Ocular hypotension in the rabbit. Receptor mechanisms of pirbuterol and nylidrin.
Pirbuterol and nylidrin, both purported sympathomimetic amines, reduced intraocular pressure (IOP) when given topically (50 microliter, 0.1%) to albino rabbits. Pirbuterol increased the cyclic-AMP concentration in aqueous humor by a factor of 3.25, while nylidrin had no effect on aqueous cyclic-AMP nor on adenylate cyclase activity of iris-ciliary body membranes assayed in vitro. Studies of the receptor affinity of pirbuterol, timolol and nylidrin were carried out on iris-ciliary body membranes by competition binding with radioactive ligands. Four ligands were used that appear to label separate subpopulations of adrenergic receptors; dihydroalprenolol (beta-receptors), WB-4101 (alpha 1-receptors) prazosin (alpha 1-receptor subpopulation) and yohimbine (alpha 2-receptors). Pirbuterol and timolol showed exclusive selectivity for beta-receptors with high affinities (Kd 12.6 and 0.48 nM, respectively) compared with other adrenergic receptor populations in iris-ciliary body. Nylidrin had high affinities for beta-receptors (Kd 22 nM) and for the subpopulation of alpha 1-receptors labelled by prazosin (Kd 6.5 nM), but showed 100-fold lower affinity and complex binding characteristics to the two other classes of alpha-adrenergic receptor sites labelled by WB-4101 and yohimbine, respectively. The results show that pirbuterol and timolol are highly beta-receptor selective and that hypotensive responses to these drugs are not mediated by the other classes of alpha-adrenergic receptor determined in this study. However, the hypotensive response to nylidrin may be related to its prazosin-like (alpha 1-receptor) antagonist properties with additional activity at beta-receptors.


Propofol injection pain: is it still an issue? The effect of premedication.
The use of propofol often results in pain upon injection. Various strategies can be used to reduce this pain, ranging from the administration of analgesics to modification of the propofol emulsion. However, basic premedication protocol aimed at peri- and postoperative pain reduction could also sufficiently reduce propofol injection pain, rendering other special interventions redundant. With the approval of the Local Ethics Committee of the Erasmus Medical Centre Rotterdam, and after obtaining written informed consent from each patient included, 209 surgical patients (ASA physical status I-III) were randomized in a double-blind manner to receive premedication consisting of 7.5 mg midazolam, 50 mg diclofenac and 1000 mg acetaminophen (all orally administered) and fentanyl (intravenously administered) or placebo medication the hour before surgery. In both groups a mixture of 40 mL propofol 1% with 2 mL lidocaine 1% was used to induce anesthesia. Pain scores were assessed using a verbal analog scale (VAS) ranging from 0-10. The premedication group was found to have significantly less pain upon injection of propofol (median VAS 0+/-0-2) (median+/-interquartile range) when compared to the control group (median VAS 1.5+/-0-4; P=0.001). In addition, more patients in the premedication group experienced no pain at all. This effect was still present one hour after extubation. Even when injection pain is reduced, the use of a premedication regimen clearly has additional value with respect to the patients' experience. Considering the low VAS scores observed overall, it might be worthwhile to reserve additional injection pain-reducing interventions for individual patients rather than adding them as a component of standard practice.


Effect of digoxin on global respiratory muscle strength after cholecystectomy: a double blind study.
Upper abdominal surgery has been shown to impair the function of the respiratory muscles. In addition, controversial results have been reported concerning the effect of digoxin on the diaphragm. The aim of this study was to investigate further the mechanism(s) of respiratory muscle dysfunction after cholecystectomy and the effect of digoxin on the impaired respiratory muscle function. Twenty three patients (four men) were studied before and 48 hours after surgery. Eleven received digoxin and 12 placebo. Respiratory muscle strength was assessed 48 hours after surgery by measuring mouth pressure during maximum static inspiratory (PImax) and expiratory (PEmax) efforts before and after 90 minutes of intravenous administration of 0.25 mg digoxin in a double blind, placebo controlled fashion. In addition, spirometric and pain measurements were performed. Postoperatively (+48 h) PImax and PEmax decreased significantly (p<0.01) from their preoperative values in both groups by a similar degree. After administration of digoxin or placebo only the digoxin group showed a significant increase in both PImax (p<0.02) and PEmax (p<0.05) with a mean increase of 15% for PImax and 12.3% for PEmax. The mean difference in PImax (DeltaPImax) and PEmax (DeltaPEmax) between the digoxin and placebo groups was 1.01 (95% CI 0.28 to 2.2) and 1.05 (95% CI 0.04 to 2.4), respectively. Estimates of postoperative pain did not differ between the two groups. Spirometric indices showed a similar restrictive defect postoperatively in both groups but did not change after digoxin or placebo. Digoxin improves the impaired global strength of the inspiratory and expiratory muscles after cholecystectomy and this may be clinically relevant. Muscle contractility could play a part in this impairment.


Antiviral ARGONAUTEs Against Turnip Crinkle Virus Revealed by Image-Based Trait Analysis.
RNA-based silencing functions as an important antiviral immunity mechanism in plants. Plant viruses evolved to encode viral suppressors of RNA silencing (VSRs) that interfere with the function of key components in the silencing pathway. As effectors in the RNA silencing pathway, ARGONAUTE (AGO) proteins are targeted by some VSRs, such as that encoded by Turnip crinkle virus (TCV). A VSR-deficient TCV mutant was used to identify AGO proteins with antiviral activities during infection. A quantitative phenotyping protocol using an image-based color trait analysis pipeline on the PlantCV platform, with temporal red, green, and blue imaging and a computational segmentation algorithm, was used to measure plant disease after TCV inoculation. This process captured and analyzed growth and leaf color of Arabidopsis (Arabidopsis thaliana) plants in response to virus infection over time. By combining this quantitative phenotypic data with molecular assays to detect local and systemic virus accumulation, AGO2, AGO3, and AGO7 were shown to play antiviral roles during TCV infection. In leaves, AGO2 and AGO7 functioned as prominent nonadditive, anti-TCV effectors, whereas AGO3 played a minor role. Other AGOs were required to protect inflorescence tissues against TCV. Overall, these results indicate that distinct AGO proteins have specialized, modular roles in antiviral defense across different tissues, and demonstrate the effectiveness of image-based phenotyping to quantify disease progression.


The genome of hibiscus hamabo reveals its adaptation to saline and waterlogged habitat.
Hibiscus hamabo is a semi-mangrove species with strong tolerance to salt and waterlogging stress. However, the molecular basis and mechanisms that underlie this strong adaptability to harsh environments remain poorly understood. Here, we assembled a high-quality, chromosome-level genome of this semi-mangrove plant and analyzed its transcriptome under different stress treatments to reveal regulatory responses and mechanisms. Our analyses suggested that H. hamabo has undergone two recent successive polyploidy events, a whole-genome duplication followed by a whole-genome triplication, resulting in an unusually large gene number (107 309 genes). Comparison of the H. hamabo genome with that of its close relative Hibiscus cannabinus, which has not experienced a recent WGT, indicated that genes associated with high stress resistance have been preferentially preserved in the H. hamabo genome, suggesting an underlying association between polyploidy and stronger stress resistance. Transcriptomic data indicated that genes in the roots and leaves responded differently to stress. In roots, genes that regulate ion channels involved in biosynthetic and metabolic processes responded quickly to adjust the ion concentration and provide metabolic products to protect root cells, whereas no such rapid response was observed from genes in leaves. Using co-expression networks, potential stress resistance genes were identified for use in future functional investigations. The genome sequence, along with several transcriptome datasets, provide insights into genome evolution and the mechanism of salt and waterlogging tolerance in H. hamabo, suggesting the importance of polyploidization for environmental adaptation.


Identification of T cell epitopes on the 33-kDa fragment of Plasmodium yoelii merozoite surface protein 1 and their antibody-independent protective role in immunity to blood stage malaria.
Merozoite surface protein 1 (MSP1) of malaria parasites undergoes proteolytic processing at least twice before invasion into a new RBC. The 42-kDa fragment, a product of primary processing, is cleaved by proteolytic enzymes giving rise to MSP1(33), which is shed from the merozoite surface, and MSP1(19), which is the only fragment carried into a new RBC. In this study, we have identified T cell epitopes on MSP1(33) of Plasmodium yoelii and have examined their function in immunity to blood stage malaria. Peptides 20 aa in length, spanning the length of MSP1(33) and overlapping each other by 10 aa, were analyzed for their ability to induce T cell proliferation in immunized BALB/c and C57BL/6 mice. Multiple epitopes were recognized by these two strains of mice. Effector functions of the dominant epitopes were then investigated. Peptides Cm15 and Cm21 were of particular interest as they were able to induce effector T cells capable of delaying growth of lethal P. yoelii YM following adoptive transfer into immunodeficient mice without inducing detectable Ab responses. Homologs of these epitopes could be candidates for inclusion in a subunit vaccine.


Insulin and β-adrenergic receptors mediate lipolytic and anti-lipolytic signalling that is not altered by type 2 diabetes in human adipocytes.
Control of fatty acid storage and release in adipose tissue is fundamental in energy homeostasis and the development of obesity and type 2 diabetes. We here take the whole signalling network into account to identify how insulin and β-adrenergic stimulation in concert controls lipolysis in mature subcutaneous adipocytes obtained from non-diabetic and, in parallel, type 2 diabetic women. We report that, and show how, the anti-lipolytic effect of insulin can be fully explained by protein kinase B (PKB/Akt)-dependent activation of the phosphodiesterase PDE3B. Through the same PKB-dependent pathway β-adrenergic receptor signalling, via cAMP and PI3Kα, is anti-lipolytic and inhibits its own stimulation of lipolysis by 50%. Through this pathway both insulin and β-adrenergic signalling control phosphorylation of FOXO1. The dose-response of lipolysis is bell-shaped, such that insulin is anti-lipolytic at low concentrations, but at higher concentrations of insulin lipolysis was increasingly restored due to inhibition of PDE3B. The control of lipolysis was not altered in adipocytes from diabetic individuals. However, the release of fatty acids was increased by 50% in diabetes due to reduced reesterification of lipolytically liberated fatty acids. In conclusion, our results reveal mechanisms of control by insulin and β-adrenergic stimulation - in human adipocytes - that define a network of checks and balances ensuring robust control to secure uninterrupted supply of fatty acids without reaching concentrations that put cellular integrity at risk. Moreover, our results define how selective insulin resistance leave lipolytic control by insulin unaltered in diabetes, while the fatty acid release is substantially increased.


Ultrahigh-temperature activation of a low-temperature Bacillus subtilis spore germination system.
Exposure of Bacillus subtilis A spores to 115 to 125 C for several seconds activated a low-temperature germination system that remained dormant after a heat treatment that activated the normal l-alanine- and glucose-stimulated germination systems. The low-temperature germination system was characterized by an optimum temperature lower than that of the l-alanine or glucose germination systems (30 C versus 45 C), germination in the absence of exogenous germination stimulants, and the capacity for heat-induced deactivation and subsequent reactivation. The rates of activation at 115 to 125 C were exponential and were not influenced by a previous heat treatment that activated the l-alanine- or glucose-stimulated germination systems. Although activation of the low-temperature germination system was accompanied by suppression of l-alanine-stimulated germination, it did not appear to be a modification of the l-alanine germination system.


Incidence trends in high-grade primary brain tumors in males and females.
The focus of the present review is to investigate whether there is a variation in the incidence rates between male and female patients with high-grade primary brain tumors and if there are altered incidence rates associated with the time at which they were diagnosed. Previous studies identified in internationally peer-reviewed journals were identified using a systematic search of the PubMed database. Due to the difficulties in data interpretation, studies that exclusively included patient data classified prior to the 2nd edition of the World Health Organization histological classification system of brain tumors were excluded. The overall incidence rates and incidence trends of male and female patients were analyzed separately. The mean age-adjusted overall incidence rate in the male population was 1.27 per 100,000 compared with 0.89 per 100,000 in the female population. The variance between the two genders differed and a Wilcoxon rank-sum test indicated that there was no significant difference in the incidence rate of high-grade primary brain tumors between males and females (P=0.3658). Furthermore, there was no significant difference in incidence rate trend between 1996-2004 and 2005-2010 for male or female populations (P=0.101 and P=0.472, respectively). The results from the present systematic review did not demonstrate a significant difference in incidence rate between the two genders. Therefore, the results from the current study are considered to be preliminary and further studies are required to elucidate this issue.


Does China's residential mobility reduce fertility intentions? The mediating role of well-being.
With declining fertility rates becoming a global trend, it is crucial to enhance the fertility intentions of mobile individuals of reproductive age. This study utilizes both questionnaire surveys and experimental methods to examine the influence of residential mobility on fertility intentions and the mediating role of well-being. The consistent findings from Study 1 and Study 2 (2a and 2b) indicate that residential mobility significantly negatively predicts individuals' fertility intentions, and well-being plays a significant mediating role between residential mobility and fertility intentions. This research, conducted from a psychological perspective, sheds light on the internal mechanisms linking residential mobility and fertility intentions, providing theoretical and empirical evidence to enhance fertility intentions among mobile populations in China.


The folding of hirudin adopts a mechanism of trial and error.
Reduced and denatured hirudin (65 amino acids and 3 disulfides) refolds in vitro to become an active molecule. The folding process adopts a mechanism of "trial and error" without predominant pathways. Throughout the entire folding process, the 6 cysteines were about equally involved in the disulfide shuffling. Among the first 20% of 3-disulfide species accumulated during the early phase of refolding, two-thirds were inactive and were reshuffled in the presence of thiol catalyst to regain correct disulfide pairing. When refolding was performed in the presence of strong denaturant (guanidinium chloride) without thiol catalyst, 8% of the active hirudin was obtained. This figure is close to the probability (6.7%) that would be expected from the random disulfide pairing of a molecule containing 6 sulfhydryl groups.


Influence of low density lipoprotein from insulin-dependent diabetic patients on platelet functions.
In the present work we studied in vitro the action of low density lipoproteins (LDL) isolated from normolipemic insulin-dependent diabetic (IDDM) patients on transmembrane cation transport, nitric oxide synthase (NOS) activity, and aggregating response to stimuli of platelets from healthy subjects to elucidate whether the modified interaction between circulating lipoproteins and cells might be one of the pathogenetic mechanisms of the increased platelet activation in IDDM. LDL were obtained by discontinuous gradient ultracentrifugation from 15 IDDM out-patients and 15 sex- and age-matched healthy subjects and used for incubation experiments with control platelets. Lipid composition and hydroperoxide concentrations were studied in LDL. Platelet aggregation responses to ADP, NOS activity, cytosolic Ca2+ concentrations, and platelet membrane Na+/K+-adenosine triphosphatase (Na+/K+-ATPase) and Ca2+-ATPase activities were measured after incubation. IDDM LDL showed an increased lysophosphatidylcholine content compared with that of control LDL. IDDM LDL significantly increased the platelet aggregating response to ADP, cytosolic Ca2+ concentrations, and plasma membrane Ca2+-ATPase activity and significantly reduced NOS activity and platelet membrane Na+/K+-ATPase activity compared with those of platelets incubated in buffer or cells incubated with control LDL. The effects exerted by IDDM LDL on platelet suspensions from healthy subjects mimic the alterations observed in platelets from diabetic subjects in basal conditions. Both the decreased activity of NOS and the higher cytoplasmic concentrations of Ca2+ might cause increased platelet activation, as observed in IDDM. In conclusion, the present study suggests a new mechanism with a potential role in the early development of atherosclerosis in diabetic patients, i.e. an altered interaction between circulating lipoproteins and platelets.


Two-dimensional straightness measurement based on optical knife-edge sensing.
Straightness error is a parasitic translation along a perpendicular direction to the primary displacement axis of a linear stage. The parasitic translations could be coupled into other primary displacement directions of a multi-axis platform. Hence, its measurement and compensation are critical in precision multi-axis metrology, calibration, and manufacturing. This paper presents a two-dimensional (2D) straightness measurement configuration based on 2D optical knife-edge sensing, which is simple, light-weight, compact, and easy to align. It applies a 2D optical knife-edge to manipulate the diffraction pattern sensed by a quadrant photodetector, whose output voltages could derive 2D straightness errors after a calibration process. This paper analyzes the physical model of the configuration and performs simulations and experiments to study the system sensitivity, measurement nonlinearity, and error sources. The results demonstrate that the proposed configuration has higher sensitivity and insensitive to beam's vibration, compared with the conventional configurations without using the knife-edge, and could achieve ±0.25 μm within a ±40 μm measurement range along a 40 mm primary axial motion.


Cell tracking: a modeling and minimization approach.
This paper presents a model of motion suitable for cell tracking. It includes a representation for cell dynamics enabling it to maintain a correspondence between successive images of cells undergoing morphological changes. This model is based on a minimization problem whose computational solution is similar in form to a Newton-Rhapson iteration. The model is supported by experimental results from an actual tracking problem.


Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment.
Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initiative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed.


Pronounced Cosolvent Effects in Polymer:Polymer Bulk Heterojunction Solar Cells with Sulfur-Rich Electron-Donating and Imide-Containing Electron-Accepting Polymers.
The performance of solar cells with a polymer:polymer bulk heterojunction (BHJ) structure, consisting of poly[4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b']dithiophene-alt-3-fluorothieno[3,4-b]thiophene-2-carboxylate] (PTB7-Th) donor and poly[[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)] (P(NDI2OD-T2)) acceptor polymers, was investigated as a function of cosolvent (p-xylene:chlorobenzene (pXL:CB)) composition ratio. A remarkable efficiency improvement (∼38%) was achieved by spin-coating the photoactive blend layer from pXL:CB = 80:20 (volume) rather than pXL alone, but the efficiency then decreased when the CB content increased further to pXL:CB = 60:40. The improved efficiency was correlated with a particular PTB7-Th:P(NDI2OD-T2) donor-acceptor blend nanostructure, evidenced by a fiber-like surface morphology, a red-shifted optical absorption, and enhanced PL quenching. Further device optimization for pXL:CB = 80:20 films yielded a power conversion efficiency of ∼5.4%. However, these devices showed very poor stability (∼15 min for a 50% reduction in initial efficiency), owing specifically to degradation of the PTB7-Th donor-component. Replacing PTB7-Th with a more stable donor polymer will be essential for any application potential to be realized.


Finite signals in planar waveguides.
We examine the evolution in phase space of an N-point signal, produced and sensed at finite arrays transverse to a planar waveguide within the framework of the finite quantization of geometric optics. We use the Kravchuk coherent states provided by the finite oscillator model to evince the nonlinear transformations that elliptic-profile waveguides produce on phase space by means of the SO(3) Wigner function.


Effect of varied recovery interventions on markers of psychophysiological stress in professional rugby union.
Rugby union is a physical demanding sport that requires optimum recovery between games to maintain performance levels. Analysis of four unique biochemical markers of stress is measured here to determine which recovery strategy currently in use by a professional team provides the necessary requirements for sustained performance. Urine and saliva samples were collected from 37 professional rugby players before, immediately after and 36 hours after five home games, and analysed by enzyme linked immunosorbent assay and high performance liquid chromatography for urinary myoglobin, total neopterin (NP; NP + 7,8-dihydroneopterin), salivary cortisol and immunoglobulin A. Subjects completed a cold water immersion (CWI) or pool session (PS), donned compression garments, consumed protein and carbohydrate food and fluid, and slept for 8 hours post-game. The following day subjects choose from one or a combination of CWI, PS or active recovery/stretching to complete. There was no difference between the recovery protocols for cortisol, total NP, immunoglobulin A concentration or myoglobin at 36 hours post-game. Immunoglobulin A secretion rate significantly increased above pre-game levels at 36 hours post-game for all protocols; however, protocol three did not increase as much (p = 0.038). Total NP was also significantly increased above pre-game levels at 36 hours post-game for all protocols. This study provides evidence that the immediate post-game recovery intervention following a game of professional rugby union may be the most important aspect of psychophysiological player recovery, irrespective of the "next-day" intervention. The concentrations of total NP and immunoglobulin A suggest these professional rugby players are still in a state of recovery 36 hours post-game.


Phenacetin nephropathy, with particular reference to the effect of surgery.
Sixteen patients suffering from phenacetin nephropathy were seen at one London hospital between June 1964 and January 1970. There were five deaths, three of them following a surgical operation. Phenacetin nephropathy occurs far more frequently than is generally considered. Unless patients are asked about the consumption of phenacetin routinely the diagnosis is usually missed. It is recommended that phenacetin and paracetamol should be available only on a doctor's prescription.


Preference of young adults for COVID-19 vaccination in the United Kingdom: a discrete choice experiment.
To determine preferences for COVID-19 vaccinations in the young adult population in the United Kingdom (UK). A discrete choice experiment survey was conducted in UK young adults. Participants were asked to choose between two hypothetical vaccines the one they preferred the most. Vaccines were defined by five attributes (effectiveness, risk of side effects, duration of protection, number of doses, confidence in available evidence), identified following a systematic literature review and qualitative interviews with 13 young adults. A random parameters logit model, a latent class model, and subgroup analyses were used to identify preferences. One hundred and forty-nine respondents were included (70% women, mean age 23 years). All five attributes significantly influenced respondents' vaccination decisions. Respondents valued higher effectiveness, lower risk of side effects, longer protection duration, and a smaller number of doses. Based on the range of levels of each attribute, vaccine effectiveness was the most important attribute (relative importance 34%), followed by risk of side effects (32%), and duration of vaccine protection (22%). The five investigated vaccine attributes appear to play an important role in young adults' decision-making process. Results of this study may help health authorities designing appropriate strategies in future vaccines campaigns in the younger UK population.


Reprint of: Early and late outcomes of acute type A aortic dissection with intramural hematoma.
Controversy remains regarding management of acute type A dissection with intramural hematoma (IMH). Our purpose was to analyze our experience and report outcomes after repair of acute type A aortic dissection with IMH. We analyzed all patients from a single center who underwent open repair for acute type A aortic dissection with IMH. Between 2000 and 2013, we performed 418 repairs for acute type A aortic dissection. These were divided into 2 groups of patients: 64 patients (15%) with type A IMH and 354 patients (85%) with typical dissection. Those with IMH were older (62.4 ± 13.9 years vs 56.7 ± 14.7 years; P < .0046) and presented with reduced renal function (ie, glomerular filtration rate) (P < .0341), less frequently with distal malperfusion, and less frequently with rupture (P < .0116). With IMH, the time from presentation to repair was, by strategy, longer (median, 67 vs 6 hours; P < .0001), but no mortality occurred within 3 days of presentation. Mortality with IMH did not differ from typical dissection: 7 out of 64 patients (10.9%) versus 52 out of 354 patients (14.7%; P = .4276). A lower incidence of postoperative dialysis in the IMH group approached significance: 6 out of 63 patients (9.5%) versus 64 out of 347 patients (18.4%; P = .0820). When adjusted for age and renal function, late survival was improved with IMH (P < .0343). Repair of acute type A aortic dissection with IMH is associated with significant early morbidity and mortality, differing minimally from typical aortic dissection. Although expectant repair within 3 days may be applied, the purposeful delay imparted little advantage. Improved late outcomes may be seen with IMH, but continued long-term surveillance is required for verification.


Plant-produced hepatitis B core protein chimera carrying anthrax protective antigen domain-4.
The hepatitis B core antigen (HBcAg) can generate a strong immune response and is recognized as an effective carrier for foreign epitopes. The domain-4 epitope of the anthrax protective antigen (PA-D4) plays an essential role in generating protective immunity against virulent Bacillus anthracis. Here we report the successful production of a recombinant protein comprised of the antigenic PA-D4 integrated into the c/e1 loop of HBcAg in transgenic low-alkaloid Nicotiana tabacum. Sera of mice injected with the plant-derived purified HB/PA-D4 protein exhibited significant anti-PA- and anti-HBcAg-specific IgG titers; however, formation of virus-like particles (VLP) was not observed. These data support the feasibility of producing complex protein chimeras in plants.


The effect of erbium-doped: yttrium, aluminium and garnet laser irradiation on the surface microstructure and roughness of double acid-etched implants.
One of the most frequent complications related to dental implants is peri-implantitis, and the characteristics of implant surfaces are closely related to the progression and resolution of inflammation. Therefore, a technical modality that can effectively detoxify the implant surface without modification to the surface is needed. The purpose of this study was to evaluate the effect of erbium-doped: yttrium, aluminium and garnet (Er:YAG) laser irradiation on the microstructural changes in double acid-etched implant surfaces according to the laser energy and the application duration. The implant surface was irradiated using an Er:YAG laser with different application energy levels (100 mJ/pulse, 140 mJ/pulse, and 180 mJ/pulse) and time periods (1 minute, 1.5 minutes, and 2 minutes). We then examined the change in surface roughness value and microstructure. In a scanning electron microscopy evaluation, the double acid-etched implant surface was not altered by Er:YAG laser irradiation under the condition of 100 mJ/pulse at 10 Hz for any of the irradiation times. However, we investigated the reduced sharpness of the specific ridge microstructure that resulted under the 140 mJ/pulse and 180 mJ/pulse conditions. The reduction in sharpness became more severe as laser energy and application duration increased. In the roughness measurement, the double acid-etched implants showed a low roughness value on the valley area before the laser irradiation. Under all experimental conditions, Er:YAG laser irradiation led to a minor decrease in surface roughness, which was not statistically significant. The recommended application settings for Er:YAG laser irradiation on double acid-etched implant surface is less than a 100 mJ/pulse at 10 Hz, and for less than two minutes in order to detoxify the implant surface without causing surface modification.


A path forward for qualitative research on sustainability in the COVID-19 pandemic.
The unique strengths of qualitative research, through in-depth inquiry and identification of unexpected themes and linkages, is essential to our growing understanding of COVID-19's impacts on the social world and its intersection with sustainability science. However, many challenges-physical, psychological, and ethical in nature-face qualitative researchers during the pandemic, as social distancing and travel restrictions prevent in-person field work. In this paper, we outline the essential contributions of qualitative study to sustainability science, discuss current challenges, and in turn, provide recommendations for researchers.


Dependence of nanoparticle-cell recognition efficiency on the surface orientation of scFv targeting ligands.
The surface activation of multifunctional nanoparticles (MNPs) with peptide ligands directing their targeting to cancer cells is an emerging research area in nanobiotechnology. In this paper, water-soluble MNPs have been synthesized and functionalized with an scFv antibody variant specific toward the HER2 receptor overexpressed in several breast cancer cell lines. The scFv was genetically engineered to introduce a cysteine residue inside the loop sequence bridging the VH and VL lobes of the molecule and a histidine tag at the C-terminus in the VL fragment. The Cys and 6 × His functionalities were exploited as orthogonal reactive groups driving the scFv conjugation to MNPs. In this way, scFv positioning on the MNP surface was forced into two different orientations depending on the molecular binding site used for conjugation. The resulting scFv-functionalized MNP1 and MNP2, respectively, were assessed as to their labeling efficiency and selectivity to HER2-positive MCF7 cells. We demonstrate that, while both MNP1 and MNP2 were selective for HER2, there is a remarkable preference for scFv presentation with VH and VL lobes concurrently available for receptor recognition (MNP1) in terms of cell binding efficiency, suggesting that ligand orientation may strongly affect cell binding from MNPs.


Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis.
Emerging evidence from epidemiologic studies and basic science suggests an inverse association between metformin use and cancer risk in diabetic patients. However, the association with lung cancer is not consistent. We summarized the evidence currently available (2009-2013) and explored sources of heterogeneity. Metformin therapy was associated with significantly lower risks of cancers of the lung (4 studies; pooled relative risk = 0.71, 95% confidence interval (CI): 0.55, 0.95; P = 0.02) and respiratory system (6 studies; pooled relative risk = 0.85, 95% CI: 0.75, 0.96; P = 0.01). There was evidence of moderate heterogeneity (I(2) > 50%). The major sources of heterogeneity were smoking adjustment status and cancer site. The relative risk from studies that adjusted for smoking was 1.16-fold (95% CI: 1.00, 1.35) closer to the null than that from studies not adjusting for smoking. The relative risk of respiratory cancer was 1.23-fold (95% CI: 1.02, 1.49) closer to the null than that for lung cancer. In conclusion, metformin use appears to be associated with lower risks of lung and respiratory cancer in diabetic patients. However, caution regarding overestimation is needed, since adjustment for smoking attenuates the association.


Endovascular treatment for intermittent claudication in patients who do not improve with clinical treatment.
To study the results including long-term follow-up obtained with endovascular treatment of patients with intermittent claudication who did not experience clinical improvement with conservative treatment. From January 1992 to January 2002, 62 of 1380 patients (4.5%) with intermittent claudication underwent endovascular treatment and were followed up for up to 120 months (mean 76 months). The variables analyzed were the functioning of the arterial segment undergoing the endovascular procedure, the evolution of the maximum walking distance, and incidence of related morbidity and mortality. Fifty-two patients (84%) experienced no walking limitation after the procedure, and 6 patients (10%) improved but still exhibited some degree of limitation, for a total improved outcome of 94%. The patency rate was 82%. There was no intraoperative mortality. One primary failure and one immediate thrombosis occurred, and both were surgically corrected. Thrombosis of the treated artery occurred in 6 patients 12, 16, 25, 29, 62, and 66 months after the procedure. These patients started to experience intermittent claudication with a walking distance to onset that was similar to their presurgical distance to onset. During follow-up, a mortality rate of 12.9% (8 patients) was observed, 6 due to myocardial infarctions and 2 due cerebral infarction. Three patients underwent coronary bypasses 22, 36, and 55 months after the endovascular surgery, and 2 patients underwent coronary angioplasty after 6 and 26 months. The mean follow up period was 76 months (range 0-120 months). This study shows that endovascular treatment of intermittent claudication brought about a lasting regression of the ischemic conditions in a significant number of patients, with excellent patency rates. It was concluded that this is a good alternative for selected patients, with low rates of complications and positive long-term results.


A phase III, placebo controlled clinical trial of 0.5% levofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis.
To compare the efficacy and safety of levofloxacin 0.5% ophthalmic solution (Quixin) with placebo for treatment of bacterial conjunctivitis. In this prospective, randomised, placebo controlled, double masked, multicentre study, 249 patients with bacterial conjunctivitis received either 0.5% levofloxacin (n = 126) or placebo (n = 123) for 5 days, administered every 2 hours on days 1-2, then every 4 hours on days 3-5. Cultures were obtained and signs/symptoms evaluated at baseline, interim, and final visits. The end point was the last evaluable observation. Primary microbial outcomes were based on culture results; clinical outcomes were based on resolution of cardinal signs. 117 patients (60 levofloxacin, 57 placebo) were evaluated. Microbial eradication rates were significantly greater with levofloxacin at all time points, reaching 90% at end point. In a subgroup analysis, differences in eradication rates at end point were most pronounced in children but were also statistically significant for levofloxacin in adults. Clinical cure rates were significantly greater with levofloxacin at final visit and end point. Statistically significant differences favouring levofloxacin were measured at end point for resolution of conjunctival discharge, bulbar conjunctival injection, palpebral conjunctival injection, burning/stinging, itching, and photophobia. Adverse events were similar between groups. Safety composite scores analysed by age indicated significantly fewer children on levofloxacin experienced worsening symptoms. Levofloxacin 0.5% ophthalmic solution is safe and effective for treatment of bacterial conjunctivitis.


Ruminococcoides bili gen. nov., sp. nov., a bile-resistant bacterium from human bile with autolytic behavior.
A strictly anaerobic, resistant starch-degrading, bile-tolerant, autolytic strain, IPLA60002T, belonging to the family Ruminococcaceae, was isolated from a human bile sample of a liver donor without hepatobiliary disease. Cells were Gram-stain-positive cocci, and 16S rRNA gene and whole genome analyses showed that Ruminococcus bromii was the phylogenetically closest related species to the novel strain IPLA60002T, though with average nucleotide identity values below 90 %. Biochemically, the new isolate has metabolic features similar to those described previously for gut R. bromii strains, including the ability to degrade a range of different starches. The new isolate, however, produces lactate and shows distinct resistance to the presence of bile salts. Additionally, the novel bile isolate displays an autolytic phenotype after growing in different media. Strain IPLA60002T is phylogenetically distinct from other species within the genus Ruminococcus. Therefore, we propose on the basis of phylogenetic, genomic and metabolic data that the novel IPLA60002T strain isolated from human bile be given the name Ruminococcoides bili gen. nov., sp. nov., within the new proposed genus Ruminococcoides and the family Ruminococcaceae. Strain IPLA60002T (=DSM 110008T=LMG 31505T) is proposed as the type strain of Ruminococcoides bili.


Future of biologics in pediatric asthma: Optimizing response, early introduction, and equitable access to treatment.
To evaluate the current evidence, its limitations, and future research directions for the use of biologics in pediatric asthma, with a particular focus on the potential use of biologics to prevent pediatric asthma and equity issues in access to biologic treatment and research participation. PubMed articles about the use of biologics in pediatric asthma were searched up to May 2023. Recent (2019-2023) original research articles and reviews were prioritized. Although there are now 5 U.S. Food and Drug Administration-approved biologics for use in pediatric asthma, there are important knowledge gaps that ongoing research seeks to address, which include (1) the long-term efficacy and safety of using biologics in children, (2) the comparative efficacy of different biologics, (3) multi-omics-based classification of asthma endotypes and phenotypes in children to find potential new therapeutic targets and enable identification and validation of new biomarkers that may predict and help monitor response to treatment, and (4) whether starting biologics in early childhood can modify the natural history of asthma and potentially prevent asthma development. To promote equitable access to biologics and optimize asthma outcomes, future research should recruit patients across the full spectrum of socioeconomic and racial/ethnic backgrounds. Large-scale national and international collaborations between asthma researchers and clinicians are also necessary to fully understand the role of biologics in pediatric asthma.


Inducibility of beta-glucuronidase in wild-type and hexuronate-negative mutants of Escherichia coli K-12.
In strain K-12 of Escherichia coli, beta-glucuronidase synthesis was induced only by beta-glucuronides: all intermediates of the hexuronate pathway able to enter the cells failed to induce the enzyme significantly. The induction pattern of beta-glucuronidase clearly differentiates the mode of regulation of its synthesis from those of the subsequent enzymes of the pathway, which are induced by fructuronate and/or tagaturonate. In mutant strains blocked in glucuronate metabolism after the isomerase step, beta-glucuronidase synthesis was still induced by a beta-glucuronide. Glucuronate and fructuronate, which are accumulated and mutually interconverted within the cells, become good inducers of beta-glucuronidase: they induce up to a level one-half that obtained in the wild-type strain in the presence of beta-glucuronide alone. In an isomerase-negative strain where fructuronate is not produced, beta-glucuronidase was no longer induced by beta-glucuronide unless supplemented with fructuronate. In this strain, glucuronate alone or fructuronate alone exhibited greater inducing ability than in the wild-type strain. Moreover, fructuronate could also enhance glucuronate-induced synthesis of beta-glucuronidase. Glucuronate was not able to activate beta-glucuronideinduced synthesis of beta-glucuronidase. Therefore, the induction of beta-glucuronidase synthesis depends upon two factors which, when acting separately, are both poor inducers but can act cooperatively; one factor is beta-glucuronide or glucuronate and the second is fructuronate. The specific inducing capacity of each of these three compounds as well as the hypothetical mechanism(s) of the action of fructuronate are discussed.


Hepatitis B Virus Reactivation with Discontinuation of Nucleoside Analogue in Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation.
Reactivation of hepatitis B virus (HBV) is known to occur frequently after hematopoietic stem cell transplantation (HSCT). The reactivation can be prevented by nucleos(t)ide analogue (NA), but it is unclear how long NA should be continued. Here, we report 3 cases of HBV reactivation with discontinuation of NA following the discontinuation of immunosuppressive therapies after HSCT. Three male patients aged 34, 59, and 54 years received allogeneic HSCT (allo-HSCT) for chronic myeloid leukemia, mixed phenotype acute leukemia, and myelodysplastic syndrome, respectively. Before HSCT, 2 patients were positive for hepatitis B surface antigen (HBsAg) and 1 patient was negative for HBsAg and positive for antibodies to hepatitis B core antigen. NA (lamivudine or entecavir) was started at the same time as HSCT and stopped after the discontinuation of immunosuppressive therapies. In all patients, the serum HBV DNA levels were increased after the discontinuation of NAs. Two of the three patients developed severe hepatitis with high levels of HBV DNA (7.5 and 7.4 log IU/mL, respectively). A patient without hepatitis was re-administered NA soon after the HBV DNA started to increase (3.3 log IU/mL). Interestingly, the 2 patients who developed hepatitis cleared HBsAg promptly after the recovery from hepatitis and they could stop NAs without the reversion of HBsAg. It was speculated that transplanted immune cells, which were naïve for HBV, react strongly with HBV antigens that were increased after the NA discontinuation. The discontinuation of NA after allo-HSCT is not recommended generally because strong hepatitis might be induced even after several years.


[Content of nitrates and nitrites in market vegetables in Wroclaw in the years 1996-1997].
The aim of analytical investigation included in this paper was the determination the nitrate and nitrite contents in 8 common vegetables: cabbage, carrot, parsley, potato, garden beet, cucumber, lettuce and radish in relation to the acceptable levels of nitrates. The samples of vegetables were taken from detail shops in Wrocław in the years 1996-1997. A total of 151 samples of vegetables were analyzed. The nitrate and nitrite level was determined collorimetricaly with sulfanilic acid after previous reduction of nitrates to nitrites by means of cadmium column. The acceptable values of nitrates were exceeded in 82% of the samples of radish and in 65% samples of lettuce. The smallest amount of samples with excess of the acceptable nitrate levels were found in potato, carrot and cucumber. It was found, that the nitrate content in the greenhouse vegetables: lettuce, cucumber and radish was greater than in the field vegetables. The potato, cabbage and carrot investigated after winter storage comprised lower content of nitrates than in freshly harvested. Nitrite accumulation in investigated vegetables was low, but the highest concentrations were found in lettuce and radish form greenhouse.


Functional rehabilitation of low back disorders.
Musculoskeletal disorders of which low back pain (LBP) accounts for more than 50% are now the most common cause of chronic incapacity in industrialized countries. The traditional approach in looking for the reason (etiology) for musculoskeletal disorders is to search structural failures but, in most cases, it is difficult to find an explicit reason for back pain. Many scientists now consider spine disorders as multifactorial, bio-psycho-social problems. Pain has clear effects on motor control. Therefore, LBP can also induce changes in neuromuscular control and motor performance, i.e., causing various functional deficits. Another feature, which deserves special consideration with reference to back problems, concerns the numerous psychological factors, which are involved in mediating the relationships between physical impairment, pain and disability. The new scientific knowledge on functional deficits is increasingly being transferred to clinical applications, where the aim is to reverse them with physical rehabilitation. As a result of the recognition of the behavioral (psychological) problems with LBP, psychological, behavioral and educational interventions are commonly combined with the physical rehabilitation for LBP also. Basically, functional rehabilitation includes systematic quantification of both the physical function and psychological factors, which drive the therapeutic process. The exercises used in the functional rehabilitation usually revolve around the treatment of the spine as a functional unit. Thus many programs for functional rehabilitation use rehabilitation equipment (iso-inertial/isokinetic) by properly trained physiotherapists. However, some centers use regular fitness equipment or aerobics-type exercises. Furthermore, some relaxation and ergonomic exercises are typically proposed, and psychological support provided along the treatment. There exists both an outpatient and an inpatient functional rehabilitation approach. They are described in the paper together with the first results obtained in Italy with the outpatient approach.


Evidence of aromatase localization in cytoplasmic droplet of human immature ejaculated spermatozoa.
Lytochrome P450 aromatase is a microsomal enzyme catalyzing the conversion of androgens to estrogens. P450arom expression has been demonstrated in testicular and epididymal sperm cells of several species but very limited data have been reported about maturating human germ cells. In this study, human spermatozoa with cytoplasmic droplet anomaly have been utilized to investigate aromatase immunolocalization in the immature germ cells of human ejaculate. Immunodetection has utilized a polyclonal antiserum as primary antibody, a biotinylated IgG as secondary antibody and then the avidin-biotin-peroxidase complex amplification followed by the diaminobenzidine staining. A strong immunoreaction was observed in the cytoplasmic droplets retained around the midpiece of immature spermatozoa and also in the descending droplets of late maturing sperm, while the other cellular components were unstained. Therefore, this investigation has demonstrated, for the first time, aromatase immunolocalization in residual cytoplasm of human ejaculated sperm, suggesting cytoplasmic droplets as possible estrogen biosynthesis sites during human sperm differentiation.


Is fertility reduced among men exposed to radiofrequency fields in the Norwegian Navy?
The effects of radiofrequency fields on human health are not well understood, and public concern about negative health effects has been rising. The aim of this study was to examine the relationship between workers exposed to electromagnetic fields and their reproductive health. We obtained data using a questionnaire in a cross-sectional study of naval military men, response rate 63% (n = 1487). We asked the respondents about exposure, lifestyle, reproductive health, previous diseases, work and education. An expert group categorized the work categories related to electromagnetic field exposure. We categorized the work categories "tele/communication," "electronics" and "radar/sonar" as being exposed to electromagnetic fields. Logistic regression adjusted for age, ever smoked, military education, and physical exercise at work showed increased risk of infertility among tele/communication odds ratio (OR = 1.72, 95% confidence interval 1.04-2.85), and radar/sonar odds ratio (OR = 2.28, 95% confidence interval 1.27-4.09). The electronics group had no increased risk. This study shows a possible relationship between exposure to radiofrequency fields during work with radiofrequency equipment and radar and reduced fertility. However, the results must be interpreted with caution.


Pharmacognostical evaluation of Cardiospermum halicacabum Linn. leaf and stem.
Cardiospermum halicacabum Linn (Sapindaceae) is an important medicinal plant in the traditional system of medicine, known as karṇasphoṭa. The root of it is officially included in Ayurvedic Pharmacopoeia for its therapeutic uses such as jvara, kuṣṭha, pāṇḍu, kṣaya and sandhivāta etc. As no detailed analysis of macroscopy, microscopy characters of the plant, except root, have been carried out till date, it was thought worth to carry out the detailed macroscopic and microscopic study of leaves and stem, following standard pharmacognostical procedures. Pharmacognostic studies of C. halicacabum were carried out, and in this, the macroscopic, microscopic, physicochemical, fluorescence and phytochemical analyses were done. Physicochemical parameters such as total ash, moisture content, extractive values were determined by World Health Organization guidelines. The microscopic features of leaf and stem components were observed. Macroscopically the leaves are bi-ternate, ovate-lanceolate in shape with dentate margin. Microscopically, leaf shows prominent midrib and thin dorsiventral lamina. The midrib shows the presence of epidermal layers, angular collenchyma, palisade cells and vascular strands comprised of thin walled xylem and thick walled phloem elements. The lamina shows prominent, narrow and cylindrical upper epidermis. The upper epidermal cells are large and contain mucilage, whereas lower epidermis possesses thin, small and elliptical epidermal cells. The mesophyll was differentiated into two zones upper and lower. The upper zones show narrow cylindrical palisade cells and lower zone shows 2-3 layers of loosely arranged spongy parenchyma cells. In the Paradermal section of the lamina we observe anomocytic stomata. The transverse section of stem shows a pentagonal appearance with five short blunt ridges and prominent cuticle. Parenchymatous cells, cortical sclerenchyma, lignified xylem fibers, phloem and pit were also found. In the powder microscopy of whole plant, glandular trichomes, non-glandular trichomes, fragments of lamina, xylem elements, parenchyma cells and fibers are observed. Phytochemical screening reveals that the C. halicacabum extract contains glycosides, carbohydrates, flavonoids, phytosterols, phenolic compounds and saponin. Various pharmacognostic characters observed in this study help in identification, quality, purity and standardization of C. halicacabum.


Aquacultured rainbow trout (Oncorhynchus mykiss) possess a large core intestinal microbiota that is resistant to variation in diet and rearing density.
As global aquaculture fish production continues to expand, an improved understanding of how environmental factors interact in fish health and production is needed. Significant advances have been made toward economical alternatives to costly fishmeal-based diets, such as grain-based formulations, and toward defining the effect of rearing density on fish health and production. Little research, however, has examined the effects of fishmeal- and grain-based diets in combination with alterations in rearing density. Moreover, it is unknown whether interactions between rearing density and diet impact the composition of the fish intestinal microbiota, which might in turn impact fish health and production. We fed aquacultured adult rainbow trout (Oncorhynchus mykiss) fishmeal- or grain-based diets, reared them under high- or low-density conditions for 10 months in a single aquaculture facility, and evaluated individual fish growth, production, fin indices, and intestinal microbiota composition using 16S rRNA gene sequencing. We found that the intestinal microbiotas were dominated by a shared core microbiota consisting of 52 bacterial lineages observed across all individuals, diets, and rearing densities. Variations in diet and rearing density resulted in only minor changes in intestinal microbiota composition despite significant effects of these variables on fish growth, performance, fillet quality, and welfare. Significant interactions between diet and rearing density were observed only in evaluations of fin indices and the relative abundance of the bacterial genus Staphylococcus. These results demonstrate that aquacultured rainbow trout can achieve remarkable consistency in intestinal microbiota composition and suggest the possibility of developing novel aquaculture strategies without overtly altering intestinal microbiota composition.


The use of screening and preventive therapies for gastroesophageal varices in patients referred for evaluation of orthotopic liver transplantation.
Screening for varices has been recommended in patients with cirrhosis to prevent variceal hemorrhage (primary prophylaxis). In addition, therapy is recommended after the initial episode of variceal bleeding to prevent recurrence (secondary prophylaxis). However, the degree of adherence to these recommendations remains unclear. The purpose of our study was to determine whether these recommendations are being followed in patients presenting for evaluation of orthotopic liver transplantation. One hundred twenty-five patients referred for liver transplantation were evaluated. Data regarding demographics, clinical information, relevant time intervals (diagnosis of cirrhosis to screening, screening to initial variceal bleeding, variceal bleeding to referral, diagnosis of cirrhosis to referral), screening strategies used, and implementation of primary or secondary prophylaxis was obtained. The differences among quantitative variables were analyzed with Student's t test. Qualitative variables were evaluated with the Mantel-Haenzel chi2 test or Fisher's exact test. Statistical significance was designated at p < 0.05. Our study found that 46% of patients presenting for evaluation of liver transplantation had screening endoscopy or radiological studies to detect the presence of varices. On the contrary, secondary prophylaxis was performed in all patients with a prior history of variceal hemorrhage. Screening for varices displayed no regional differences. In our cohort, screening for varices is not being consistently performed, thus delaying the timely implementation of primary prophylaxis. Therefore, the adherence to currently available practice guidelines and the education of physicians to implement screening in this patient population is an important goal.


Sequestration of cholesterol within the host late endocytic pathway restricts liver-stage Plasmodium development.
While lysosomes are degradative compartments and one of the defenses against invading pathogens, they are also hubs of metabolic activity. Late endocytic compartments accumulate around Plasmodium berghei liver-stage parasites during development, and whether this is a host defense strategy or active recruitment by the parasites is unknown. In support of the latter hypothesis, we observed that the recruitment of host late endosomes (LEs) and lysosomes is reduced in uis4- parasites, which lack a parasitophorous vacuole membrane protein and arrest during liver-stage development. Analysis of parasite development in host cells deficient for late endosomal or lysosomal proteins revealed that the Niemann-Pick type C (NPC) proteins, which are involved in cholesterol export from LEs, and the lysosome-associated membrane proteins (LAMP) 1 and 2 are important for robust liver-stage P. berghei growth. Using the compound U18666A, which leads to cholesterol sequestration in LEs similar to that seen in NPC- and LAMP-deficient cells, we show that the restriction of parasite growth depends on cholesterol sequestration and that targeting this process can reduce parasite burden in vivo. Taken together, these data reveal that proper LE and lysosome function positively contributes to liver-stage Plasmodium development.


Sharing cases: the Observationes in early modern medicine.
This paper examines the rise of an epistemic genre, the Observationes, a new form of medical writing that emerged in Renaissance humanistic medicine. The Observationes (collections of case-histories) originated in the second half of the sixteenth century, grew rapidly over the course of the seventeenth, and had become a primary form of medical writing by the eighteenth century. The genre developed initially as a form of self-advertisement by court and town physicians, who stressed success in practice, over and above academic learning, as a core element of their professional identity. This unprecedented emphasis on practice as a source of knowledge remained a key feature of the Observationes in its subsequent development. As the genre evolved, the original emphasis on therapeutic success gave way to a new focus on the descriptive knowledge of disease through detailed observation. The authorial identity projected by the writers of Observationes was increasingly that of the learned and experienced observer, bent on comparing notes and sharing his cases with the fellow members of the res publica medica. This paper charts the development of the genre, examining how its growth contributed to the new epistemological value of observation in the age of the Scientific Revolution.


Long-term prognosis after intracerebral haemorrhage: systematic review and meta-analysis.
There is uncertainty about the long-term prognosis after spontaneous intracerebral haemorrhage (ICH). Therefore, we systematically reviewed the literature for studies reporting long-term survival and ICH recurrence, and their predictors. We searched Ovid Medline 1946-2011 inclusive for cohort studies of ≥50 patients reporting long-term (>30 days) outcome after ICH. Two reviewers independently extracted data from each study. We meta-analysed 1-year and 5-year survival data from population-based studies using a random effects model (and quantified inconsistency using the I2 statistic). We identified 122 eligible studies. The pooled estimate of 1-year survival was 46% (95% CI 43% to 49%; nine population-based studies (n=2408); I2=27%) and 5-year survival was 29% (95% CI 26% to 33%; three population-based studies (n=699); I2=6%). In 27 cohort studies, predictors most consistently associated with death were increasing age, decreasing Glasgow Coma Scale score, increasing ICH volume, presence of intraventricular haemorrhage, and deep/infratentorial ICH location. The annual risk of recurrent ICH varied from 1.3% to 7.4% in nine studies and this risk was higher after lobar ICH than non-lobar ICH in two of three hospital-based studies. Four studies reporting the risks of recurrent ICH and ischaemic stroke after ICH found no significant differences between these risks. Less than a half of patients with ICH survive 1 year and less than a third survive 5 years. Risks of recurrent ICH and ischaemic stroke after ICH appear similar after ICH, provoking uncertainties about the use of antithrombotic drugs.


Joint hypermobility: the use of a new assessment tool to measure lower limb hypermobility.
The aim of the study was to compare the use of a new assessment tool for diagnosis of hypermobility in the lower limb to the Beighton score for generalised hypermobility. Three groups of children were compared (n = 225) and included a "normal" population of 116 school children, a "possible hypermobile" group of 88 children attending afoot and gait clinic and a "known hypermobile" group of 21 children referred from a paediatrician or rheumatologist. The Beighton score was used to measure generalised hypermobility. The Lower Limb Assessment Score was used to measure hypermobility in the lower limbs. The Lower Limb Assessment Score was able to distinguish between the three groups of children better than the Beighton score. At a threshold of 5/9 indicating hypermobility, the Beighton score identified hypermobility in 34% of school children; the lower limb score identified hypermobility in 21% of school children after a threshold was identified. There was disagreement between the scores in school children where 26.7% of children appeared to have a positive Beighton score that was not accompanied by a positive lower limb score. In the "known hypermobile" group the Beighton score was positive in only 10% of children when the lower limb score was negative for hypermobility. In this group of school children, the Beighton score appeared to over-diagnose hypermobility at the threshold of 5/9. Specific thresholds for diagnosis need to be set dependant on the age and ethnic group of the population being studied. The Lower Limb Assessment Score may be a useful score for health professionals specifically interested in lower limb hypermobility.


Outcome of liver transplantation in patients with prior bariatric surgery.
Nonalcoholic fatty liver disease is becoming the leading cause of disease resulting in liver transplantation (LT). As a result of this trend, more LT candidates are presenting with prior history of bariatric surgery (BS). Over the last decade, 960 patients underwent LT at our institution; 11 (1.1%) had prior BS. The most common type of BS was Roux-en-Y gastric bypass (n = 9) with 1 sleeve gastrectomy and 1 jejunoileal bypass. A total of 9 patients underwent LT alone, and 2 underwent simultaneous liver-kidney transplantation. The most common indication for LT was nonalcoholic steatohepatitis (n = 10) with 5 having additional diagnosis of alcoholic liver disease. The 30-day reoperation rate was 36.4% (n = 4); indications were bile duct repair (n = 3) and wound repair (n = 1). In the first 6 months after LT, biliary complications were seen in 54.5% (n = 6) of the patients. Both patient and graft survival rates at 1 and 2 years were 81.8% (n = 9) and 72.7% (n = 8), respectively. A total of 8 patients (72.7%) had indications for liver biopsy after LT; significant macrovesicular steatosis was found in 2 (18.2%). In patients with a history of alcohol consumption, 2 (40.0%) relapsed after LT. Two patients (18.2%) had a history of diet-controlled diabetes before LT; 1 of these patients became insulin dependent after LT. Mean body mass index (BMI) at LT was 31.0 ± 5.7 kg/m2 . Mean BMI at 1, 6, and 12 months after LT was 28.3 ± 5.8, 28.0 ± 3.2, and 31.0 ± 6.6 kg/m2 , respectively. Mean preoperative albumin was 2.6 ± 0.6 mg/dL. Patients showed improvement in albumin after LT, with mean albumin of 2.7 ± 0.6 and 3.2 ± 0.5 mg/dL at 1 and 3 months, respectively. The liver profile was stable after LT, with mean aspartate aminotransferase of 32.9 ± 18.4 and 26.6 ± 19.8 IU/L and alanine aminotransferase of 28.0 ± 17.5 and 30.2 ± 17.0 IU/L at 6 and 12 months, respectively. In conclusion, outcomes of LT patients with prior BS are comparable with other transplant recipients with regards to patient and graft survival and post-LT complication rates. Liver Transplantation 23 1415-1421 2017 AASLD.


Deep brain and cortical stimulation for epilepsy.
Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. Since the 1970s interest has grown in invasive intracranial neurostimulation as a treatment for these patients. Intracranial stimulation includes both deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes). This is an updated version of a previous Cochrane review published in 2014. To assess the efficacy, safety and tolerability of DBS and cortical stimulation for refractory epilepsy based on randomized controlled trials (RCTs). We searched the Cochrane Epilepsy Group Specialized Register on 29 September 2015, but it was not necessary to update this search, because records in the Specialized Register are included in CENTRAL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 11, 5 November 2016), PubMed (5 November 2016), ClinicalTrials.gov (5 November 2016), the WHO International Clinical Trials Registry Platform ICTRP (5 November 2016) and reference lists of retrieved articles. We also contacted device manufacturers and other researchers in the field. No language restrictions were imposed. RCTs comparing deep brain or cortical stimulation versus sham stimulation, resective surgery, further treatment with antiepileptic drugs or other neurostimulation treatments (including vagus nerve stimulation). Four review authors independently selected trials for inclusion. Two review authors independently extracted the relevant data and assessed trial quality and overall quality of evidence. The outcomes investigated were seizure freedom, responder rate, percentage seizure frequency reduction, adverse events, neuropsychological outcome and quality of life. If additional data were needed, the study investigators were contacted. Results were analysed and reported separately for different intracranial targets for reasons of clinical heterogeneity. Twelve RCTs were identified, eleven of these compared one to three months of intracranial neurostimulation with sham stimulation. One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); two trials on centromedian thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; three trials on cerebellar stimulation (n = 22; 39 treatment periods); three trials on hippocampal DBS (n = 15; 21 treatment periods); one trial on nucleus accumbens DBS (n = 4; 8 treatment periods); and one trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods). In addition, one small RCT (n = 6) compared six months of hippocampal DBS versus sham stimulation. Evidence of selective reporting was present in four trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in five cross-over trials without any or a sufficient washout period. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after one to three months of anterior thalamic DBS in (multi)focal epilepsy, responsive ictal onset zone stimulation in (multi)focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (mean difference (MD), -17.4% compared to sham stimulation; 95% confidence interval (CI) -31.2 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (MD -24.9%; 95% CI -40.1 to -6.0; high-quality evidence) and hippocampal DBS (MD -28.1%; 95% CI -34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence). Electrode implantation resulted in postoperative asymptomatic intracranial haemorrhage in 1.6% to 3.7% of the patients included in the two largest trials and 2.0% to 4.5% had postoperative soft tissue infections (9.4% to 12.7% after five years); no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P = 0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation seemed to be well-tolerated with few side effects.The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality. Except for one very small RCT, only short-term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi)focal epilepsy), responsive ictal onset zone stimulation ((multi)focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS, nucleus accumbens DBS and cerebellar stimulation. There is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments.


Acoustic radiation force impulse imaging for non-invasive assessment of liver fibrosis in chronic hepatitis B.
Acoustic radiation force impulse (ARFI) imaging is a novel ultrasound-based elastography method that is integrated in a conventional ultrasound machine. It might provide an alternative method to transient elastography for the noninvasive assessment of liver fibrosis. While previous studies have shown comparable diagnostic accuracy of ARFI to transient elastography in chronic hepatitis C, the aim of the present prospective multicenter study was to evaluate ARFI for the assessment of liver fibrosis in chronic hepatitis B. ARFI imaging involves the mechanical excitation of tissue using short-duration acoustic pulses to generate localized displacements in tissue. The displacements result in shear-wave propagation which is tracked using ultrasonic, correlation-based methods and recorded in m/s. In the present international prospective study, patients infected with chronic hepatitis B received ARFI imaging, blood tests and if available transient elastography. The results were compared to liver biopsy as reference method analysed by a central pathologist. In 92 of 114 patients, a comparison of ARFI with transient elastography was possible. ARFI imaging and transient elastography correlated significantly with histological fibrosis stage. The diagnostic accuracy expressed as areas under ROC curves for ARFI imaging and transient elastography was 0.75 and 0.83 for the diagnosis of significant fibrosis (F ≥ 2), 0.93 and 0.94 for the diagnosis of severe fibrosis (F ≥ 3), and 0.97 and 0.93 for the diagnosis of liver cirrhosis, respectively. No significant difference was found between ARFI and transient elastography. ARFI imaging is a reliable ultrasound-based method for the assessment of advanced stages of liver fibrosis in chronic hepatitis B.


Link Between Cardiovascular and Cerebrovascular Controls in Patients Undergoing Surgical Aortic Valve Replacement.
Although the autonomic influence on cardiovascular (CV) and cerebrovascular (CBV) regulations has been widely recognized, their relationship is poorly explored especially in pathological situations. This study investigates the correlation between CV and CBV markers in 73 patients (48 males, age 63.6±13.1 yrs) undergoing surgical aortic valve replacement (SAVR) evaluated before the intervention (PRE), within 1-week post-surgery (POST) and after a 3-month follow-up (POST3). Patients were acquired before and after an orthostatic challenge. Frequency domain analysis assessing transfer function gain (TFG), phase (Ph), and squared coherence (K2) between heart period and systolic arterial pressure was exploited to evaluate CV control. The same frequency domain functions were derived to assess CBV regulation from mean cerebral blood velocity and mean arterial pressure. A correlation analysis between indexes of CV and CBV controls was carried out. Results showed that CV control was impaired in PRE, worsened in POST, and recovered in POST3, while CBV markers were almost unchanged. A significant positive relationship between CV and CBV markers was observed, especially in POST and POST3, thus suggesting that the compensation of a baroreflex impairment with a more efficient CBV control and vice versa. The maintenance of this relationship between CV and CBV controls in patients undergoing SAVR could be fundamental to prevent risky situations.Clinical Relevance- After surgical aortic valve replacement an impaired baroreflex control could be compensated by a more efficient cerebral autoregulation.


Determination of viral load thresholds in cervical scrapings to rule out CIN 3 in HPV 16, 18, 31 and 33-positive women with normal cytology.
An increased high-risk human papillomavirus (hrHPV) viral load in cervical scrapings has been proposed as a determinant for high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer (> or =CIN 2), but data so far for HPV types different from HPV 16 are limited and inconsistent. In addition, a viral load threshold to distinguish hrHPV positive women without > or =CIN 2 still has not been defined. Here, we used baseline cervical scrapings of women with normal cytology participating in a large population-based cervical screening trial (i.e. POBASCAM) who were GP5+/6+-PCR positive for 4 common hrHPV types, i.e. HPV 16, 18, 31 or 33, as a reference to arbitrarily define various viral load thresholds (i.e. 25th, 33rd, 50th, 67th and 75th percentiles of the lowest viral load values) for distinguishing women having single infections with these types without high-grade CIN. Viral load assessment was performed by real time type-specific PCR. The viral load threshold values were subsequently validated on abnormal cervical scrapes of 162 women with underlying, histologically confirmed CIN lesions containing 1 of these 4 hrHPV types. All 59 women with CIN 3 had viral load levels that were higher than those of 33% of the women with normal cytology containing the respective hrHPV type detectable by GP5+/6+-PCR (i.e. higher than the 33rd percentile of viral load). By using this 33rd percentile viral load cut-off, sensitivity for CIN 3 of 100% (95% CI 93.9-100) was obtained. Hence, application of this viral load threshold would increase the specificity of HPV testing for HPV 16, 18, 31 and 33-associated prevalent CIN 3 without the cost of a marked reduction in sensitivity. In practice, on the basis of viral load analysis, a less aggressive management can be foreseen for 33% of the women with normal cytology participating in a population-based screening program who are GP5+/6+-PCR positive for HPV 16, 18, 31 or 33.


Nonsupervised ranking of different segmentation approaches: application to the estimation of the left ventricular ejection fraction from cardiac cine MRI sequences.
A statistical methodology is proposed to rank several estimation methods of a relevant clinical parameter when no gold standard is available. Based on a regression without truth method, the proposed approach was applied to rank eight methods without using any a priori information regarding the reliability of each method and its degree of automation. It was only based on a prior concerning the statistical distribution of the parameter of interest in the database. The ranking of the methods relies on figures of merit derived from the regression and computed using a bootstrap process. The methodology was applied to the estimation of the left ventricular ejection fraction derived from cardiac magnetic resonance images segmented using eight approaches with different degrees of automation: three segmentations were entirely manually performed and the others were variously automated. The ranking of methods was consistent with the expected performance of the estimation methods: the most accurate estimates of the ejection fraction were obtained using manual segmentations. The robustness of the ranking was demonstrated when at least three methods were compared. These results suggest that the proposed statistical approach might be helpful to assess the performance of estimation methods on clinical data for which no gold standard is available.


Watching the Interplay between Photoinduced Ultrafast Charge Dynamics and Nuclear Vibrations.
Here is presented the ultrafast hole-electron dynamics of photoinduced metal to ligand charge-transfer (MLCT) states in a Ru(II) complex, [Ru(dcbpy)2(NCS)2]4- (dcbpy = 4,4'-dicarboxy-2,2'-bipyridine), a photoactive molecule employed in dye sensitized solar cells. Via cutting-edge computational techniques, a tailored computational protocol is here presented and developed to provide a detailed analysis of the electronic manifold coupled with nuclear vibrations to better understand the nonradiative pathways and the resulting overall dye performances in light-harvesting processes (electron injection). Thus, the effects of different vibrational modes were investigated on both the electronic levels and charge transfer dynamics through a theoretical-computational approach. First, the linear response time-dependent density functional (LR-TDDFT) formalism was employed to characterize excitation energies and spacing among electronic levels (the electronic layouts). Then, to understand the ultrafast (femtosecond) charge dynamics on the molecular scale, we relied on the nonperturbative mean-field quantum electronic dynamics via real-time (RT-) TDDFT. Three vibrational modes were selected, representative for collective nuclear movements that can have a significant influence on the electronic structure: two involving NCS- ligands and one involving dcbpy ligands. As main results, we observed that such MLCT states, under vibrational distortions, are strongly affected and a faster interligand electron transfer mechanism is observed along with an increasing MLCT character of the adiabatic electronic states approaching closer in energy due to the vibrations. Such findings can help both in providing a molecular picture of multidimensional vibro-electronic spectroscopic techniques, used to characterize ultrafast coherent and noncoherent dynamics of complex systems, and to improve dye performances with particular attention to the study of energy or charge transport processes and vibronic couplings.


A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain.
In US emergency departments (EDs), patients with low back pain are often treated with nonsteroidal anti-inflammatory drugs and muscle relaxants. We compare functional outcomes among patients randomized to a 1-week course of naproxen+placebo versus naproxen+orphenadrine or naproxen+methocarbamol. This was a randomized, double-blind, comparative effectiveness trial conducted in 2 urban EDs. Patients presenting with acute, nontraumatic, nonradicular low back pain were enrolled. The primary outcome was improvement on the Roland-Morris Disability Questionnaire (RMDQ) between ED discharge and 1 week later. All patients were given 14 tablets of naproxen 500 mg, to be used twice a day, as needed for low back pain. Additionally, patients were randomized to receive a 1-week supply of orphenadrine 100 mg, to be used twice a day as needed, methocarbamol 750 mg, to be used as 1 or 2 tablets 3 times per day as needed, or placebo. All patients received a standardized 10-minute low back pain educational session before discharge. Two hundred forty patients were randomized. Baseline demographic characteristics were comparable. The mean RMDQ score of patients randomized to naproxen+placebo improved by 10.9 points (95% confidence interval [CI] 8.9 to 12.9). The mean RMDQ score of patients randomized to naproxen+orphenadrine improved by 9.4 points (95% CI 7.4 to 11.5). The mean RMDQ score of patients randomized to naproxen+methocarbamol improved by 8.1 points (95% CI 6.1 to 10.1). None of the between-group differences surpassed our threshold for clinical significance. Adverse events were reported by 17% (95% CI 10% to 28%) of placebo patients, 9% (95% CI 4% to 19%) of orphenadrine patients, and 19% (95% CI 11% to 29%) of methocarbamol patients. Among ED patients with acute, nontraumatic, nonradicular low back pain, combining naproxen with either orphenadrine or methocarbamol did not improve functional outcomes compared with naproxen+placebo.


Primary immunodeficiency in south China: clinical features and a genetic subanalysis of 138 children.
We analyzed the clinical features of 138 patients with primary immunodeficiency (PID) and performed genetic testing on a subset of patients in order to complete gaps in research on PID in South China and thus improve pediatricians' ability to recognize and diagnose PID. We performed a retrospective analysis based on the medical records of PID patients hospitalized in our institution between May 1999 and June 2012. Gene sequencing was performed in 59 cases. Children with PID usually present with fever and repeated infections that generally affect the respiratory and digestive tracts. Growth retardation is observed in some cases. Of the 138 patients, 113 were boys, median age at onset was 5 months (range, 0-119 months), and age at diagnosis was 10 months (2-159 months). A family history of repeated infection or death of family members in infancy because of recurrent infections was recorded in 20 cases (14.49%). Antibody defects were detected in 48 cases (34.78%), combined immunodeficiency disease in 45 cases (32.61%), and other well-defined immunodeficiency syndromes in 45 cases (32.61%). Of the 59 patients from the genetic subanalysis, 24 (15.94%) had a genetic mutation (x-linked agammaglobulinemia, 8 cases; severe combined immunodeficiency, 8 cases; hyperimmunoglobulin M syndrome, 3 cases; hyperimmunoglobulin E syndrome, 3 cases; chronic granulomatous disease, 2 cases). We detected 4 novel mutations. No relevant mutations were found in the remaining 35 cases.After treatment with intravenous immunoglobulin and anti-infectious agents, 16 patients died in hospital, and 5 cases died after discontinuing treatment (mortality, 15.22%). In recent years, the number of patients with PID has risen gradually in South China. Genetic testing can confirm diagnosis. Since PID seriously affects children's quality of life, it is important to diagnose, treat, and intervene early.We hope our clinical and genetic analyses of children with PID can provide diagnostic guidance for clinicians.


The prevalence of lower urinary tract symptoms in korean men aged 40 years or older: a population-based survey.
The aim of this study was to evaluate the prevalence of lower urinary tract symptoms (LUTS) among Korean men aged ≥40 years. We performed a population-based, cross-sectional door-to-door survey on a geographically stratified random sample of men aged ≥40 years. All respondents were asked about the presence of individual LUTS using a questionnaire based on 2002 International Continence Society definitions. For comparison, we also defined nocturia as two or more nocturnal micturitions per night. The International Prostate Symptom Score (IPSS) questionnaire was used to assess LUTS severity. Responses from 1,842 subjects were analyzed. The overall prevalence of LUTS was 83.4%. Storage LUTS (70.1%) were more prevalent than voiding (60.4%) or postmicturition LUTS (38.3%). When nocturia was defined as two or more nocturnal micturitions per night, voiding symptoms became most prevalent (storage, 39.7%; voiding, 60.4%; and postmicturition, 38.3%). More than 90% of our population described the severity of their urinary symptoms as moderate (8-19) or severe (20-35). The prevalence and severity of LUTS increased with age. LUTS are highly prevalent among Korean men, and its prevalence increases with age. Increased public awareness and a larger number of treatment options are needed to appropriately manage symptoms and their consequences.


Oncolytic vesicular stomatitis virus quantitatively and qualitatively improves primary CD8+ T-cell responses to anticancer vaccines.
The ability of heterologous prime-boost vaccination to elicit robust CD8+ T cell responses has been well documented. In contrast, relatively little is known about how this immunotherapeutic strategy impacts the functional qualities of expanded T cells in the course of effector and memory responses. Using vesicular stomatitis virus (VSV) as a boosting vector in mice, we demonstrate that a massive secondary expansion of CD8+ T cells can be achieved shortly after priming with recombinant adenoviral vectors. Importantly, VSV-boosted CD8+ T cells were more potent than those primed by adenoviruses only, as measured by cytokine production, granzyme B expression, and functional avidity. Upon adoptive transfer, equivalent numbers of VSV-expanded CD8+ T cells were more effective (on a per-cell basis) in mediating antitumor and antiviral immunity than T cells only primed with adenoviruses. Furthermore, VSV boosting accelerated the progression of expanded CD8+ T lymphocytes to a central memory phenotype, thereby altering the effector memory profile typically associated with adenoviral vaccination. Finally, the functional superiority of VSV-expanded T cells remained evident 100 d after boosting, suggesting that VSV-driven immunological responses are of sufficient duration for therapeutic applications. Our data strongly support the choice of VSV as a boosting vector in prime-boost vaccination strategies, enabling a rapid amplification of CD8+ T cells and improving the quality of expanded T cells during both early and late immunological responses.


Epidemiology of urothelial carcinoma.
The epithelium lining is defined as the mucosal surfaces of the renal collecting tubules, calyces and pelvis, as well as the ureter, bladder and urethra. The term "urothelium" is used to refer to these surfaces. Upper tract urothelial carcinoma is a rare subset of urothelial cancers with a poor prognosis. Urinary bladder cancer is the most common malignancy involving the urinary system. Upper tract urothelial carcinoma is more common in men than in women, with a male-to-female ratio of 2:1. The incidence of urinary bladder cancer is also higher in men. Cigarette smoking and occupational exposure are the main upper tract urothelial carcinoma and urinary bladder cancer risk factors, while other factors are more specific to the carcinogenesis of upper tract urothelial carcinoma (i.e. Balkan endemic nephropathy, Chinese herb nephropathy). In Egypt until recent years, urinary bladder cancer was the most frequently diagnosed cancer due to Schistosoma haematobium. Substantial knowledge exists regarding the causes of upper tract urothelial carcinoma and urinary bladder cancer, and epidemiological studies have identified various chemical carcinogens that are believed to be responsible for most cases of urothelial carcinoma. In the era of precision medicine, genetic effects might play a direct role in the initiation and progression of urothelial carcinoma.


Serotonin transporter density in binge eating disorder and pathological gambling: A PET study with [11C]MADAM.
Behavioral addictions, such as pathological gambling (PG) and binge eating disorder (BED), appear to be associated with specific changes in brain dopamine and opioid function, but the role of other neurotransmitter systems is less clear. Given the crucial role of serotonin in a number of psychiatric disorders, we aimed to compare brain serotonergic function among individuals with BED, PG and healthy controls. Seven BED patients, 13 PG patients and 16 healthy controls were scanned with high-resolution positron emission tomography (PET) using the serotonin transporter (SERT) tracer [11C]MADAM. Both region-of-interest and voxel-wise whole brain analyses were performed. Patients with BED showed increased SERT binding in the parieto-occipital cortical regions compared to both PG and healthy controls, with parallel decreases in binding in the nucleus accumbens, inferior temporal gyrus and lateral orbitofrontal cortex. No differences between PG patients and controls were observed. None of the subjects were on SSRI medications at the time of imaging, and there were no differences in the level of depression between PG and BED patients. The results highlight differences in brain SERT binding between individuals with BED and PG and provide further evidence of different neurobiological underpinnings in behavioral addictions that are unrelated to the co-existing mood disorder. The results aid in the conceptualization of behavioral addictions by characterizing the underlying serotonin changes and provide a framework for additional studies to examine syndrome-specific pharmaceutical treatments.


DipM links peptidoglycan remodelling to outer membrane organization in Caulobacter.
Cell division in Gram-negative organisms requires coordinated invagination of the multilayered cell envelope such that each daughter receives an intact inner membrane, peptidoglycan (PG) layer and outer membrane (OM). Here, we identify DipM, a putative LytM endopeptidase in Caulobacter crescentus, and show that it plays a critical role in maintaining cell envelope architecture during growth and division. DipM localized to the division site in an FtsZ-dependent manner via its PG-binding LysM domains. Although not essential for viability, DeltadipM cells exhibited gross morphological defects, including cell widening and filamentation, indicating a role in cell shape maintenance and division that we show requires its LytM domain. Strikingly, cells lacking DipM also showed OM blebbing at the division site, at cell poles and along the cell body. Cryo electron tomography of sacculi isolated from cells depleted of DipM revealed marked thickening of the PG as compared to wild type, which we hypothesize leads to loss of trans-envelope contacts between components of the Tol-Pal complex. We conclude that DipM is required for normal envelope invagination during division and to maintain a sacculus of constant thickness that allows for maintenance of OM connections throughout the cell envelope.


Long-term outcomes of biological mesh repair following extra levator abdominoperineal excision of the rectum: an observational study of 100 patients.
Current evidence suggests that pelvic floor reconstruction following extralevator abdominoperineal excision of rectum (ELAPER) may reduce the risk of perineal herniation of intra-abdominal contents. Options for reconstruction include mesh and myocutaneous flaps, for which long-term follow-up data is lacking. The aim of this study was to evaluate the long-term outcomes of biological mesh (Surgisis®, Biodesign™) reconstruction following ELAPER. A retrospective review of all patients having ELAPER in a single institution between 2008 and 2018 was perfomed. Clinic letters were scrutinised for wound complications and all available cross sectional imaging was reviewed to identify evidence of perineal herniation (defined as presence of intra-abdominal content below a line between the coccyx and the lower margin of the pubic symphysis on sagittal view). One hundred patients were identified (median age 66, IQR 59-72 years, 70% male). Median length of follow-up was 4.9 years (IQR 2.3-6.7 years). One, 2- and 5-year mortality rates were 3, 8 and 12%, respectively. Thirty three perineal wounds had not healed by 1 month, but no mesh was infected and no mesh needed to be removed. Only one patient developed a symptomatic perineal hernia requiring repair. On review of imaging a further 7 asymptomatic perineal hernias were detected. At 4 years the cumulative radiologically detected perineal hernia rate was 8%. This study demonstrates that pelvic floor reconstruction using biological mesh following ELAPER is both safe and effective as a long-term solution, with low major complication rates. Symptomatic perineal herniation is rare following mesh reconstruction, but may develop sub clinically and be detectable on cross-sectional imaging.


Acyl hydrolases from trans-AT polyketide synthases target acetyl units on acyl carrier proteins.
Acyl hydrolase (AH) domains are a common feature of trans-AT PKSs. They have been hypothesised to perform a proofreading function by removing acyl chains from stalled sites. This study determines the substrate tolerance of the AH PedC for a range of acyl-ACPs. Clear preference towards short, linear acyl-ACPs is shown, with acetyl-ACP the best substrate. These results imply a more targeted housekeeping role for PedC: namely the removal of unwanted acetyl groups from ACP domains caused by erroneous transfer of acetyl-CoA, or possibly by decarboxylation of malonyl-ACP.


Trauma and humanitarian translation in Liberia: the tale of open mole.
The focus of this paper is the intercultural process through which Open Mole and trauma-related mental illnesses are brought together in the postconflict mental health encounter. In this paper, I explore the historical dimension of this process by reviewing the history of Open Mole, and the ways in which it has been interpreted, acted on, and objectified by external observers over the last half-century. Moving into Liberia's recent war and postconflict period, I examine the process by which Open Mole is transformed from a culture-bound disorder into a local idiom of trauma, and how it has become a gateway diagnosis of PTSD-related mental illnesses, and consider how it is produced as an objectified experience of psychiatric disorder in clinical humanitarian contexts. By studying how Open Mole is transformed in the humanitarian encounter, I address the structure and teleology of the humanitarian encounter and challenge some of the foundational assumptions about cultural sensitivity and community-based mental health care in postconflict settings that are prevalent in scholarship and practice today.


Neutral and Anionic Diboron Compounds Bearing Electron-Precise B-B Bond.
Electron-precise B-B bonded compounds are valuable reagents in organic syntheses, which can be used as key starting material for the synthesis of functionalized organoboranes. Bis(pinacolato)diborane(4) B2 pin2 and its derivatives are among the most studied diboron species. However, their B-B bonds usually need to be activated by transition metal catalysts or bases for further transformations. Recently, many well-designed/reactive electron-precise B-B bonded compounds have been developed, which could facilitate direct reactions with small molecules, unsaturated substrates, and electrophiles. This review highlights the synthesis, structure, and reactivity of neutral and anionic B-B bonded compounds.