for lipid metabolism in the BAT. Our results suggest that sEH may play a critical role in brown adipogenesis, and sEHI may be beneficial in improving BAT protein expression involved in lipid metabolism. Further studies using the sEHI combined with EpFA generating diets for obesity treatment and prevention are warranted.


Outwardly rectifying tonically active GABAA receptors in pyramidal cells modulate neuronal offset, not gain.
Hippocampal pyramidal cell excitability is regulated both by fast synaptic inhibition and by tonically active high-affinity extrasynaptic GABA(A) receptors. The impact of tonic inhibition on neuronal gain and offset, and thus on information processing, is unclear. Offset is altered by shunting inhibition, and the gain of a neuronal response to an excitatory input can be modified by changing the level of "background" synaptic noise. Therefore, tonic activation of GABA(A) receptors would be expected to modulate offset and, in addition, to alter gain through a shunting effect on synaptic noise. Here we show that tonically active GABA(A) receptors in CA1 pyramidal cells show marked outward rectification, while the peaks of IPSCs exhibit a linear current-voltage relationship. As a result, tonic GABA(A) receptor-mediated currents have a minimal effect upon subthreshold membrane potential variation due to synaptic noise, but predominantly affect neurons at spiking threshold. Consistent with this, tonic GABA(A) receptor-mediated currents in pyramidal cells exclusively affect offset and not gain. Modulation of tonically active GABA(A) receptors by fluctuations in extracellular GABA concentrations or neuromodulators acting on high-affinity receptors potentially provides a powerful mechanism to alter neuronal offset independently of neuronal gain.


Substrate specificity of atrazine chlorohydrolase and atrazine-catabolizing bacteria.
Bacterial atrazine catabolism is initiated by the enzyme atrazine chlorohydrolase (AtzA) in Pseudomonas sp. strain ADP. Other triazine herbicides are metabolized by bacteria, but the enzymological basis of this is unclear. Here we begin to address this by investigating the catalytic activity of AtzA by using substrate analogs. Purified AtzA from Pseudomonas sp. strain ADP catalyzed the hydrolysis of an atrazine analog that was substituted at the chlorine substituent by fluorine. AtzA did not catalyze the hydrolysis of atrazine analogs containing the pseudohalide azido, methoxy, and cyano groups or thiomethyl and amino groups. Atrazine analogs with a chlorine substituent at carbon 2 and N-alkyl groups, ranging in size from methyl to t-butyl, all underwent dechlorination by AtzA. AtzA catalyzed hydrolytic dechlorination when one nitrogen substituent was alkylated and the other was a free amino group. However, when both amino groups were unalkylated, no reaction occurred. Cell extracts were prepared from five strains capable of atrazine dechlorination and known to contain atzA or closely homologous gene sequences: Pseudomonas sp. strain ADP, Rhizobium strain PATR, Alcaligenes strain SG1, Agrobacterium radiobacter J14a, and Ralstonia picketti D. All showed identical substrate specificity to purified AtzA from Pseudomonas sp. strain ADP. Cell extracts from Clavibacter michiganensis ATZ1, which also contains a gene homologous to atzA, were able to transform atrazine analogs containing pseudohalide and thiomethyl groups, in addition to the substrates used by AtzA from Pseudomonas sp. strain ADP. This suggests that either (i) another enzyme(s) is present which confers the broader substrate range or (ii) the AtzA itself has a broader substrate range.


Promotion of oral insulin absorption in diabetic rabbits using pH-dependent coated capsules containing sodium cholate.
The hypoglycemic effect of oral insulin (40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing various doses of sodium cholate (20, 50, 100 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). Sodium cholate (20 and 50 mg/capsule) produced a dose-related enhancement of an insulin-induced decrease in the blood glucose level. Insulin capsules containing sodium cholate (50 mg/capsule) produced a steady reduction of the blood glucose level reaching 69% of the initial values (P < 0.01) by 3 h and 48% (P < 0.001) by 5 h after administration. This capsule produced an AUC0-5 h of 125 +/- 14.8 mg.h/dl with relative hypoglycemia (R.H.) of 25.8% compared with insulin s.c. The capsules containing sodium cholate (100 mg), however, did not significantly (P > 0.05) improve the hypoglycemic effect of insulin more than the smaller dose (50 mg/capsule) producing an AUC and R.H. of 135 +/- 12.3 mg.h/dl and 27.9%, respectively. The capsule coated with Eudragit S100 and containing insulin mixed with sodium cholate seems to be a promising formulation to overcome the unavailability of oral insulin.


Intrauterine contraception.
Intrauterine devices have been used for over 2000 years. The modern devices (loop, coil and bow) were developed in 1959. The data on 11,222 first insertions from 43 contributing institutions were analyzed by the National Committee on Maternal Health. With the intrauterine loop, expulsions occurred in less than 10% of patients, removals for medical and personal reasons in a further 15%, and pelvic infections in 1.7% during the first year following insertion. Pregnancies occurred during the first year in 2.4% of patients fitted with a loop. Typical of the modern intrauterine devices, the loop is highly effective, readily accepted, and well tolerated by approximately 75% of patients.


Rapid development of tolerance to analgesia during remifentanil infusion in humans.
Studies in experimental animals have demonstrated a rapidly developing acute tolerance to the analgesic effect of opioids administered by continuous i.v. infusion. The aim of the present study was to determine whether acute tolerance plays an important role in the analgesic effect of remifentanil provided by i.v. infusion to humans. The analgesic effect of remifentanil, infused at a constant rate of 0.1 microg x kg(-1) x min(-1) for 4 h, was evaluated by measuring pain tolerance with thermal (2 degrees C water) and mechanical (pressure) noxious stimulations in 13 paid volunteers. The constant-rate infusion of remifentanil resulted in a threefold increase in pain tolerance with both tests. After reaching its maximum in 60-90 min, the analgesic effect of remifentanil began to decline despite the constant-rate infusion, and after 3 h of infusion, it was only one fourth of the peak value. A comparative rate in the development of acute tolerance measured in terms of time to 50% recovery during infusion was 129 +/- 27 min (mean +/- SD) with the cold water test and 138 +/- 39 min with the pressure test. We conclude that the development of tolerance should be included in the calculations for target-controlled infusions. Our study shows that tolerance to analgesia during remifentanil infusion is profound and develops very rapidly. The administration of opioids during anesthesia based on target-controlled infusions should include corrections for the development of tolerance.


CoQ10 in progressive supranuclear palsy: A randomized, placebo-controlled, double-blind trial.
An investigator-initiated, multicenter, randomized, placebo-controlled, double-blind clinical trial to determine whether coenzyme Q10 (CoQ10) is safe, well tolerated, and effective in slowing functional decline in progressive supranuclear palsy (PSP). Sixty-one participants received CoQ10 (2,400 mg/d) or placebo for up to 12 months. Progressive Supranuclear Palsy Rating Scale (PSPRS), Unified Parkinson's Disease Rating Scale, activities of daily living, Mini-Mental State Examination, the 39-item Parkinson's Disease Questionnaire, and 36-item Short Form Health Survey were monitored at baseline and months 3, 6, 9, and 12. The safety profile of CoQ10 was determined by adverse events, vital signs, and clinical laboratory values. Primary outcome measures were changes in PSPRS and Unified Parkinson's Disease Rating Scale scores from baseline to month 12. CoQ10 was well tolerated. No statistically significant differences were noted between CoQ10 and placebo groups in primary or secondary outcome measures. A nonsignificant difference toward slower clinical decline in the CoQ10 group was observed in total PSPRS among those participants who completed the trial. Before the final study visit at 12 months, 41% of participants withdrew because of travel distance, lack of perceived benefit, comorbidities, or caregiver issues. High doses of CoQ10 did not significantly improve PSP symptoms or disease progression. The high withdrawal rate emphasizes the difficulty of conducting clinical trials in patients with PSP. NCT00382824. This study provides Class II evidence that CoQ10 does not significantly slow functional decline in PSP. The study lacks the precision to exclude a moderate benefit of CoQ10.


Thermospray collisionally induced dissociation with single and multiple mass analyzers.
A thermospray discharge ionization source has been used to obtain a collisionally induced dissociation (CID) spectrum of nabilone (MW 372) using a single stage quadrupole mass spectrometer. The resulting CID-mass spectrometry (MS) data show only a few structural features. Since most of the important fragments are above mass 200, it is difficult to assign structural identities to the primary daughter fragments or the nabilone molecule. Further information was obtained by using the thermospray discharge ionization source with a triple stage quadrupole mass spectrometer. Selected primary daughter ions were subjected to a second stage of CID fragmentation. Many of the resulting granddaughter ions are now in the mass range of 50-150 daltons and confident structure assignments can be made. The CID-MS-CID-MS data on nabilone showed the following features: a C9 aliphatic chain with a branch giving a C6 chain; losses of masses 58, 86, and 100 suggesting a ketonic structure that can break with up to 6 aliphatic carbons; losses of masses 60, 61, and 102 suggesting an ether or alcoholic oxygen; presence of one aromatic ring with one or two phenolic oxygens; low mass fragments of masses 55, 69, and 83 indicative of rings or unsaturation. It is audacious to suggest that the information given here is sufficient to write the full structure of nabilone. Nevertheless, the granddaughter fragment information permits a reasonable reconstruction of possible structures that could not be made with the first-order collisional fragmentation.


Preclinical studies identify non-apoptotic low-level caspase-3 as therapeutic target in pemphigus vulgaris.
The majority of pemphigus vulgaris (PV) patients suffer from a live-threatening loss of intercellular adhesion between keratinocytes (acantholysis). The disease is caused by auto-antibodies that bind to desmosomal cadherins desmoglein (Dsg) 3 or Dsg3 and Dsg1 in mucous membranes and skin. A currently unresolved controversy in PV is whether apoptosis is involved in the pathogenic process. The objective of this study was to perform preclinical studies to investigate apoptotic pathway activation in PV pathogenesis with the goal to assess its potential for clinical therapy. For this purpose, we investigated mouse and human skin keratinocyte cultures treated with PV antibodies (the experimental Dsg3 monospecific antibody AK23 or PV patients IgG), PV mouse models (passive transfer of AK23 or PVIgG into adult and neonatal mice) as well as PV patients' biopsies (n=6). A combination of TUNEL assay, analyses of membrane integrity, early apoptotic markers such as cleaved poly-ADP-ribose polymerase (PARP) and the collapse of actin cytoskeleton failed to provide evidence for apoptosis in PV pathogenesis. However, the in vitro and in vivo PV models, allowing to monitor progression of lesion formation, revealed an early, transient and low-level caspase-3 activation. Pharmacological inhibition confirmed the functional implication of caspase-3 in major events in PV such as shedding of Dsg3, keratin retraction, proliferation including c-Myc induction, p38MAPK activation and acantholysis. Together, these data identify low-level caspase-3 activation downstream of disrupted Dsg3 trans- or cis-adhesion as a major event in PV pathogenesis that is non-synonymous with apoptosis and represents, unlike apoptotic components, a promising target for clinical therapy. At a broader level, these results posit that an impairment of adhesive functions in concert with low-level, non-lethal caspase-3 activation can evoke profound cellular changes which may be of relevance for other diseases including cancer.


Depression, selective serotonin reuptake inhibitors, and osteoporosis.
An increasing number of studies suggest an association between depression and osteoporosis. In a mouse model, depression induces bone loss, mediated by brain-to-bone sympathetic signaling. Depression and bone antianabolic sympathetic tone are alleviated by increasing central serotonin (5-hydroxytryptamine, 5-HT) levels. However, selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressants, increase extracellular 5-HT levels but have deleterious skeletal effects. The skeletal serotonergic system consists of 5-HT receptors and the 5-HT transporter (5-HTT) in osteoblasts and osteocytes. 5-HTT is a transmembrane protein targeted by SSRIs. 5-HT restrains osteoblastic activity, thus leading to bone loss. Apparently, the negative skeletal effects of the peripheral SSRI-induced increase in 5-HT outweighs the skeletal benefits resulting from the enhanced central 5-HT antidepressant and antisympathetic activity. Overall, major depression appears as an important risk factor for osteoporosis. However, antidepressants, mainly SSRIs, should be evaluated in view of the causal relationship between depression and bone loss, and vis-à-vis their skeletal adverse effects. Patients with depressive disorders should undergo a routine skeletal evaluation and receive timely antiosteoporotic therapy, especially when SSRI treatment is prescribed.


Characterization of tumor reactivity of human V gamma 9V delta 2 gamma delta T cells in vitro and in SCID mice in vivo.
Human Vgamma9Vdelta2 gammadelta T cells are selectively activated by bacterial phosphoantigens and aminobisphosphonates and exert potent cytotoxicity toward various tumor cells. In this study we have characterized the cytotoxic reactivity of gammadelta T cell lines established from healthy donors by stimulation with aminobisphosphonate alendronate toward melanoma MeWo and pancreatic adenocarcinomas Colo357 and PancTu1 lines in vitro and in vivo upon adoptive transfer into SCID mice. Lysis of all tumor cells was enhanced when gammadelta effector cells were preactivated with phosphoantigens. Recognition of MeWo was TCR dependent, as shown by anti-TCR Ab blockade, whereas only the phosphoantigen-mediated increased, but not the basal, lysis of Colo357 and PancTu1 was inhibited by anti-TCR Ab. Furthermore, lysis of Colo357, but not that of MeWo or PancTu1, was completely inhibited by the pan-caspase inhibitor zVAD, indicating different recognition and effector mechanisms involved in the gammadelta T cell/tumor cell interactions. Upon transfer into SCID mice, alendronate-activated gammadelta T cells given together with IL-2 and alendronate significantly prolonged the survival of SCID mice inoculated with human tumor cells. The best results were thus obtained when gammadelta T cells were repetitively given five times over a period of 30 days. With this protocol, human gammadelta T cells prolonged the mean survival of mice inoculated with MeWo melanoma from 28.5 to 87.3 days (p < 0.0001) and in the case of PancTu1 adenocarcinoma from 23.0 to 48.4 days (p < 0.0001). We conclude that an effective gammadelta T cell-based immunotherapy might require activation of endogenous gammadelta T cells with aminobisphosphonate (or phosphoantigen) and IL-2, followed by adoptive transfer of in vitro expanded gammadelta T cells.


Mössbauer Spectral Properties of Yttrium Iron Garnet, Y3Fe5O12, and Its Isovalent and Nonisovalent Yttrium-Substituted Solid Solutions.
Several high-resolution Mössbauer spectra of yttrium iron garnet, Y3Fe5O12, have been fit as a function of temperature with a new model based on a detailed analysis of the spectral changes that result from a reduction from the cubic Ia3̅d space group to the trigonal R3̅ space group. These spectral fits indicate that the magnetic sextet arising from the 16a site in cubic symmetry is subdivided into three sextets arising from the 6f, the 3d, 3d, and the 1a, 1b, 2c sites in rhombohedral-axis trigonal symmetry. The 24d site in cubic Ia3̅d symmetry is subdivided into four sextets arising from four different 6f sites in R3̅ rhombohedral-axis trigonal symmetry, sites that differ only by the angles between the principal axis of the electric field gradient tensor and the magnetic hyperfine field assumed to be parallel with the magnetic easy axis. This analysis, when applied to the potential nuclear waste storage compounds Y(3-x)Ca(0.5x)Th(0.5x)Fe5O12 and Y(3-x)Ca(0.5x)Ce(0.5x)Fe5O12, indicates virtually no perturbation of the structural, electronic, and magnetic properties upon substitution of small amounts of calcium(II) and thorium(IV) or cerium(IV) onto the yttrium(III) 24c site as compared with Y3Fe5O12. The observed broadening of the four different 6f sites derived from the 24d site results from the substitution of yttrium(III) with calcium(II) and thorium(IV) or cerium(IV) cations on the next-nearest neighbor 24c site. In contrast, the same analysis applied to Y(2.8)Ce(0.2)Fe5O12 indicates a local perturbation of the magnetic exchange pathways as a result of the presence of cerium(IV) in the 24c next-nearest neighbor site of the iron(III) 24d site.


Unusual chromosome 9 variant with an extra G-dark and C-negative segment in the short arm, proximal to the centromere: a case study.
Polymorphic variation of constitutive heterochromatin in human chromosomes is commonly seen in clinical cytogenetic analyses. Normal variant can be confirmed with C-banding and are generally considered clinically insignificant. However, it may be a concern if an unusual variant chromosome is detected in a prenatal specimen. We report an unusual chromosome 9 variant with an extra G-dark and C-negative segment in the short arm, proximal to the centromere. This chromosome 9 variant has been previously reported in only nine independent families. Whether this is a rare variant or an underestimation requires further evaluation. Of note is that all probands so far reported in the literature are clinically normal.


Relations of hepatic steatosis with liver functions, inflammations, glucolipid metabolism in chronic hepatitis B patients.
To investigate the relations between the steatosis and liver functions, inflammations, and glucolipid metabolism in chronic hepatitis B patients. A total of 144 chronic hepatitis B patients who were admitted to our hospital from January 2015 to April 2017 were selected and divided into the steatosis group (n=73) and the non-steatosis group (n=71) according to the detection of hepatic puncture biopsy. The general information of the patients including age, sex, and body mass index (BMI) was collected, and patients' liver functions, inflammations, and glucolipid metabolism indicators were determined and compared between the chronic hepatitis patients with steatosis and without steatosis. The chronic hepatitis patients with steatosis were further divided into the normal group and the abnormal group based on the level of C-reactive protein (CRP) (8 mg/L). Besides, according to the level of aspartate aminotransferase (AST), these patients were divided into the normal liver function group (AST<40 U/L) and the abnormal liver function group (AST>40 U/L), among whom the hepatic steatosis, glucolipid metabolism, and inflammations were compared. At the same time, the chronic hepatitis B patients with steatosis were divided into Group F1, Group F2, and Group F3 based on the fatty degeneration grade, the correlations of steatosis with inflammations, glucolipid metabolism, and liver functions were analyzed. At last, the regression analyses between steatosis and the inflammation grade, glucolipid metabolism and liver function indicators were conducted for Group F1, F2, and F3, respectively. In the chronic hepatitis B patients with steatosis, liver function indicators-alanine aminotransferase (ALT) and AST, levels of inflammatory factors-interleukin-2 (IL-2), IL-6 and CRP and glucolipid metabolism indicators-fasting blood glucose (FBG), 2h postprandial blood glucose (2h PBG), fasting insulin (FINS), triacylglycerol (TG), total cholesterol (TC), and low-density lipoprotein (LDL) were significantly higher than those without steatosis (p<0.05). The steatosis, liver functions, and glucolipid metabolism indicators were statistically different between patients in the normal inflammatory factor group and the abnormal inflammatory factor group (p<0.06). In addition, the liver function indicators (ALT and AST) and glucolipid metabolism indicators (FBG, 2h PBG, FINS, TG, TC, HDL, and LDL) in the abnormal group were statistically higher than those of normal inflammatory factor group (p<0.05). In the normal liver function group, the average fatty degeneration grade was statistically lower than that in the abnormal liver function group (p<0.05), and glucolipid metabolism indicators (FBG, 2h PBG, FINS, TG, TC, IL-2, IL-6, CRP, HDL, and LDL) were also markedly lower than those in the abnormal liver function group (p<0.05). The steatosis was positively correlated with relevant indicators, including the blood glucose indicator of FBG (r=0.509, p<0.05), liver function indicator of AST (r=0.602, p<0.05), the blood lipid indicator of TG (r=0.740, p<0.05), and the inflammatory factor of CRP (r=0.882, p<0.05), respectively. The disease course, BMI, 2h FBG, FINS, TG, TC, HDL, LDL, AST, ALT, and inflammatory factors of IL-2, IL-6, and CRP were involved in risk factors of steatosis (p<0.05). Our data demonstrates that the steatosis is correlated with liver functions, glucolipid metabolism and inflammation level in chronic hepatitis B patients, and the foregoing indicators can affect the disease development of chronic hepatitis B patients with steatosis.


Competitive markets for individual health insurance.
A more dynamic individual insurance market could match benefits with individual preferences, provide more portable and permanent coverage, and stimulate consumer-focused service. Necessary reforms, such as tax parity and targeted assistance to high-risk pools, would enable individual coverage to expand efficiently. In contrast, requirements for guaranteed issue and community rating drive low-risk persons out of voluntary individual markets and raise overall premiums. Guaranteed renewability and switching costs would stabilize individual-market risk pools. As the individual market becomes more representative of the overall population, insurers' perceived needs to underwrite and market selectively will lessen, making administrative loading factors less significant.


CRAFTing Delivery of Membrane Proteins into Protocells using Nanodiscs.
For the successful generative engineering of functional artificial cells, a convenient and controllable means of delivering membrane proteins into membrane lipid bilayers is necessary. Here we report a delivery system that achieves this by employing membrane protein-carrying nanodiscs and the calcium-dependent fusion of phosphatidylserine lipid membranes. We show that lipid nanodiscs can fuse a transported lipid bilayer with the lipid bilayers of small unilamellar vesicles (SUVs) or giant unilamellar vesicles (GUVs) while avoiding recipient vesicles aggregation. This is triggered by a simple, transient increase in calcium concentration, which results in efficient and rapid fusion in a one-pot reaction. Furthermore, nanodiscs can be loaded with membrane proteins that can be delivered into target SUV or GUV membranes in a detergent-independent fashion while retaining their functionality. Nanodiscs have a proven ability to carry a wide range of membrane proteins, control their oligomeric state, and are highly adaptable. Given this, our approach may be the basis for the development of useful tools that will allow bespoke delivery of membrane proteins to protocells, equipping them with the cell-like ability to exchange material across outer/subcellular membranes.


Prevention of hepatocellular carcinoma in the Asia-Pacific region: consensus statements.
Among approximately 650,000 people who die from hepatocellular carcinoma (HCC) each year, at least two-thirds live in Asia. Efforts to improve early diagnosis and treatment have not yet impacted mortality. An Asia-Pacific Working Party convened in Hong Kong in June 2008 to consider ways to prevent HCC in this region. Separate reviews have summarized epidemiology of HCC, preventive approaches related to hepatitis B virus (HBV), hepatitis C virus (HCV) and non-viral liver diseases, and the role of surveillance to detect HCC at a curative stage. We now present Consensus Statements from these deliberations and reviews. As chronic hepatitis B is the most common cause of HCC in Asia, effective hepatitis B vaccination programs are the most important strategy to reduce HCC incidence. Prevention of HCV by screening blood donors, universal precautions against blood contamination in health-care settings and reducing HCV transmission from injection drug use are also vital. There is strong evidence that effective antiviral therapy to control HBV infection or eradicate HCV substantially reduces (but does not abolish) HCC risk. With hemochromatosis, family screening, early diagnosis and correcting iron overload to prevent liver fibrosis prevents HCC. There is currently insufficient evidence to give firm recommendations on alcohol, obesity/metabolic risk factors and other liver diseases. HCC surveillance for high-risk groups is recommended in individual cases but cost-effectiveness is not as high as infant hepatitis B vaccination and screening blood for HCV. Widespread application of HCC surveillance in Asia-Pacific countries depends on economic factors and health-care priorities.


Biotin production and utilization in a sewage treatment lagoon.
Biotin, in a sewage oxidation lagoon also receiving potato processing wastes, was observed to increase two logs during the summer period of waste stabilization and then to decline to near earlier concentrations. Three organisms, Aerobacter aerogenes, Chlorella vulgaris, and Thiocapsa floridana, were at least partially responsible for these fluctuations; the latter two organisms were associated with biotin utilization and the former with biotin production. Since copious quantities of biotin are produced in these waste treatment facilities, the vitamin may act as a useful indicator of microbial action on certain organic molecules, especially in domestic and industrial wastes such as those from municipalities and potato and sugar beet processing plants. Furthermore, the presence of biotin in rivers and streams may be indicative of the discharge of incompletely stabilized wastes from these sources.


Ultrafast treatment plan optimization for volumetric modulated arc therapy (VMAT).
To develop a novel aperture-based algorithm for volumetric modulated are therapy (VMAT) treatment plan optimization with high quality and high efficiency. The VMAT optimization problem is formulated as a large-scale convex programming problem solved by a column generation approach. The authors consider a cost function consisting two terms, the first enforcing a desired dose distribution and the second guaranteeing a smooth dose rate variation between successive gantry angles. A gantry rotation is discretized into 180 beam angles and for each beam angle, only one MLC aperture is allowed. The apertures are generated one by one in a sequential way. At each iteration of the column generation method, a deliverable MLC aperture is generated for one of the unoccupied beam angles by solving a subproblem with the consideration of MLC mechanic constraints. A subsequent master problem is then solved to determine the dose rate at all currently generated apertures by minimizing the cost function. When all 180 beam angles are occupied, the optimization completes, yielding a set of deliverable apertures and associated dose rates that produce a high quality plan. The algorithm was preliminarily tested on five prostate and five head-and-neck clinical cases, each with one full gantry rotation without any couch/collimator rotations. High quality VMAT plans have been generated for all ten cases with extremely high efficiency. It takes only 5-8 min on CPU (MATLAB code on an Intel Xeon 2.27 GHz CPU) and 18-31 s on GPU (CUDA code on an NVIDIA Tesla C1060 GPU card) to generate such plans. The authors have developed an aperture-based VMAT optimization algorithm which can generate clinically deliverable high quality treatment plans at very high efficiency.


An institutional analysis and systematic review with meta-analysis of pneumatic versus hydrostatic reduction for pediatric intussusception.
Intussusception remains a frequent cause of bowel obstruction in children and typically is treated by reduction via enema. Controversy persists regarding the optimal reduction technique to maximize success while minimizing morbidity. We reviewed our institutional data comparing outcomes of enema reduction that use contrast medium versus air. A systematic review also was undertaken of comparative studies evaluating pneumatic (oxygen or air) versus hydrostatic (any contrast medium) reduction. Critical appraisal was performed with the Methodological Index for Non Randomized Studies scale for observational studies, Jadad score for randomized trials. Meta-analysis was performed with REVMAN 5.1. Institutional data revealed a failed reduction rate of 20.4% (20/98) with air and 29.6% (8/27) with contrast reduction. Nineteen studies were included in the systematic review. The cumulative failure rate favored pneumatic reduction (odds ratio [OR] 0.45; 95% confidence interval [95% CI] 0.34-0.60); sensitivity analysis of prospective studies demonstrated similar results (OR 0.39; 95% CI 0.24-0.63). The number needed to treat to eliminate one failed reduction was nine pneumatic reductions. No difference was noted in reported perforations (OR 0.98; 95% CI 0.48-2.03). Pneumatic reduction is more likely to successfully reduce intussusception in children without evidence of increased morbidity. In the context of available expertise, pneumatic reduction should be the method of choice for the treatment of intussusception barring an indication for immediate operative intervention.


The role of neuropeptide Y in vascular sympathetic neurotransmission may be enhanced in hypertension.
The effect of neuropeptide Y on the contractile response to field stimulation was examined in isolated blood vessels. Exogenous neuropeptide Y at a concentration of 100 nmol/l significantly potentiated the response to field stimulation in rabbit ear artery and canine saphenous vein. Administration of neuropeptide Y antiserum to tissues not previously exposed to neuropeptide Y significantly reduced the response to field stimulation; greater effects were observed in the rabbit ear artery than in the canine saphenous vein. Furthermore, this antiserum depressed the response to field stimulation in caudal arteries from spontaneously hypertensive rats (SHR), but not in those from normotensive Wistar-Kyoto rats (WKY). The depression by the anti-neuropeptide Y antibody did not appear to be produced by a non-specific mechanism, since antiserum against either thyrotrophin-releasing factor or platelet-derived growth factor did not affect the response to field stimulation. It is concluded that endogenous neuropeptide Y can contribute to the vascular contractile response to field stimulation, and that this contribution may be enhanced in hypertensive animals.


Growth-stage-related shifts in diatom endometabolome composition set the stage for bacterial heterotrophy.
Phytoplankton-derived metabolites fuel a large fraction of heterotrophic bacterial production in the global ocean, yet methodological challenges have limited our understanding of the organic molecules transferred between these microbial groups. In an experimental bloom study consisting of three heterotrophic marine bacteria growing together with the diatom Thalassiosira pseudonana, we concurrently measured diatom endometabolites (i.e., potential exometabolite supply) by nuclear magnetic resonance (NMR) spectroscopy and bacterial gene expression (i.e., potential exometabolite uptake) by metatranscriptomic sequencing. Twenty-two diatom endometabolites were annotated, with nine increasing in internal concentration in the late stage of the bloom, eight decreasing, and five showing no variation through the bloom progression. Some metabolite changes could be linked to shifts in diatom gene expression, as well as to shifts in bacterial community composition and their expression of substrate uptake and catabolism genes. Yet an overall low match indicated that endometabolome concentration was not a good predictor of exometabolite availability, and that complex physiological and ecological interactions underlie metabolite exchange. Six diatom endometabolites accumulated to higher concentrations in the bacterial co-cultures compared to axenic cultures, suggesting a bacterial influence on rates of synthesis or release of glutamate, arginine, leucine, 2,3-dihydroxypropane-1-sulfonate, glucose, and glycerol-3-phosphate. Better understanding of phytoplankton metabolite production, release, and transfer to assembled bacterial communities is key to untangling this nearly invisible yet pivotal step in ocean carbon cycling.


Non-Roman Catholic Physicians Should Be Permitted to Write Prescriptions for Birth Control in Roman Catholic Institutions.
The legal and ethical asymmetry between honoring positive claims of conscience versus negative claims of conscience was recently analyzed by several articles in this journal. The first author of this article (ALB) identified unique but defeasible reasons against honoring positive claims of conscience, such as the greater threat they post to institutional values and institutional resources than negative claims of conscience. However, ALB wrote, when these reasons can be overcome, positive claims of conscience should enjoy the same ethical and legal respect as negative claims of conscience. This article argues that the prescription of birth control by non-Roman Catholic physicians in Roman Catholic institutions is an example of a positive claim of conscience that can overcome concerns of institutional values and resources, and therefore ought to receive the same ethical respect and legal protection as negative claims of conscience. In making this argument, this article also responds to several of the thoughtful comments raised by Alberto Giubilini and Dominic Wilkinson.


Male Paget's disease of the breast.
Paget's disease is an extremely rare condition of the male breast that presents as an eczematous change of the nipple and areola. It is almost always associated with an underlying intraductal carcinoma. A case of Paget's disease of the male breast with extension into adnexal structures is reported. A MEDLINE search for cases of Paget's disease of the male breast was performed and the cases were reviewed. The following antibodies were used in immunohistochemical staining: Rabbit Anti-Human c-erbB-2 Oncoprotein, monoclonal Mouse Anti-Human Estrogen Receptor (IgG1, kappa), and monoclonal Mouse Anti-Human Progesterone Receptor (Clone PgR 636). This is only the 43rd histologically proven case of Paget's disease of the male breast in the world literature and, to our knowledge, the first to document extension of Paget's cells into adnexal structures, including eccrine glands. Mammary Paget's disease is a rare phenomenon among men.