Preserved scleral patch graft for unexpected extreme scleral thinning found at the scleral buckling procedure: a case report.
Pre-existing scleral pathology is an important risk factor for globe rupture during scleral buckling procedures. We report here, the surgical management of an unexpected scleral pathology found at the scleral buckling procedure in a retinal detachment patient. A 77-year-old white female with retinal detachment underwent a scleral buckling procedure. The surgery was converted into a scleral graft procedure, as extreme scleral thinning was found intraoperatively. An alcohol-preserved donor sclera graft was used. The second surgery for definitive retinal alignment was performed two weeks later. The presented case of an unexpected scleral pathology in a retinal detachment patient was managed with a combination of scleral grafting and pars plana vitrectomy, without any major complications. The anatomical outcome was excellent and the scleral rupture was prevented; the visual outcome was satisfactory. A conversion of the scleral buckling procedure into a scleral graft procedure has proved to be safe and effective for unexpected scleral pathology.


Preventing gun injuries in children.
Firearms are involved in the injury and death of a large number of children each year from both intentional and unintentional causes. Gun ownership in homes with children is common, and pediatricians should incorporate evidence-based means to discuss firearms and protect children from gun-related injuries and violence. Safe storage of guns, including unloaded guns locked and stored separately from ammunition, can decrease risks to children, and effective tools are available that pediatricians can use in clinical settings to help decrease children's access to firearms. Furthermore, several community-based interventions led by pediatricians have effectively reduced firearm-related injury risks to children. Educational programs that focus on children's behavior around guns have not proven effective.


Quantum chemistry study of uranium(VI), neptunium(V), and plutonium(IV,VI) complexes with preorganized tetradentate phenanthrolineamide ligands.
The preorganized tetradentate 2,9-diamido-1,10-phenanthroline ligand with hard-soft donors combined in the same molecule has been found to possess high selectivity toward actinides in an acidic aqueous solution. In this work, density functional theory (DFT) coupled with the quasi-relativistic small-core pseudopotential method was used to investigate the structures, bonding nature, and thermodynamic behavior of uranium(VI), neptunium(V), and plutonium(IV,VI) with phenanthrolineamides. Theoretical optimization shows that Et-Tol-DAPhen and Et-Et-DAPhen ligands are both coordinated with actinides in a tetradentate chelating mode through two N donors of the phenanthroline moiety and two O donors of the amide moieties. It is found that [AnO2L(NO3)](n+) (An = U(VI), Np(V), Pu(VI); n = 0, 1) and PuL(NO3)4 are the main 1:1 complexes. With respect to 1:2 complexes, the reaction [Pu(H2O)9](4+)(aq) + 2L(org) + 2NO3(-)(aq) → [PuL2(NO3)2](2+)(org) + 9H2O(aq) might be another probable extraction mechanism for Pu(IV). From the viewpoint of energy, the phenanthrolineamides extract actinides in the order of Pu(IV) > U(VI) > Pu(VI) > Np(V), which agrees well with the experimental results. Additionally, all of the thermodynamic reactions are more energetically favorable for the Et-Tol-DAPhen ligand than the Et-Et-DAPhen ligand, indicating that substitution of one ethyl group with one tolyl group can enhance the complexation abilities toward actinide cations (anomalous aryl strengthening).


Critical assessment of wet-chemical oxidation synthesis of silicon quantum dots.
Wet-chemical synthetic procedures are powerful strategies to afford fluorescent silicon quantum dots (Si QDs) in a versatile and scalable manner. However, development of Si QDs is still hampered by a lack of control over photoluminescence emission, in addition to synthesis and characterization complexities. The wet-chemical Si QD synthesis by oxidation of magnesium silicide (Mg2Si) with bromine (Br2) was revisited and a control reaction was carried out where the silicon source was omitted. Both reaction conditions resulted in substantial quantities of fluorescent material. Moreover, a comparative analysis of their optical properties (UV-vis/fluorescence) revealed no apparent differences. Other characterization techniques also confirmed the resemblance of the two materials as 1H NMR, FTIR and XPS spectra were nearly identical for both samples. Elemental analysis revealed the presence of only 2 wt% silicon in the Si QD sample. No evidence was found for the formation of significant amounts of Si QDs via this wet-chemical procedure.


Chromatographic analysis of olopatadine in hydrophilic interaction liquid chromatography.
In this paper, chromatographic analysis of active substance olopatadine hydrochloride, which is used in eye drops as antihistaminic agent, and its impurity E isomer by hydrophilic interaction liquid chromatography (HILIC) and application of design of experiments (DoE) methodology are presented. In addition, benzalkonium chloride is very often used as a preservative in eye drops. Therefore, the evaluation of its chromatographic behavior in HILIC was carried out as well. In order to estimate chromatographic behavior and set optimal chromatographic conditions, DoE methodology was applied. After the selection of important chromatographic factors, Box-Behnken design was utilized, and on the basis of the obtained models factor effects were examined. Then, multi-objective robust optimization is performed aiming to obtain chromatographic conditions that comply with several quality criteria simultaneously: adequate and robust separation of critical peak pair and maximum retention of the first eluting peak. The optimal conditions are identified by using grid point search methodology. The experimental verification confirmed the adequacy of the defined optimal conditions. Finally, under optimal chromatographic conditions, the method was validated and applicability of the proposed method was confirmed.


The role of topical antifungal therapy for onychomycosis and the emergence of newer agents.
Onychomycosis is a common infection of the nail unit that is usually caused by a dermatophyte (tinea unguium) and most frequently affects toenails in adults. In most cases, onychomycosis is associated with limited treatment options that are effective in achieving complete clearance in many cases. In addition, recurrence rates are high in the subset of treated patients who have been effectively cleared, usually with an oral antifungal agent. There has been a conspicuous absence of medical therapies approved in the United States since the introduction of topical ciclopirox (8% nail lacquer), with no new effective agents introduced for more than 10 years. Fortunately, newer agents and formulations have been under formal development. While patients might prefer a topical therapy, efficacy with ciclopirox 8% nail lacquer, the only available agent until the very recent approval of efinaconazole 10% solution, has been disappointing. The poor therapeutic outcomes achieved with ciclopirox 8% nail lacquer were not unexpected as the cure rates achieved in the clinical trials were unimpressive, despite concomitant nail debridement, which was an integral part of the pivotal trials with ciclopirox 8% nail lacquer. Efinaconazole 10% solution and tavaborole 5% solution are new topical antifungals specifically developed for the treatment of dermatophyte onychomycosis. In Phase 3 clinical trials, both newer agents were applied once daily for 48 weeks without concomitant nail debridement. Mycologic cure rates with efinaconazole 10% solution are markedly superior to what was achieved with ciclopirox 8% nail lacquer. To add, they appear to be nearly comparable to those achieved with oral itraconazole in pivotal clinical trials. However, it is important to remember that direct comparisons between different studies are not conclusive, are not generally considered to be scientifically sound, and may not be entirely accurate due to differences in study design and other factors. Well-designed and properly powered head-to-head studies are needed in order to draw definitive conclusions about efficacy comparisons between therapies, at least based on academic and regulatory standards. Although tavaborole 5% solution is in an earlier phase of development for onychomycosis, treatment success rates reported thus far for both efinaconazole 10% solution and tavaborole 5% solution are superior to ciclopirox 8% nail lacquer. As a result, a new era of onychomycosis appears to be upon us that incorporates topical therapy more effectively than in the past. Not only may these newer topical agents provide viable monotherapy alternatives to oral therapy for onychomycosis, topical therapy for onychomycosis that is effective, well tolerated, and easy to use may also find a role in combination therapy, and/or as continued therapy after initial clearance to reduce recurrence or re-infection.


Fundamental insights into interfacial catalysis.
Surface and interfacial catalysis plays a vital role in chemical industries, electrochemistry and photochemical reactions. The challenges of modern chemistry are to optimize the chemical reaction processes and understand the detailed mechanism of chemical reactions. Since the early 1960s, the foundation of surface science systems has allowed the study of surface and interfacial phenomena on atomic/molecular level, and thus brought a number of significant developments to fundamental and technological processes, such as catalysis, material science and biochemistry, just to name a few. This themed issue describes the recent advances and developments in the fundamental understanding of surface and interfacial catalysis, encompassing areas of knowledge from metal to metal oxide, carbide, graphene, hexagonal boron nitride, and transition metal dichalcogenides under ultrahigh vacuum conditions, as well as under realistic reaction conditions.


The Influence of 24-hr Sleep Deprivation on Psychomotor Vigilance in Young Women and Men.
The number of studies on gender differences in psychomotor performance and sleepiness is small and the results are contradictory. The aim of this study was to assess the changes in psychomotor performance, due to 24 h of sleep deprivation in young women and men. Eighty-nine students (49 women and 40 men) took part in the study. Participants were randomized into two groups: experimental (sleep deprived) and control (non-sleep deprived). The research was carried out using computer-based tests of the Vienna Test System (COG, DT, WAFF) and pupillography (F2D Fit-For-Duty). There were no statistically significant effects of the main genders and groups on sleepiness measured by the pupillography. There was no deterioration in the results after deprivation among women and men in the COG test. Changes were noted in the DT and WAFF tests, and their size depended on the test. The number of false responses in psychomotor test was higher in women after sleep deprivation. One night of sleep deprivation may not have been a negative enough stimulus for young, healthy women and men to reveal gender differences in psychomotor tests. Low sleep levels can lead to low productivity at work and accidents due to reduced vigilance. Insufficient sleep in the long term can lead to poor health, resulting in hypertension, obesity and depression.


Extreme temperatures, foundation species, and abrupt ecosystem change: an example from an iconic seagrass ecosystem.
Extreme climatic events can trigger abrupt and often lasting change in ecosystems via the reduction or elimination of foundation (i.e., habitat-forming) species. However, while the frequency/intensity of extreme events is predicted to increase under climate change, the impact of these events on many foundation species and the ecosystems they support remains poorly understood. Here, we use the iconic seagrass meadows of Shark Bay, Western Australia--a relatively pristine subtropical embayment whose dominant, canopy-forming seagrass, Amphibolis antarctica, is a temperate species growing near its low-latitude range limit--as a model system to investigate the impacts of extreme temperatures on ecosystems supported by thermally sensitive foundation species in a changing climate. Following an unprecedented marine heat wave in late summer 2010/11, A. antarctica experienced catastrophic (>90%) dieback in several regions of Shark Bay. Animal-borne video footage taken from the perspective of resident, seagrass-associated megafauna (sea turtles) revealed severe habitat degradation after the event compared with a decade earlier. This reduction in habitat quality corresponded with a decline in the health status of largely herbivorous green turtles (Chelonia mydas) in the 2 years following the heat wave, providing evidence of long-term, community-level impacts of the event. Based on these findings, and similar examples from diverse ecosystems, we argue that a generalized framework for assessing the vulnerability of ecosystems to abrupt change associated with the loss of foundation species is needed to accurately predict ecosystem trajectories in a changing climate. This includes seagrass meadows, which have received relatively little attention in this context. Novel research and monitoring methods, such as the analysis of habitat and environmental data from animal-borne video and data-logging systems, can make an important contribution to this framework.


Dermatoses of pregnancy.
The dermatoses of pregnancy represent a heterogeneous group of pruritic inflammatory skin diseases related to pregnancy and/or the postpartum period. Whereas some dermatoses are distressing only to the mother because of severe pruritus, others are associated with fetal risks including fetal distress, prematurity, and stillbirth. Early diagnosis and prompt treatment are essential for improving maternal and fetal prognosis. This review discusses the various pregnancy dermatoses in detail and offers an algorithmic approach to their diagnosis and management.


Medical care of adults with mental retardation.
Persons with mental retardation are living longer and integrating into their communities. Primary medical care of persons with mental retardation should involve continuity of care, maintenance of comprehensive treatment documentation, routine periodic health screening, and an understanding of the unique medical and behavioral disorders common to this population. Office visits can be successful if physicians familiarize patients with the office and staff, plan for difficult behaviors, and administer mild sedation when appropriate. Some syndromes that cause mental retardation have specific medical and behavioral features. Health issues in these patients include respiratory problems, gastrointestinal disorders, challenging behaviors, and neurologic conditions. Some commonly overlooked health concerns are sexuality, sexually transmitted diseases, and end-of-life decisions.


Clinical and genetic significance of unilateral Lisch nodules.
Bilateral Lisch nodules are highly characteristic for neurofibromatosis type 1 (NF1). We wished to study the clinical and genetic implications of unilateral Lisch nodules. Retrospective study of the clinical data of 59 patients who received genetic counselling for neurofibromatosis type 1 (NF1) or type 2 (NF2) and were examined at the department of ophthalmology. Unilateral Lisch nodules were observed in 4 cases: one child with NF1 initially presented unilateral Lisch nodules but developed bilateral Lisch nodules by the age of 9. In 2 cases segmental NF1 was the most probable diagnosis and in one case isolated Lisch nodules were observed. Of the 35 NF1 patients 28 ultimately developed bilateral Lisch nodules. Seven NF1 patients did not demonstrate the nodules. At follow-up no Lisch nodules were detected in 2 neurofibromatosis type 2 patients, in 4 patients in whom the diagnosis of NF1 remained doubtful and in 15 patients without NF1. Because isolated Lisch nodules are very rare, their presence warrants a thorough patient history and clinical examination to either confirm or exclude generalised or segmental neurofibromatosis type 1.


Observation of direct photons in central 158A GeV (208)P(208)b+Pb collisions
A measurement of direct photon production in 208Pb+208Pb collisions at 158A GeV has been carried out in the CERN WA98 experiment. The invariant yield of direct photons in central collisions is extracted as a function of transverse momentum in the interval 0.5<p(T)<4 GeV/c. A significant direct photon signal, compared to statistical and systematical errors, is seen at p(T)>1.5 GeV/c. The result constitutes the first observation of direct photons in ultrarelativistic heavy-ion collisions. It could be significant for diagnosis of quark-gluon-plasma formation.


Different lipid variables predict incident coronary artery disease in patients with type 1 diabetes with or without diabetic nephropathy: the FinnDiane study.
To study the ability of lipid variables to predict incident coronary artery disease (CAD) events in patients with type 1 diabetes at different stages of nephropathy. Patients (n = 3,520) with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were included in the study. During a follow-up period of 10.2 years (8.6-12.0), 310 patients suffered an incident CAD event. Apolipoprotein B (ApoB)/ApoA-I ratio was the strongest predictor of CAD in normoalbuminuric patients (hazard ratio 1.43 [95% CI 1.17-1.76] per one SD increase), and ApoB was the strongest in macroalbuminuric patients (1.47 [1.19-1.81]). Similar results were seen when patients were stratified by sex or glycemic control. LDL cholesterol was a poor predictor of CAD in women, normoalbuminuric patients, and patients with HbA1c below the median (8.3%, 67 mmol/L). The current recommended triglyceride cutoff of 1.7 mmol/L failed to predict CAD in normoalbuminuric patients, whereas the cohort median 0.94 mmol/L predicted incident CAD events. In patients with type 1 diabetes, the predictive ability of the lipid variables differed substantially depending on the patient's sex, renal status, and glycemic control. In normoalbuminuric patients, the ratios of atherogenic and antiatherogenic lipoproteins and lipids were the strongest predictors of an incident CAD event, whereas in macroalbuminuric patients, no added benefit was gained from the ratios. Current treatment recommendations may need to be revised to capture residual CAD risk in patients with type 1 diabetes.


IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer.
Interleukin-27 signaling is mediated by the JAK-STAT pathway via activation of STAT1 and STAT3, which have tumor suppressive and oncogenic activities, respectively. Epithelial-mesenchymal transition (EMT) and angiogenesis are key processes in carcinogenesis. Although IL-27 has been shown to have potent anti-tumor activity in various cancer models, the role of IL-27 in EMT and angiogenesis is poorly understood. In this study, we investigated the role of IL-27 in regulating EMT and angiogenesis through modulation of the STAT pathways in human non-small cell lung carcinoma (NSCLC) cells. STAT activation following IL-27 exposure was measured in human NSCLC cell lines. Expression of epithelial (E-cadherin, γ-catenin) and mesenchymal (N-cadherin, vimentin) markers were assessed by Western blot analysis. Production of pro-angiogenic factors (VEGF, IL-8/CXCL8, CXCL5) were examined by ELISA. Cell motility was examined by an in vitro scratch and transwell migration assays. Selective inhibitors of STAT1 (STAT1 siRNAs) and STAT3 (Stattic) were used to determine whether both STAT1 and STAT3 are required for IL-27 mediated inhibition of EMT and secretion of angiogenic factors. Our results demonstrate that IL-27 stimulation in NSCLC resulted in 1) STAT1 and STAT3 activation in a JAK-dependent manner, 2) development of epithelial phenotypes, including a decrease in the expression of a transcriptional repressor for E-cadherin (SNAIL), and mesenchymal marker (vimentin) with a reciprocal increase in the expression of epithelial markers, 3) inhibition of cell migration, and 4) reduced production of pro-angiogenic factors. STAT1 inhibition in IL-27-treated cells reversed the IL-27 effect with resultant increased expression of Snail, vimentin and the pro-angiogenic factors. The inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. IL-27 induces mesenchymal to epithelial transition and inhibits the production of pro-angiogenic factors in a STAT1-dominant pathway. These findings highlight the importance of STAT1 in repressing lung carcinogenesis and describe a new anti-tumor mechanism of IL-27.


High plasma concentration of factor VIII coagulant is also a risk factor for venous thromboembolism in the elderly.
A high level of coagulant factor VIII is a well known risk factor for venous thromboembolism, but most studies have enrolled patients under 70 years old. This study aimed to test the hypothesis that an association also exists in the elderly. This hospital-based case-referent study took place at the Department of Internal Medicine and Chest Diseases, University Hospital, Brest, France. We enrolled 161 patients with a first episode of venous thrombosis and 239 subjects, referred for a clinical suspicion of venous thromboembolism which was subsequently ruled out. Factor VIII coagulant activity and plasma fibrinogen concentration were measured. High factor VIII coagulant activity was significantly associated with venous thromboembolism, irrespective of the age group. Patients over 70 years with factor VIII coagulant activity above 225% had a 2.4-fold increased risk of venous thromboembolism compared to those patients with levels below 130% (age- and fibrinogen-adjusted odds ratio: 2.6, 95% CI 1.1 to 6.1). Our results show that high levels of factor VIII coagulant, a determinant of venous thrombosis in adulthood, is also a risk factor in the elderly.


HDAC3 as a molecular chaperone for shuttling phosphorylated TR2 to PML: a novel deacetylase activity-independent function of HDAC3.
TR2 is an orphan nuclear receptor specifically expressed in early embryos (Wei and Hsu, 1994), and a transcription factor for transcriptional regulation of important genes in stem cells including the gate keeper Oct4 (Park et al. 2007). TR2 is known to function as an activator (Wei et al. 2000), or a repressor (Chinpaisal et al., 1998, Gupta et al. 2007). Due to the lack of specific ligands, mechanisms triggering its activator or repressor function have remained puzzling for decades. Recently, we found that all-trans retinoic acid (atRA) triggers the activation of extracellular-signal-regulated kinase 2 (ERK2), which phosphorylates TR2 and stimulates its partitioning to promyelocytic leukemia (PML) nuclear bodies, thereby converting the activator function of TR2 into repression (Gupta et al. 2008; Park et al. 2007). Recruitment of TR2 to PML is a crucial step in the conversion of TR2 from an activator to a repressor. However, it is unclear how phosphorylated TR2 is recruited to PML, an essential step in converting TR2 from an activator to a repressor. In the present study, we use both in vitro and in vivo systems to address the problem of recruiting TR2 to PML nuclear bodies. First, we identify histone deacetylase 3 (HDAC3) as an effector molecule. HDAC3 is known to interact with TR2 (Franco et al. 2001) and this interaction is enhanced by the atRA-stimulated phosphorylation of TR2 at Thr-210 (Gupta et al. 2008). Secondly, in this study, we also find that the carrier function of HDAC3 is independent of its deacetylase activity. Thirdly, we find another novel activity of atRA that stimulates nuclear enrichment of HDAC3 to form nuclear complex with PML, which is ERK2 independent. This is the first report identifying a deacetylase-independent function for HDAC3, which serves as a specific carrier molecule that targets a specifically phosphorylated protein to PML NBs. This is also the first study delineating how protein recruitment to PML nuclear bodies occurs, which can be stimulated by atRA in an ERK2-independent manner. These findings could provide new insights into the development of potential therapeutics and in understanding how orphan nuclear receptor activities can be regulated without ligands.


Structural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing.
Structural variants (SVs), accounting for a larger fraction of the genome than SNPs/InDels, are an important pool of genetic variation, enabling environmental adaptations. Here, we perform long-read sequencing data of 320 Tibetan and Han samples and show that SVs are highly involved in high-altitude adaptation. We expand the landscape of global SVs, apply robust models of selection and population differentiation combining SVs, SNPs and InDels, and use epigenomic analyses to predict enhancers, target genes and biological functions. We reveal diverse Tibetan-specific SVs affecting the regulatory circuitry of biological functions, including the hypoxia response, energy metabolism and pulmonary function. We find a Tibetan-specific deletion disrupts a super-enhancer and downregulates EPAS1 using enhancer reporter, cellular knock-out and DNA pull-down assays. Our study expands the global SV landscape, reveals the role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles of SVs in human biology.


Digital pathology: A systematic evaluation of the patent landscape.
Digital pathology is a relatively new field. Inventors of technology in this field typically file for patents to protect their intellectual property. An understanding of the patent landscape is crucial for companies wishing to secure patent protection and market dominance for their products. To our knowledge, there has been no prior systematic review of patents related to digital pathology. Therefore, the aim of this study was to systematically identify and evaluate United States patents and patent applications related to digital pathology. Issued patents and patent applications related to digital pathology published in the United States Patent and Trademark Office (USPTO) database (www.uspto.gov) (through January 2014) were searched using the Google Patents search engine (Google Inc., Mountain View, California, USA). Keywords and phrases related to digital pathology, whole-slide imaging (WSI), image analysis, and telepathology were used to query the USPTO database. Data were downloaded and analyzed using the Papers application (Mekentosj BV, Aalsmeer, Netherlands). A total of 588 United States patents that pertain to digital pathology were identified. In addition, 228 patent applications were identified, including 155 that were pending, 65 abandoned, and eight rejected. Of the 588 patents granted, 348 (59.18%) were specific to pathology, while 240 (40.82%) included more general patents also usable outside of pathology. There were 70 (21.12%) patents specific to pathology and 57 (23.75%) more general patents that had expired. Over 120 unique entities (individual inventors, academic institutions, and private companies) applied for pathology specific patents. Patents dealt largely with telepathology and image analysis. WSI related patents addressed image acquisition (scanning and focus), quality (z-stacks), management (storage, retrieval, and transmission of WSI files), and viewing (graphical user interface (GUI), workflow, slide navigation and remote control). An increasing number of recent patents focused on computer-aided diagnosis (CAD) and digital consultation networks. In the last 2 decades, there have been an increasing number of patents granted and patent applications filed related to digital pathology. The number of these patents quadrupled during the last decade, and this trend is predicted to intensify based on the number of patent applications already published by the USPTO.


Do anticoagulants improve survival in patients presenting with venous thromboembolism?
Anticoagulants have been available since around 1940 and have become the standard of treatment for venous thromboembolism (VTE) for over four decades. However, as with other treatments which became established before the evidence-based era, there is a paucity of evidence from randomized controlled trials validating their effectiveness in preventing the most feared complication of VTE, recurrent fatal pulmonary embolism (PE). Only two such trials have been performed, the results of which conflict. The bulk of data supporting their use are derived from three sources. First, studies of thromboprophylaxis, and comparisons of shorter and longer courses of anticoagulants in high-risk patients with established VTE have clearly demonstrated their effectiveness in primary and late secondary prevention. Given that heparin has an immediate onset of action, anticoagulants should therefore also be effective in early secondary prevention, the proposed mechanism of action in the acute treatment of VTE. Secondly, studies of inadequately treated patients have consistently shown higher recurrence rates than in those adequately treated. Finally, comparisons of outcomes in untreated and treated historical series, and of untreated historical series to treated series in the modern era have shown substantially lower rates of fatal PE in anticoagulated patients. Because these differences are so marked, harmonize with our current understanding of the mechanism of action of anticoagulants and are supported by other evidence, it is much more likely that they at least partly reflect the effectiveness of anticoagulants as opposed to being explicable purely in terms of accumulated biases and a changing distribution of disease severity.


Cost-effectiveness of 13-valent pneumococcal conjugate vaccine: Germany, Greece, and The Netherlands.
Seven-valent pneumococcal conjugate vaccine (PCV7) had profound public-health impacts and is considered cost-effective and potentially cost saving. Two new PCVs have been launched, a 10-valent vaccine (PCV10) and a 13-valent vaccine (PCV13). We examined public-health and economic impacts of PCV pediatric national immunization programs (NIPs) in Germany, Greece, and the Netherlands. A decision-analytic model was developed to estimate the impact of PCV13, PCV7, and 10-valent pneumococcal conjugate vaccine (PCV10) on invasive pneumococcal disease (IPD), pneumonia (PNE), and acute otitis media (AOM). Using epidemiological data, we calculated the cases of IPD, PNE, and AOM, using country-specific incidence, serotype coverage, disease sequelae, mortality, vaccine effectiveness, indirect effects, costs, and utilities. Direct effects for PCV13- and PCV10-covered serotypes were assumed similar to PCV7. PCV13 was assumed to confer an indirect effect, while PCV10 was not. Assumptions were tested in sensitivity analyses. In a NIP, PCV13 was estimated to eliminate 31.7%, 46.4%, and 33.8% of IPD in Germany, Greece, and the Netherlands, respectively. Compared with PCV7 and PCV10, PCV13 was found to be cost-effective or cost saving in all cases when PCV13 indirect effects were included. Pediatric NIPs with PCV13 in Europe are expected to have dramatic public-health impacts and be cost-effective or cost saving.


The evaluation of minimal residual disease in multiple myeloma by fluorescent molecular beacons in real time PCR of IgH gene rearrangements and correlation with flow cytometry.
Multiple myeloma (MM) patients relapse after a period of time despite longer disease-free survival due to novel treatment options. In this study we aimed to assess the value of real-time polymerase chain reaction (RT-PCR) for detecting the immunoglobulin heavy chain (IgH) gene rearrangement using allele-specific molecular beacons as fluorescence probes to quantify minimal residual disease (MRD) and also to correlate post-treatment flow cytometric detection of plasma cells' (PCs) expression of CD19, CD38, CD45, CD56 and CD138 in MM. After diagnosis of 17 MM patients, the CDR1, CDR2 and CDR3 regions of the IgH gene were analysed and sequenced to identify IgH's clonal nature. Unique sequences of the clonal IgH rearrangement were used to design specific molecular beacon probes for each MM patient. Examined were also the co-expression of CD19, CD38, CD45, CD56, and CD138 molecules in bone marrow aspirates of patients with MM by flow cytometry. Detection of MRD was positive in 13 (76%) of 17 patients by RT-PCR. The infiltration ratio was significantly correlated with CD138 expression (p=0.009). Significant correlation was also found between RT-PCR detection of MRD and CD138 expression (p=0.006). Nevertheless, no correlation was observed among other surface antigens (CD38, CD45, CD56). Our results indicated that RT-PCR with specific molecular beacons provide a feasible, accurate and reproducible method for the determination of MRD in MM. Flow cytometry detection of CD138 expression may be used as a disease marker in addition to RT-PCR.


Bilayer structure and lipid dynamics in a model stratum corneum with oleic acid.
The stratum corneum is the uppermost layer of the skin and acts as a barrier to keep out contaminants and retain moisture. Understanding the molecular structure and behavior of this layer will provide guidance for optimizing its biological function. In this study we use a model mixture comprised of equimolar portions of ceramide NS (24:0), lignoceric acid, and cholesterol to model the effect of the addition of small amounts of oleic acid to the bilayer at 300 and 340 K. Five systems at each temperature have been simulated with concentrations between 0 and 0.1 mol % oleic acid. Our major finding is that subdiffusive behavior over the 200 ns time scale is evident in systems at 340 K, with cholesterol diffusion being enhanced with increased oleic acid. Importantly, cholesterol and other species diffuse faster when radial densities indicate nearest neighbors include more cholesterol. We also find that, with the addition of oleic acid, the bilayer midplane and interfacial densities are reduced and there is a 3% decrease in total thickness occurring mostly near the hydrophilic interface at 300 K with reduced overall density at 340 K. Increased interdigitation occurs independent of oleic acid with a temperature increase. Slight ordering of the long non-hydroxy fatty acid of the ceramide occurs near the hydrophilic interface as a function of the oleic acid concentration, but no significant impact on hydrogen bonding is seen in the chosen oleic acid concentrations.


The problem of complementary and alternative medicine use today: eyes half closed?
Commentators such as Goldacre, Dawkins, and Singh and Ernst are worried that the rise in complementary and alternative medicine (CAM) represents a flight from science propagated by enemies of reason. We outline what kind of problem CAM use is for these commentators, and find that users of CAM have been constituted as duped, ignorant, irrational, or immoral in explaining CAM use. However, this form of problematization can be described as a flight from social science. We explore CAM use in light of a rigorous and robust social scientific body of knowledge about how individuals engage with CAM. By pointing to the push and pull factors, CAM user's experiences of their body, and the problem of patient choice in CAM use, we summarize some of the key findings made by social scientists and show how they trouble many of the reasoned assumptions about CAM use.


Primary aortoduodenal fistula: a case report and review of the literature.
The case of a 22-year-old female with spontanteous aortoduodenal fistula is presented, and a group of 185 other cases from the world literature are analyzed. Three additional cases were identified which did not appear to have an underlying pathologic process involving the aorta. Successful surgical correction depends upon a high index of suspicion. In the majority of patients the "herald bleed" allows a period for aggressive investigation. The "herald bleed" is usually rapid, painless, of large volume, and may present as hematochezia. Normal barium studies and endoscopy should heighten suspicion in patients with gastrointestinal hemorrhage. Arteriography may define the case of bleeding and may also delineate the nature and extent of the vascular disease. If the aortic wall is of sufficient quality, direct oversewing has the advantage of avoiding the use of a foreign body in a potentially infected field. In the vast majority of patients a vascular prosthesis is required. Consideration should be given to subcutaneous extraanatomic reconstruction.


[The use of immobilized enzymes for the synthesis of nucleosides and nucleotides including the ones labeled with radioactive isotopes].
Nucleoside phosphorylases from E. coli immobilized in polyacrylamide gel were used for production of nucleosides from nitrous bases during the transglucosylase reaction. Phosphorylation of nucleosides resulted in the formation of 5'-nucleotides was performed in the presence of carrot nucleoside phosphotransferase immobilized in polyacrylamide gel. Using 14C-labelled nitrous bases as starting substrates, labelled nucleosides and nucleotides can be obtained with the 75-80% yield that have radioactive purity of 95-99%. The stability of the immobilized enzymes was being studied under the conditions of the reactions using them in the batch and plug flow reactors.


Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial.
Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. Our aim was thus to test the hypothesis that protocol-guided individualised nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk. The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicentre study. We recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥3 points) and with an expected length of hospital stay of more than 4 days from eight Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualised nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomisation was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualised nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 h after admission. Patients in the control group received no dietary consultation. The composite primary endpoint was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomised patients who completed the trial. This trial is registered with ClinicalTrials.gov, number NCT02517476. 5015 patients were screened, and 2088 were recruited and monitored between April 1, 2014, and Feb 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [OR] 0·79 [95% CI 0·64-0·97], p=0·023). By day 30, 73 [7%] patients had died in the intervention group compared with 100 [10%] patients in the control group (adjusted OR 0·65 [0·47-0·91], p=0·011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs 145 [14%], adjusted OR 1·16 [0·90-1·51], p=0·26). In medical inpatients at nutritional risk, the use of individualised nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualised nutritional support in patients at risk. The Swiss National Science Foundation and the Research Council of the Kantonsspital Aarau, Switzerland.


Reading men's faces: women's mate attractiveness judgments track men's testosterone and interest in infants.
This study investigated whether women track possible cues of paternal and genetic quality in men's faces and then map perception of those cues onto mate attractiveness judgments. Men's testosterone concentrations served as a proxy for genetic quality given evidence that this hormone signals immunocompetence, and men's scores on an interest in infants test were chosen as prima facie markers of paternal quality. Women's perceptions of facial photographs of these men were in fact sensitive to these two variables: men's scores on the interest in infants test significantly predicted women's ratings of the photos for how much the men like children, and men's testosterone concentrations significantly predicted women's ratings of the men's faces for masculinity. Furthermore, men's actual and perceived affinity for children predicted women's long-term mate attractiveness judgments, while men's testosterone and perceived masculinity predicted women's short-term mate attractiveness judgments. These results suggest that women can detect facial cues of men's hormone concentrations and affinity for children, and that women use perception of these cues to form mate attractiveness judgments.


Dental materials: 1996 literature review. Part 2.
This critical review of the published literature on dental materials for the year 1996 has been compiled by the Dental Materials Panel of the UK. It continues the series of annual reviews started in 1973 and published in the Journal of Dentistry. Emphasis has been placed upon publications which report upon the materials science or clinical performance of the materials. The review has been divided by accepted materials classifications (fissure sealants, glass polyalkenoate cements, dentine bonding, dental amalgam, endodontic materials, casting alloys, resin-bonded bridges and ceramo-metallic restorations, ceramics, denture base resins and soft lining materials, impression materials, implants materials, orthodontic materials, biomechanics and image processing, resin composites and casting investment materials and waxes). Three hundred and thirteen articles have been reviewed.


Comparison of lower body strength, power, acceleration, speed, agility, and sprint momentum to describe and compare playing rank among professional rugby league players.
Success in rugby league football seems heavily reliant on players possessing an adequate degree of various physical fitness qualities, such as strength, power, speed, agility, and endurance, as well as the individual skills and team tactical abilities. The purpose of this study was to describe and compare the lower body strength, power, acceleration, maximal speed, agility, and sprint momentum of elite first-division national rugby league (NRL) players (n = 20) to second-division state league (SRL) players (n = 20) players from the same club. Strength and maximal power were the best discriminators of which players were in the NRL or SRL squads. None of the sprinting tests, such as acceleration (10-m sprint), maximal speed (40-m sprint), or a unique 40-m agility test, could distinguish between the NRL or SRL squads. However, sprint momentum, which was a product of 10-m velocity and body mass, was better for discriminating between NRL and SRL players as heavier, faster players would possess better drive forward and conversely be better able to repel their opponents' drive forward. Strength and conditioning specialists should therefore pay particular attention to increasing lower body strength and power and total body mass through appropriate resistance training while maintaining or improving 10-m sprint speed to provide their players with the underlying performance characteristics of play at the elite level in rugby leagues.


Event-based contact angle measurements inside porous media using time-resolved micro-computed tomography.
Capillary-dominated multiphase flow in porous materials is strongly affected by the pore walls' wettability. Recent micro-computed tomography (mCT) studies found unexpectedly wide contact angle distributions measured on static fluid distributions inside the pores. We hypothesize that analysis on time-resolved mCT data of fluid invasion events may be more directly relevant to the fluid dynamics. We approximated receding contact angles locally in time and space on time-resolved mCT datasets of drainage in a glass bead pack and a limestone. Whenever a meniscus suddenly entered one or more pores, geometric and thermodynamically consistent contact angles in the surrounding pores were measured in the time step just prior to the displacement event. We introduced a new force-based contact angle, defined to recover the measured capillary pressure in the invaded pore throat prior to interface movement. Unlike the classical method, the new geometric and force-based contact angles followed plausible, narrower distributions and were mutually consistent. We were unable to obtain credible results with the thermodynamically consistent method, likely because of sensitivity to common imaging artifacts and neglecting dissipation. Time-resolved mCT analysis can yield a more appropriate wettability characterization for pore scale models, despite the need to further reduce image analysis uncertainties.


[Paternity in the perspective of a group of fathers].
Looking upon occidental silence which involves the paternity, we performed this research with the intention to conceive some associated aspects: the family role, birth of son expectation and father social role. For that, 7 fathers have been interviewed with ages between 21 and 45 years. This study allowed us observed that the paternity of the interviewed fathers is experienced by the father-son relationship preoccupation, kids education and the constant search of ways to experience the paternity as a form to be near of the kids and the wife.


Conditional genealogies and the age of a neutral mutant.
This paper is concerned with the structure of the genealogy of a sample in which it is observed that some subset of chromosomes carries a particular mutation, assumed to have arisen uniquely in the history of the population. A rigorous theoretical study of this conditional genealogy is given using coalescent methods. Particular results include the mean, variance, and density of the age of the mutation conditional on its frequency in the sample. Most of the development relates to populations of constant size, but we discuss the extension to populations which have grown exponentially to their present size.


Pharmacotherapy of Mood Disorders in Epilepsy: The Role of Newer Psychotropic Drugs.
Depression in patients with epilepsy (PWE) is a relatively common comorbidity that has a significant negative impact on their quality of life. Therefore, recognition and management of a comorbid depressive disorder is paramount to achieve successful comprehensive treatment in PWE. Depression in epilepsy may mimic primary depressive disorders, but in a significant percentage of depressed PWE, the clinical semiology has an atypical presentation and fails to meed any of the diagnostic criteria established in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Despite the relatively high prevalence of depression in epilepsy and its frequent atypical presentation, there has been only one controlled study (in 1979) to establish the safety and efficacy of antidepressant drugs in PWE. Accordingly, clinicians must rely on data from studies of pharmacotherapy of primary depression. These data are adequate to guide the clinician in the basic principles of pharmacotherapy of depression in PWE. Many questions are yet to be answered, including: 1) are the expectations of symptom remission to pharmacotherapy in PWE different in typical and atypical forms of depression, and do they differ from those of patients with primary depression? and 2) are the doses of antidepressant drugs necessary to yield symptom remission different between PWE and those patients with primary mood disorders?


Effects of xenon and hypothermia on cerebrovascular pressure reactivity in newborn global hypoxic-ischemic pig model.
Autoregulation of cerebral perfusion is impaired in hypoxic-ischemic encephalopathy. We investigated whether cerebrovascular pressure reactivity (PRx), an element of cerebral autoregulation that is calculated as a moving correlation coefficient between averages of intracranial and mean arterial blood pressure (MABP) with values between -1 and +1, is impaired during and after a hypoxic-ischemic insult (HI) in newborn pigs. Associations between end-tidal CO2, seizures, neuropathology, and PRx were investigated. The effect of hypothermia (HT) and Xenon (Xe) on PRx was studied. Pigs were randomized to Sham, and after HI to normothermia (NT), HT, Xe or xenon hypothermia (XeHT). We defined PRx >0.2 as peak and negative PRx as preserved. Neuropathology scores after 72 hours of survival was grouped as 'severe' or 'mild.' Secondary PRx peak during recovery, predictive of severe neuropathology and associated with insult severity (P=0.05), was delayed in HT (11.5 hours) than in NT (6.5 hours) groups. Seizures were associated with impaired PRx in NT pigs (P=0.0002), but not in the HT/XeHT pigs. PRx was preserved during normocapnia and impaired during hypocapnia. Xenon abolished the secondary PRx peak, increased (mean (95% confidence interval (CI)) MABP (6.5 (3.8, 9.4) mm Hg) and cerebral perfusion pressure (5.9 (2.9, 8.9) mm Hg) and preserved the PRx (regression coefficient, -0.098 (95% CI (-0.18, -0.01)), independent of the insult severity.


Using TRIM5α as an HIV therapeutic: the alpha gene?
As HIV continues to spread worldwide, new therapies which have the potential to treat and cure infected patients need to be developed. The results observed with the "Berlin patient" who received a bone marrow transplant with HIV-resistant hematopoietic stem cells highlight the potential of HIV gene therapy to be used as an alternative treatment. With the discovery of TRIM5α, an HIV inhibitor and species-specific restriction factor, a new molecule can be evaluated as an HIV gene therapeutic. Nonhuman primate TRIM5α orthologs restrict HIV infection, whereas human TRIM5α does not. However, upon genetic modification, variations to human TRIM5α have been made which are capable of potent HIV restriction. This review seeks to cover the discovery and biology of various HIV-restrictive nonhuman primate TRIM5α orthologs, modifications made to human TRIM5α to enable HIV restriction, and the use of these molecules in an HIV gene therapy setting. Engineered human TRIM5α molecules, demonstrated to be strong inhibitors of HIV infection, have the potential of being used as new HIV therapeutics in human gene therapy clinical trials. By combining TRIM5α with other highly potent anti-HIV molecules, the generation of an HIV-resistant immune system and potential cure for infected patients may be accomplished.


Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures.
Perioperative fluid strategies influence clinical outcomes following major surgery. Many intravenous fluid preparations are based on simple solutions, such as normal saline, that feature an electrolyte composition that differs from that of physiological plasma. Buffered fluids have a theoretical advantage of containing a substrate that acts to maintain the body's acid-base status - typically a bicarbonate or a bicarbonate precursor such as maleate, gluconate, lactate, or acetate. Buffered fluids also provide additional electrolytes, including potassium, magnesium, and calcium, more closely matching the electrolyte balance of plasma. The putative benefits of buffered fluids have been compared with those of non-buffered fluids in the context of clinical studies conducted during the perioperative period. This review was published in 2012, and was updated in 2017. To review effects of perioperative intravenous administration of buffered versus non-buffered fluids for plasma volume expansion or maintenance, or both, on clinical outcomes in adults undergoing all types of surgery. We electronically searched the Clinicaltrials.gov major trials registry, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6) in the Cochrane Library, MEDLINE (1966 to June 2016), Embase (1980 to June 2016), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2016). We handsearched conference abstracts and, when possible, contacted leaders in the field. We reran the search in May 2017. We added one potential new study of interest to the list of 'Studies awaiting classification' and will incorporate this trial into formal review findings when we prepare the review update. Only randomized controlled trials that compared buffered versus non-buffered intravenous fluids for surgical patients were eligible for inclusion. We excluded other forms of comparison such as crystalloids versus colloids and colloids versus different colloids. Two review authors screened references for eligibility, extracted data, and assessed risks of bias. We resolved disagreements by discussion and consensus, in collaboration with a third review author. We contacted trial authors to request additional information when appropriate. We presented pooled estimates for dichotomous outcomes as odds ratios (ORs) and for continuous outcomes as mean differences (MDs), with 95% confidence intervals (CIs). We analysed data via Review Manager 5.3 using fixed-effect models, and when heterogeneity was high (I² > 40%), we used random-effects models. This review includes, in total, 19 publications of 18 randomized controlled trials with a total of 1096 participants. We incorporated five of those 19 studies (330 participants) after the June 2016 update. Outcome measures in the included studies were thematically similar, covering perioperative electrolyte status, renal function, and acid-base status; however, we found significant clinical and statistical heterogeneity among the included studies. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Trial authors variably reported outcome data at disparate time points and with heterogeneous patient groups. Consequently, many outcome measures are reported in small group sizes, reducing overall confidence in effect size, despite relatively low inherent bias in the included studies. Several studies reported orphan outcome measures. We did not include in the results of this review one large, ongoing study of saline versus Ringer's solution.We found insufficient evidence on effects of fluid therapies on mortality and postoperative organ dysfunction (defined as renal insufficiency leading to renal replacement therapy); confidence intervals were wide and included both clinically relevant benefit and harm: mortality (Peto OR 1.85, 95% CI 0.37 to 9.33; I² = 0%; 3 trials, 6 deaths, 276 participants; low-quality evidence); renal insufficiency (OR 0.82, 95% CI 0.34 to 1.98; I² = 0%; 4 trials, 22 events, 276 participants; low-quality evidence).We noted several metabolic differences, including a difference in postoperative pH measured at end of surgery of 0.05 units - lower in the non-buffered fluid group (12 studies with a total of 720 participants; 95% CI 0.04 to 0.07; I² = 61%). However, this difference was not maintained on postoperative day one. We rated the quality of evidence for this outcome as moderate. We observed a higher postoperative serum chloride level immediately after operation, with use of non-buffered fluids reported in 10 studies with a total of 530 participants (MD 6.77 mmol/L, 95% CI 3.38 to 10.17), and this difference persisted until day one postoperatively (five studies with a total of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). We rated the quality of evidence for this outcome as moderate. Current evidence is insufficient to show effects of perioperative administration of buffered versus non-buffered crystalloid fluids on mortality and organ system function in adult patients following surgery. Benefits of buffered fluid were measurable in biochemical terms, particularly a significant reduction in postoperative hyperchloraemia and metabolic acidosis. Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Larger studies are needed to assess these relevant clinical outcomes.


Prevalence of MED12 mutations in uterine and extrauterine smooth muscle tumours.
To determine the prevalence of MED12 mutations in smooth muscle tumours of different organs. A total of 142 smooth muscle tumours of the uterus, gastrointestinal tract, retroperitoneum and soft tissue were analysed for MED12 mutations using Sanger sequencing. Among the uterine tumours that were examined, MED12 mutations were identified in 36 of 45 conventional leiomyomas (80%), two of six cellular leiomyomas (33%), one of four bizarre leiomyomas (25%), none of four lipoleiomyomas (0%), and two of 12 leiomyosarcomas (17%). The two MED12-mutated leiomyosarcomas were associated with benign leiomyomatous components that also harboured MED12 mutations identical to those in the respective leiomyosarcomatous components. None of the extrauterine smooth muscle tumours, including the leiomyomas, leiomyosarcomas, and angioleiomyomas, had MED12 mutations. Among uterine smooth muscle tumours, MED12 mutations are frequently present in conventional leiomyomas, but are significantly less common in histological variants of leiomyoma and leiomyosarcoma. In contrast to uterine lesions, none of the extrauterine smooth muscle tumours had MED12 mutations.


Developmental dyslexia and explicit long-term memory.
The reduced verbal long-term memory capacities often reported in dyslexics are generally interpreted as a consequence of their deficit in phonological coding.The present study was aimed at evaluating whether the learning deficit exhibited by dyslexics was restricted only to the verbal component of the long-term memory abilities or also involved visual-object and visual-spatial domain. A further goal of the present study was to investigate the predictive value of non-verbal long-term memory abilities with respect to word and non-word reading in dyslexic children.In accordance with these aims, performances of 60 dyslexic children were compared with that of 65 age-matched normal readers on verbal, visual-spatial and visual-object task.Results documented a generalized impairment of episodic long-term memory capacities in dyslexic children and the results did not vary as a function of children's age.Furthermore, in addition to verbal measures, also individual differences in non-verbal long-term memory tasks turn out to be good predictors of reading difficulties in dyslexics.Our findings indicate that the long-term memory deficit in dyslexia is not limited to the dysfunction of phonological components but also involves visual-object and visual-spatial aspect, thus suggesting that dyslexia is associated to multiple cognitive deficits.


[Lipid risk factors of atherosclerosis: who, when, how to treat?].
Hyperlipidemia, particularly hypercholesterolemia, is a well established risk factor for cardiovascular disease, specially coronary heart disease. Lipid-lowering therapies are associated with a reduction in cardiovascular morbidity and mortality in secondary as well as primary prevention. A precise lipid pattern is necessary before any treatment. The target level depends on the clinical data and associated cardiovascular risk factors. Diet is the first step approach and should always be continued. Cholestyramine and statins are the treatments of choice in case of hypercholesterolemia (type IIa). In case of isolated or associated hypertriglyceridemia (types IV and IIb) fibrates are the most efficient. No treatment is really efficient on Lp(a) level. A good observance is required for a lifelong treatment.


Oxidation of pristanic acid in fibroblasts and its application to the diagnosis of peroxisomal beta-oxidation defects.
Pristanic acid oxidation measurements proved a reliable tool for assessing complementation in fused heterokaryons from patients with peroxisomal biogenesis defects. We, therefore, used this method to determine the complementation groups of patients with isolated defects in peroxisomal beta-oxidation. The rate of oxidation of pristanic acid was reduced in affected cell lines from all of the families with inherited defects in peroxisomal beta-oxidation, thus excluding the possibility of a defective acyl CoA oxidase. Complementation analyses indicated that all of the patients belonged to the same complementation group, which corresponded to cell lines with bifunctional protein defects. Phytanic acid oxidation was reduced in fibroblasts from some, but not all, of the patients. Plasma samples were still available from six of the patients. The ratio of pristanic acid to phytanic acid was elevated in all of these samples, as were the levels of saturated very long chain fatty acids (VLCFA). However, the levels of bile acid intermediates, polyenoic VLCFA, and docosahexaenoic acid were abnormal in only some of the samples. Pristanic acid oxidation measurements were helpful in a prenatal assessment for one of the families where previous experience had shown that cellular VLCFA levels were not consistently elevated in affected individuals.


Determination of fat- and water-soluble vitamins by supercritical fluid chromatography: A review.
Vitamins are compounds that take part in all basic functions of an organism but also are subject of number of studies performed by different researchers. Two groups of vitamins are distinguished taking into consideration their solubility. Chromatography with supercritical CO2 has found application in the determination, separation, and quantitative analyses of both fat- and water-soluble vitamins. The methods of vitamins separation have developed and improved throughout the years. Both groups of compounds were separated using supercritical fluid chromatography with different detection on different stationary phases. The main aim of this review is to provide an overview of the studies of vitamins separation that have been determined so far.


Gene expression analysis suggests bone development-related genes GDF5 and DIO2 are involved in the development of Kashin-Beck disease in children rather than adults.
To investigate the differences in gene expression between children and adults with Kashin-Beck disease (KBD). 12 children with KBD and 12 healthy children were selected and divided into 4 KBD vs. control pairs matched according to age and gender, with each pair having 3 KBD children and 3 healthy children. Additionally, 15 adults with KBD and 15 healthy adults were selected and divided into 5 KBD vs. control pairs matched according to age and gender, with each pair having 3 KBD adults and 3 healthy adults. Total RNA was isolated from peripheral blood mononuclear cells (PBMCs) respectively. A total of 367 target genes were selected based on previous genome-wide gene expression profile analysis. Expression levels of the 367 genes were evaluated by customized oligonucleotide microarray and the differentially expressed genes were identified. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was conducted to validate the microarray data. A total of 95 (25.9%) genes in KBD children and 158 (43.1%) genes in KBD adults were found to exhibit more than two-fold change in gene expression level relative to healthy controls. By comparing differentially expressed genes identified in KBD children to those of KBD adults, 42 genes were found to be differentially expressed only in KBD children. And 105 genes were found to be differentially expressed only in KBD adults. Further, 16 differentially expressed genes common to both KBD children and adults were found to be asynchronously expressed in KBD children compared to KBD adults. Significant differences in gene expression pattern were identified between KBD children and KBD adults, indicating different molecular mechanisms underlying cartilage lesions of KBD children and KBD adults. In addition, bone development-related genes GDF5 (expression ratio = 2.14±0.02) and DIO2 (expression ratio = 0.11±0.05) may contribute to the development of KBD in children rather than in adults.


Morphology and life history of Petasiger variospinosus (trematoda: echinostomatidae) in the Free State, South Africa.
Specimens of the freshwater snail Bulinus tropicus (Krauss, 1848) collected in the Free State, South Africa shed cercariae with an oral collar bearing 27 spines. Tadpoles of the African clawed toad Xenopus laevis laevis Daudin, 1802 collected from the same waters harbored metacercariae with a similar collar of spines. Adults were obtained after feeding infected tadpoles to laboratory-reared reed cormorants, Phalacrocorax africanus (Gmelin, 1789). The parasite was identified as Petasiger variospinosus (Odhner, 1910), the life cycle was experimentally completed, and stages described by the use of light and scanning electron microscopy.


Generation of deletions and precise point mutations in Dictyostelium discoideum using the CRISPR nickase.
The CRISPR/Cas9 system enables targeted genome modifications across a range of eukaryotes. Although we have reported that transient introduction of all-in-one vectors that express both Cas9 and sgRNAs can efficiently induce multiple gene knockouts in Dictyostelium discoideum, concerns remain about off-target effects and false-positive amplification during mutation detection via PCR. To minimise these effects, we modified the system to permit gene deletions of greater than 1 kb via use of paired sgRNAs and Cas9 nickase. An all-in-one vector expressing the Cas9 nickase and sgRNAs was transiently introduced into D. discoideum, and the resulting mutants showed long deletions with a relatively high efficiency of 10-30%. By further improving the vector, a new dual sgRNA expression vector was also constructed to allow simultaneous insertion of two sgRNAs via one-step cloning. By applying this system, precise point mutations and genomic deletions were generated in the target locus via simultaneous introduction of the vector and a single-stranded oligonucleotide template without integrating a drug resistance cassette. These systems enable simple and straightforward genome editing that requires high specificity, and they can serve as an alternative to the conventional homologous recombination-based gene disruption method in D. discoideum.


Methods Used to Control the Reproductive Choices of Women Who Are Sex Trafficked: Considerations for Health Care Providers.
Reproductive control or reproductive coercion has negative health consequences but has not been systematically studied within the context of sex trafficking. Our goal is to identify the range of methods used by sex traffickers and buyers to control the reproductive choices of trafficked women and to provide specific examples of these methods. We searched PubMed, Embase, and PsycInfo using the terms "reproductive control" or "reproductive coercion" and "human trafficking" or "sex trafficking," including papers that contained original, specific examples of reproductive control occurring within the context of sex trafficking. These reports were described and categorized into established domains of reproductive control. Eight articles were located that met our inclusion criteria, of which 6 described outcomes of birth control sabotage, 2 described pressuring into pregnancy, 5 described controlling the outcome of a pregnancy, and 2 described forced birth control or sterilization. Our findings have implications for how to take sexual histories and for identifying and assisting trafficked persons.


Coypu insulin. Primary structure, conformation and biological properties of a hystricomorph rodent insulin.
Insulin from a hystricomorph rodent, coypu (Myocaster coypus), was isolated and purified to near homogeneity. Like the other insulins that have been characterized in this Suborder of Rodentia, coypu insulin also exhibits a very low (3%) biological potency, relative to pig insulin, on lipogenesis in isolated rat fat-cells. The receptor-binding affinity is significantly higher (5-8%) in rat fat-cells, in rat liver plasma membranes and in pig liver cells, indicating that the efficacy of coypu insulin on receptors is about 2-fold lower than that of pig insulin. The primary structures of the oxidized A- and B-chains were determined, and our sequence analysis confirms a previous report [Smith (1972) Diabetes 21, Suppl. 2, 457-460] that the C-terminus of the A-chain is extended by a single residue (i.e. aspartate-A22), in contrast with most other insulin sequences, which terminate at residue A21. In spite of a large number of amino acid substitutions (relative to mammalian insulins), computer-graphics model-building studies suggest a similar spatial arrangement for coypu insulin to that for pig insulin. The substitution of the zinc-co-ordinating site (B10-His----Gln) along with various substitutions on the intermolecular surfaces involved in the formation of higher aggregates are consistent with the observation that this insulin is predominantly 'monomeric' in nature. The c.d. spectrum of coypu insulin is relatively similar to those of casiragua insulin and of bovine insulin at low concentration.


A novel sequential sampling technique for the surveillance of transmitted HIV drug resistance by cross-sectional survey for use in low resource settings.
This article describes the development of a novel sequential sampling method for the surveillance of transmitted HIV drug resistance by cross-sectional survey. Two commonly used sequential sampling methods are described and their applicability to the problem of classifying the prevalence of transmitted HIV drug resistance investigated. Both methods are rejected due to insufficient savings in sample size and operational complexity. A novel method is proposed and this is tested using computer-based simulation. This method provides useful sample size savings and operational simplicity and could provide the basis for a rapid and reliable survey method for classifying the prevalence of transmitted HIV drug resistance in circumstances where monitoring HIV drug resistance is an important issue, but resources do not allow fullscale surveillance to be established. The method is currently being used in several such settings.


Evaluation of drug physical form during granulation, tabletting and storage.
An active pharmaceutical ingredient (API) was found to dissociate from the highly crystalline hydrochloride form to the amorphous free base form, with consequent alterations to tablet properties. Here, a wet granulation manufacturing process has been investigated using in situ Fourier transform (FT)-Raman spectroscopic analyses of granules and tablets prepared with different granulating fluids and under different manufacturing conditions. Dosage form stability under a range of storage stresses was also investigated. Despite the spectral similarities between the two drug forms, low levels of API dissociation could be quantified in the tablets; the technique allowed discrimination of around 4% of the API content as the amorphous free base (i.e. less than 1% of the tablet compression weight). API dissociation was shown to be promoted by extended exposure to moisture. Aqueous granulating fluids and manufacturing delays between granulation and drying stages and storage of the tablets in open conditions at 40 degrees C/75% relative humidity (RH) led to dissociation. In contrast, non-aqueous granulating fluids, with no delay in processing and storage of the tablets in either sealed containers or at lower temperature/humidity prevented detectable dissociation. It is concluded that appropriate manufacturing process and storage conditions for the finished product involved minimising exposure to moisture of the API. Analysis of the drug using FT-Raman spectroscopy allowed rapid optimisation of the process whilst offering quantitative molecular information concerning the dissociation of the drug salt to the amorphous free base form.


Subglottic secretion drainage for ventilator-associated pneumonia prevention: an underused efficient measure.
Subglottic secretion drainage (SSD) is one of the recommended strategies to prevent ventilator-associated pneumonia (VAP) with a high level of evidence, especially regarding early-onset pneumonia. All meta-analysis found that the use of SSD reduces VAP occurrence with a relative risk (RR) reduction of 45%. In some of them, SSD reduces the duration of mechanical ventilation (MV) but without beneficial effect on intensive care unit (ICU) or hospital mortality. In spite of the edited recommendations, SSD has not been widely implemented in ICUs and remains underused. Several factors could account for this: doubts on the innocuousness of using SSD, persisting reservations on the SSD effect on other outcomes than VAP, a high variability in the volume of secretions suctioned between patients and, for each individual patient, during the period of MV and the initial increased expense of the specific endotracheal tubes (ETs) allowing SSD which limits the availability of these devices.


Risk mapping for COVID-19 outbreaks in Australia using mobility data.
COVID-19 is highly transmissible and containing outbreaks requires a rapid and effective response. Because infection may be spread by people who are pre-symptomatic or asymptomatic, substantial undetected transmission is likely to occur before clinical cases are diagnosed. Thus, when outbreaks occur there is a need to anticipate which populations and locations are at heightened risk of exposure. In this work, we evaluate the utility of aggregate human mobility data for estimating the geographical distribution of transmission risk. We present a simple procedure for producing spatial transmission risk assessments from near-real-time population mobility data. We validate our estimates against three well-documented COVID-19 outbreaks in Australia. Two of these were well-defined transmission clusters and one was a community transmission scenario. Our results indicate that mobility data can be a good predictor of geographical patterns of exposure risk from transmission centres, particularly in outbreaks involving workplaces or other environments associated with habitual travel patterns. For community transmission scenarios, our results demonstrate that mobility data add the most value to risk predictions when case counts are low and spatially clustered. Our method could assist health systems in the allocation of testing resources, and potentially guide the implementation of geographically targeted restrictions on movement and social interaction.


Structure and regulation of a nuclear gene in Saccharomyces cerevisiae that specifies MRP7, a protein of the large subunit of the mitochondrial ribosome.
The gene for MRP7, a 40-kilodalton protein of the large subunit of the yeast mitochondrial ribosome, was identified in a lambda gt11 expression library by immunological screening with a monoclonal antibody to MRP7. An intact copy of MRP7 was then isolated from a yeast genomic library by colony hybridization. Gene disruption showed that MRP7 protein was essential for ribosomal function. Sequencing of MRP7 revealed a coding region for a basic (pI 10.6), 43.2-kilodalton protein containing 371 amino acid residues. Amino acid residues 28 to 112 of the deduced MRP7 sequence aligned with the 84 residues of the Escherichia coli ribosomal protein L27, but no significant similarity was detected between the carboxy-terminal 259 amino acids of MRP7 and other protein sequences in existing computer data bases. Within the aligned region, there was 49% amino acid identity between MRP7 and L27, compared with the 57% identity observed between L27 and its homolog in Bacillus stearothermophilus. The steady-state levels of the MRP7 protein and its mRNA were monitored in response to catabolite repression and to increased dosage of the MRP7 gene. The response to catabolite repression was characterized by a ninefold change in the level of the protein and little, if any, change in the level of the mRNA. In cells carrying the MRP7 gene on a high-copy-number plasmid, the mRNA was increased 20-fold, but there was no significant increase in MRP7 protein. Furthermore, MRP7 mRNA and protein accumulated at normal levels in [rho0] cells, which are devoid of 21S rRNA, indicating that the protein is relatively stable in the absence of ribosome assembly. Together, these results suggest that MRP7 is regulated posttranscriptionally, probably at the level of protein synthesis rather than protein turnover.


Intracranial relapse rates and patterns, and survival trends following post-resection cavity radiosurgery for patients with single intracranial metastases.
The objective of this study is to evaluate the patterns of relapse and survival trends in patients with single brain metastases treated with post-operative adjuvant Gamma knife stereotactic radiosurgery (GKS) without whole brain radiotherapy (WBRT). Retrospective analysis of all consecutive patients who underwent GKS to the tumor cavity following resection of solitary brain metastasis was performed at a single institution. Between March 2001 and June 2010, 56 patients underwent GKS to the resection cavity following resection of intracranial metastases; no patient received pre- or post-operative WBRT as an adjuvant (salvage WBRT was permissible). The mean marginal dose was 17.1 Gy (range 14-20 Gy). The mean follow-up period was 24 months (range 3-99 months). Five patients (8.9%) had local recurrence in the immediate vicinity of the resection cavity, qualifying as "local failures", and 21 (37.5%) recurred at distant intracranial sites. Median intracranial recurrence free survival was 13 months. Median overall survival was 20.5 months. Salvage interventions were required in 26 patients, and included repeat radiosurgery in 17 patients, further surgery in two patients, and salvage WBRT in eight (14.3%; two of whom had also been locally salvaged with repeat radiosurgery) patients. As expected, avoidance of WBRT results in a high rate of intracranial failure (26/56 patients, 46%), even in well-selected patients with only single brain metastases. As anticipated, the majority of failures (21, 37.5%) are "distant intracranial", and in this well-selected cohort the local failure rate is low (5/56 patients, <9%). All patients failing intracranially (46%) are potential candidates for salvage therapies, but WBRT as salvage was utilized in only 14.3% of patients. The median intracranial relapse-free was 13 months and overall survival was 20.5 months.


Benzimidazole derivatives: new enhancers of influenza virus multiplication.
The enhancing activity of 5-methyl-2-D-ribobenzimidazole on influenza B (Lee) virus yield in chorioallantoic membranes from 10-day old embryonated eggs was compared with that of eight other polyhydroxyalkyl-benzimidazoles. No marked differences in activity were noted with the following six derivatives: 5,6-dimethyl-2-D-ribo; 2-D-gluco; 5-methyl-2-D-gluco; 5,6-dimethyl-2-D-gluco; 5-methyl-2-D-galacto; and 5-methyl-2-L-rhamno. None caused morphological damage to the membranes at a concentration of 3.5 mM. The solubility of the 5-methyl-2-D-arabo and 5-methyl-2-D-manno derivatives was too low to permit quantitative comparisons, but both were active and nontoxic at a concentration of 1.75 mM. 5-Hydroxy-1-methylbenzimidazole and 5-methoxy-1-methylbenzimidazole are more active than 5-methyl-2-D-ribobenzimidazole both with respect to specific activity and maximal enhancement at the highest tolerated dose. The hydroxyl substituent is superior to the methoxyl grouping. Substitution at position 5 is superior to substitution at position 6 with respect to the tolerated dose level and therefore the maximal effect obtainable, but the 6-hydroxy-1-methyl derivative showed the highest specific activity. 5-Methoxy-1-methylbenzimidazole increases the yield to a comparable extent as measured by infectivity and hemagglutination titrations. The responses of membranes from individual chicken embryos to the enhancing action of 5-methoxy-1-methylbenzimidazole and 5-methyl-2-D-ribobenzimidazole are similar. 5-Methoxy-1-methylbenzimidazole restores the capacity of membranes from older chicken embryos to produce a large amount of virus after a small inoculum. This derivative increases the yield of virus in membranes treated before infection only. Maximal enhancement is obtained with prolonged treatment, starting before, and continuing after infection. 5-Methoxy-1-methyl-benzimidazole increases the yield of virus from COFAL-negative embryos in which the control yield is very low. Combined treatment with moderate doses of 5-methoxy-1-methylbenzimidazole and 5-methyl-2-D-ribobenzimidazole gives an additive effect.


Prolactin desensitizes the prostaglandin E1-dependent adenylyl cyclase in the rat prostate gland.
Prior exposure of the rat ventral prostate to a high dose of ovine prolactin in vivo or in vitro caused the specific desensitization of the prostaglandin E1-dependent adenylyl cyclase. Maximal desensitization was achieved in vivo 6 h after exposure to 100 micrograms prolactin and complete resensitization occurred after 7 days. No heterologous desensitization of the response of the cyclase to other hormones tested was observed. Incubation of isolated secretory cells with prolactin and prostaglandin E1 desensitized the subsequent response to the same prostaglandin. Simultaneous exposure of the cells to indomethacin prevented the prolactin-induced effect. Prolactin could also induce similar changes in the prostaglandin E1-dependent cyclase of rat Leydig cell tumour cells in vivo, suggesting that this may represent a phenomenon shared by other prolactin target organs. This study supports the hypothesis that prostaglandins may constitute second messengers for prolactin effects on the prostate gland.


Thermal effects in stretching of Go-like models of titin and secondary structures.
The effect of temperature on mechanical unfolding of proteins is studied using a Go-like model with a realistic contact map and Lennard-Jones contact interactions. The behavior of the I27 domain of titin and its serial repeats is contrasted to that of simple secondary structures. In all cases, thermal fluctuations accelerate the unraveling process, decreasing the unfolding force nearly linearly at low temperatures. However, differences in bonding geometry lead to different sensitivity to temperature and different changes in the unfolding pattern. Due to its special native-state geometry, titin is much more thermally and elastically stable than the secondary structures. At low temperatures, serial repeats of titin show a parallel unfolding of all domains to an intermediate state, followed by serial unfolding of the domains. At high temperatures, all domains unfold simultaneously, and the unfolding distance decreases monotonically with the contact order, that is, the sequence distance between the amino acids that form the native contact.


[Validation of the French version of the Snaith-Hamilton Pleasure Scale (SHAPS, Snaith et al. 1995). Determination of the statistical parameters in 208 normal subjects and 103 hospitalized patients presenting with depression or schizophrenia].
The aim of the study is to explore the validity and the reliability of the French version of the SHAPS in two groups of subjects. 208 healthy students and 103 inpatients meeting the RDC criteria for schizophrenia or depression filled out the French versions of the SHAPS and the revised Physical Anhedonia Scale of Chapman and Chapman. The internal consistency of the SHAPS was measured in each group using first the Kuder Richardson coefficient (point biserial) between the items and the total score. The concurrent validity was studied using the Pearson correlation coefficient between the SHAPS and the PAS in each group. The predictive validity was determined by the comparison of the SHAPS score between the two groups. The reliability was studied using a test-retest in a sub-group (n = 32) extracted of the control group. The values of the KR 20 in the healthy and psychiatric groups were respectively 0.47 and 0.80. The mean of the correlations between the items and the total score were respectively 0.35 and 0.52. The values of the correlations between the SHAPS and the PAS were respectively in the normal and psychiatric groups 0.39 (p < 0.001) and 0.34 (p < 0.001). Psychiatric subjects had a higher score (m = 2.33, sd = 2.68) on the SHAPS than the normals (m = 0.89, sd = 1.18) [F (1,303) = 12.26, p = 0.0005]. The test-retest showed a correlation of 0.56 (p < 0.01) between the two passations of the SHAPS. The metrological parameters of the SHAPS were discussed as well as the utility of that scale compared to the PAS.


Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect.
Epidermal growth factor receptor (EGFR) and protein kinase A type I(PKAI) play an important role in the control of cancer cell growth and angiogenesis. Inhibitors of EGFR and PKAI have antitumor activity in vitro and in vivo in a variety of tumor types, and some of these agents are active after oral administration. Increasing evidence shows that cyclooxygenase (COX)-2 also plays a role in promoting cancer cell proliferation and angiogenesis. COX-2 expression can be induced by EGFR activation and is regulated by cAMP and PKA. Combination of an EGFR inhibitor with a nonselective COX-1/COX-2 inhibitor prevents the development of intestinal cancer in nude mice. Therefore, we investigated whether any cooperative antitumor effect can be obtained by the combined blockade of COX-2, EGFR, and PKAI. The COX-2 inhibitor SC-236 was combined with the selective EGFR tyrosine kinase inhibitor ZD1839 (Iressa) and the DNA/RNA-mixed backbone oligonucleotide AS-PKAI to study their effect on human cancer growth and angiogenesis, measuring vascular endothelial growth factor (VEGF) and basic fibroblast growth factor expression and vessel formation, in vitro and after oral administration of these agents in mice. A cooperative effect was observed with SC-236 in combination with either ZD1839 or AS-PKAI, as well as with all three agents together, on the proliferation of human colon and breast cancer cells in soft agar at doses that were ineffective for each agent alone. The antiproliferative effect was accompanied by inhibition of COX-2 expression. Moreover, combination of SC-236 with either agent or the triple combination markedly reduced VEGF secretion in the conditioned medium and completely suppressed VEGF and basic fibroblast growth factor expression. In nude mice bearing human colon cancer xenografts, a low, noninhibitory dose of SC-236 with ZD1839 and AS-PKAI, all given p.o., caused a dramatic cooperative antitumor effect, with no histological evidence of tumor in 60% of mice 5 weeks after treatment withdrawal, at which time all mice were alive. Moreover, analysis of tumor specimens revealed inhibition of vessel formation and expression of COX-2 and VEGF. This is the first demonstration that three novel agents blocking multiple signaling pathways, in absence of cytotoxic drugs, may have a potent antitumor and antiangiogenic activity after oral administration. Because all agents are under clinical evaluation, our results provide a rationale to translate this feasible therapeutic strategy into a clinical setting.


Survival model analysis of tuberculosis treatment among patients with human immunodeficiency virus coinfection.
Tuberculosis (TB) with human immunodeficiency virus (HIV) coinfection is the highest clinical epidemiology and public health issue. Despite many programs established to tackle the epidemic, TB target controls have not been reached. One of the many factors attributed to the failure in TB treatment is HIV coinfection. The aim of this study is to assess the survival rate of HIV infection among TB patients and the risk factors of death among the TB patients with HIV coinfection during the retro of directly observed treatment, short-course (DOTS) program. This study is a retrospective cohort conducted to compare the survivorship between TB/HIV patients for 8 months DOTS. Death among TB patients was considered as failures and those defaulted or survived were censored. The Cox proportional-hazards regression and log-linear model were used to establish the hazard ratio (HR) of death for each variable at baseline and estimate the risk factors effect among TB patients. The findings revealed that 50% of death from TB/HIV patients were from HIV coinfection (advanced HR = 2.01, 95% confidence interval = 1.13-3.17). The risk of death was significantly higher in HIV-positive TB patients (P = 0.000) during the extension care phase. TB/HIV-positive patients on antiretroviral therapy have decreased survival rate (log-rank test = 14.88, df = 2, P = 0.0001). The probability of TB patients surviving is significantly decreased in HIV positive with some factors such as age, weight, smoking, and alcohol found significant. The probability of survival in HIV-positive TB patients was significantly lower during the TB treatment. Weight loss, age, alcohol, smoking, and pregnancy were showed to affect the survival probability of TB/HIV patients' coinfection significantly.


Association Between Dietary Fiber Intake and Bone Loss in the Framingham Offspring Study.
Dietary fiber may increase calcium absorption, but its role in bone mineralization is unclear. Furthermore, the health effect of dietary fiber may be different between sexes. We examined the association between dietary fiber (total fiber and fiber from cereal, fruits, vegetables, nuts, and legumes) and bone loss at the femoral neck, trochanter, and lumbar spine (L2 to L4 ) in older men and women. In the Framingham Offspring Study, at baseline (1996-2001), diet was assessed using the Willett food-frequency questionnaire, and bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Follow-up BMD was measured in 2001-2005 and 2005-2008 among 792 men (mean age 58.1 years; BMI 28.6 kg/m2 ) and 1065 women (mean age 57.3 years; BMI 27.2 kg/m2 ). We used sex-specific generalized estimating equations in multivariable regressions to estimate the difference (β) of annualized BMD change in percent (%ΔBMD) at each skeletal site per 5 g/d increase in dietary fiber. We further estimated the adjusted mean for bone loss (annualized %ΔBMD) among participants in each higher quartile (Q2, Q3, or Q4) compared with those in the lowest quartile (Q1) of fiber intake. Higher dietary total fiber (β = 0.06, p = 0.003) and fruit fiber (β = 0.10, p = 0.008) was protective against bone loss at the femoral neck in men but not in women. When examined in quartiles, men in Q2-Q4 of total fiber had significantly less bone loss at the femoral neck versus those in Q1 (all p < 0.04). For women, we did not observe associations with hip bone loss, although fiber from vegetables appeared to be protective against spine bone loss in women but not men. There were no associations with cereal fiber or nut and legume fiber and bone loss in men or women. Our findings suggest that higher dietary fiber may modestly reduce bone loss in men at the hip. © 2017 American Society for Bone and Mineral Research.


Bleeding risk of surgery and its prevention in patients with inherited platelet disorders.
Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence.


A Practical Guide to Modeling and Conducting a Cost-Effectiveness Analysis of Companion Biomarker Tests for Targeted Therapies Using R: Tutorial Paper.
Despite the increasing number of potential biomarkers identified in laboratories and reported in much literature, the adoption of biomarkers routinely available in clinical practice to inform treatment decisions is very limited. Reimbursement decisions for new health technologies are often informed by economic evaluations; however, economic evaluations of diagnostics/testing technologies, such as companion biomarker tests, are far less frequently reported than drugs. Furthermore, few countries provide the health economic evaluation methods guide specific to co-dependent technologies such as companion diagnostics or precision medicines. Therefore, this paper aims to guide the process of the development of cost-effectiveness models of cancer biomarkers for targeted therapies, focusing on companion diagnostics. This tutorial paper provides practical guidance on how to conduct economic evaluations of cancer biomarkers and how to model the characteristics of the biomarker tests as part of the value for money of corresponding targeted therapies. This paper presents a brief introduction to the methods and data requirements, a step-by-step guide to constructing a health economic model of companion cancer biomarkers, and a discussion of issues that arise in their application to healthcare decision making. This practical guidance is provided in R, and worked examples are provided in this paper with R codes in the accompanying electronic supplementary material.