Targeting dendritic cells in pancreatic ductal adenocarcinoma.
Dendritic cells (DC) are an integral part of the tumor microenvironment. Pancreatic cancer is characterized by reduced number and function of DCs, which impacts antigen presentation and contributes to immune tolerance. Recent data suggest that exosomes can mediate communication between pancreatic cancer cells and DCs. Furthermore, levels of DCs may serve as prognostic factors. There is also growing evidence for the effectiveness of vaccination with DCs pulsed with tumor antigens to initiate adaptive cytolytic immune responses via T cells. Most experience with DC-based vaccination has been gathered for MUC1 and WT1 antigens, where clinical studies in advanced pancreatic cancer have provided encouraging results. In this review, we highlight the role of DC in the course, prognosis and treatment of pancreatic cancer.


Baseline/post-nitrate Tc-99m tetrofosmin mismatch for the assessment of myocardial viability in patients with severe left ventricular dysfunction: comparison with baseline Tc-99m tetrofosmin scintigraphy/FDG PET imaging.
Positron emission tomography (PET) flow/metabolic mismatch is considered the nuclear medicine gold standard for the assessment of myocardial viability. The aim of this study was to investigate whether baseline/nitrate technetium 99m tetrofosmin single photon emission computed tomography (SPECT) mismatch may provide equivalent clinical information. We studied 23 patients (aged 62 +/- 10 years, 19 men) with previous myocardial infarction (16 anterior, 4 inferior, and 3 anterior plus inferior) and postischemic heart failure (gated SPECT [G-SPECT] ejection fraction, 26% +/- 8%). All patients underwent Tc-99m tetrofosmin G-SPECT at rest and after nitrates (intravenous isosorbide dinitrate, 0.2 mg/mL, 10 mL/h) as well as a fluorine 18 fluoro-2-deoxy-d-glucose (FDG) PET scan. Regional wall motion analysis was performed with quantitative G-SPECT (QGS). Myocardial dysfunction was defined as a regional QGS score of 2 or greater. Regional perfusion was assessed by quantitative perfusion score (QPS) providing percent Tc-99m tetrofosmin uptake in a 20-segment model. Semiquantitative analysis of FDG uptake was performed by use of polar maps generated by Siemens ECAT HR + software. In areas with a perfusion rate lower than 80%, PET viability was identified by a normalized FDG percent uptake/baseline Tc-99m tetrofosmin percent uptake ratio greater than 1.2. We analyzed 460 segments; 298 (64%) were dysfunctional by QGS analysis. Of these, 170 were viable by PET imaging whereas 128 were nonviable. Regional Tc-99m tetrofosmin uptake was higher in viable than in nonviable segments both at rest (60% +/- 24% vs 42% +/- 12%, P <.01) and after nitrates (67% +/- 20% vs 41% +/- 18%, P <.01). According to receiver operating characteristic curve analysis, a cutoff value of 63% for resting as well as post-nitrate G-SPECT provided the highest diagnostic accuracy for the detection of myocardial viability (67% and 72% at rest and after nitrates, respectively). When the same algorithm used for the comparison with PET (normalized nitrate percent uptake/baseline percent uptake) was applied to G-SPECT, we obtained the highest agreement with PET (accuracy, 93%; sensitivity, 95%; specificity, 92%). In patients with severe left ventricular dysfunction, perfusion data alone, both at rest and after nitrates, do not allow an accurate estimate of myocardial viability. In dysfunctioning segments, the analysis of rest/post-nitrate Tc-99m tetrofosmin mismatch provides results similar to those obtained by PET flow/metabolic mismatch.


Interaction of Thiol Antioxidants with α,β-Unsaturated Ketone Moiety: Its Implication for Stability and Bioactivity of Curcuminoids.
Many biological functions of curcumin have been reported. As certain bioactivities of curcumin are eliminated by antioxidants, reactive oxygen species generated by curcumin have been suggested as a relevant mechanism. In the present study, the effects of different types of antioxidants on the stability and bioactivities of curcumin were analyzed. High concentrations (>4 mM) of thiol antioxidants, including N-acetylcysteine (NAC), glutathione (GSH), and β-mercaptoethanol, accelerated the decomposition of curcumin and other curcuminoids; the submillimolar levels (<0.5 mM) of GSH and NAC rather improved their stability. Ascorbic acid or superoxide dismutase also stabilized curcumin, regardless of their concentration. The cellular levels and bioactivities of curcumin, including its cytotoxicity and the induction of heme oxygenase-1, were significantly reduced in the presence of 8 mM of GSH and NAC. The effects were enhanced in the presence of submillilmolar GSH and NAC, or non-thiol antioxidants. The present results indicate that antioxidants with a reduced thiol group could directly interact with the α,β-unsaturated carbonyl moiety of curcuminoids and modulate their stability and bioactivity.


Clinical outcome of preimplantation genetic diagnosis and screening using next generation sequencing.
Next generation sequencing (NGS) is now being used for detecting chromosomal abnormalities in blastocyst trophectoderm (TE) cells from in vitro fertilized embryos. However, few data are available regarding the clinical outcome, which provides vital reference for further application of the methodology. Here, we present a clinical evaluation of NGS-based preimplantation genetic diagnosis/screening (PGD/PGS) compared with single nucleotide polymorphism (SNP) array-based PGD/PGS as a control. A total of 395 couples participated. They were carriers of either translocation or inversion mutations, or were patients with recurrent miscarriage and/or advanced maternal age. A total of 1,512 blastocysts were biopsied on D5 after fertilization, with 1,058 blastocysts set aside for SNP array testing and 454 blastocysts for NGS testing. In the NGS cycles group, the implantation, clinical pregnancy and miscarriage rates were 52.6% (60/114), 61.3% (49/80) and 14.3% (7/49), respectively. In the SNP array cycles group, the implantation, clinical pregnancy and miscarriage rates were 47.6% (139/292), 56.7% (115/203) and 14.8% (17/115), respectively. The outcome measures of both the NGS and SNP array cycles were the same with insignificant differences. There were 150 blastocysts that underwent both NGS and SNP array analysis, of which seven blastocysts were found with inconsistent signals. All other signals obtained from NGS analysis were confirmed to be accurate by validation with qPCR. The relative copy number of mitochondrial DNA (mtDNA) for each blastocyst that underwent NGS testing was evaluated, and a significant difference was found between the copy number of mtDNA for the euploid and the chromosomally abnormal blastocysts. So far, out of 42 ongoing pregnancies, 24 babies were born in NGS cycles; all of these babies are healthy and free of any developmental problems. This study provides the first evaluation of the clinical outcomes of NGS-based pre-implantation genetic diagnosis/screening, and shows the reliability of this method in a clinical and array-based laboratory setting. NGS provides an accurate approach to detect embryonic imbalanced segmental rearrangements, to avoid the potential risks of false signals from SNP array in this study.


Structural and energetic basis for the inhibitory selectivity of both catalytic domains of dimeric HDAC6.
HDAC6 is a protein involved in cancer, neurodegenerative disease and inflammatory disorders. To date, the full three-dimensional (3D) structure of human HDAC6 has not been elucidated; however, there are some experimental 3D structural homologs to HDAC6 that can be used as templates. In this work, we utilized molecular modeling procedures to model both of the catalytic domains of HDAC6 connected by the linker region where DMB region is placed. Once the 3D structure of human HDAC6 was obtained, it was structurally evaluated and submitted to docking and molecular dynamic (MD) simulations along with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method to explore the stability and the binding free energy properties of the HDAC6-ligand complexes. In addition, its structural and energetic behavior was explored with each one of the catalytic domains in the molecular recognition of six selective HDAC6 inhibitors, HPOB, CAY10603, Nexturastat, Rocilinostat, Tubacin and Tubastatin A for DD2, and with the so-called 9-peptide which is DD1-HDAC6 selective substrate. The use of the whole system (DD1-DMB-DD2) showed a tendency toward the ligand affinity of DD2, CAY10603> Tubacin > Rocilinostat > Nexturastat > HPOB > Tubastatin > 9-peptide, which is in line with experimental reports. However, 9-peptide showed a higher affinity for DD1, which agrees with experimental reports elsewhere. Principal component analysis provided important information about the structural changes linked to the molecular recognition process, whereas per-residue decomposition analysis revealed the energetic contribution of the key residues in the molecular binding and structural characteristics that could assist in drug design.


Development of monoclonal antibodies against bovine mucin core 2 beta6 N-acetylglucosaminyltransferase.
Molecular cloning techniques have been used to produce abundant amounts of recombinant glycosyltransferases for biochemical studies. We recently cloned a cDNA which encoded bovine mucin core 2 beta6N-acetylglucosaminyl transferase (C2TF). Poly-histidine-C2TF fusion protein was generated from the cloned cDNA in the E. coli Xpress system and used to produce monoclonal antibodies (MAbs). We obtained seven hybridomas which secreted MAbs against bovine C2TF in mouse ascites with titers ranging from 1:1280 to 1:40960 as assessed by immunofluorescence assay (IF). Isotyping revealed that all seven MAbs were IgG (4 IgG1, 2 IgG2b and 1 IgG2a). The affinity constants (M(-1)) for these MAbs range from 5.4 x 10(7) to 1.2 x 10(9). These MAbs recognized bovine C2TF in tissue sections and on Western blottings. Six of these MAbs reacted with human core 2-M enzyme and one with both core 2-L and core 2-M enzymes on Western blottings. Therefore, these antibodies should be useful for further study of bovine and human core 2 enzymes.


Molecular Changes Associated with Suicide.
Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual's vulnerability to suicide. These factors include various potential causes, from psychiatric disorders to genetic and epigenetic alterations. These changes can induce dysfunctions in crucial systems such as the serotonergic, cannabinoid, and hypothalamic-pituitary-adrenal axes. In addition, early life experiences of abuse can profoundly impact an individual's ability to cope with stress, ultimately leading to changes in the inflammatory system, which is a significant risk factor for suicidal behavior. Thus, it is clear that suicidal behavior may result from a confluence of multiple factors. This review examines the primary risk factors associated with suicidal behavior, including psychiatric disorders, early life adversities, and epigenetic modifications. Our goal is to elucidate the molecular changes at the genetic, epigenetic, and molecular levels in the brains of individuals who have taken their own lives and in the plasma and peripheral mononuclear cells of suicide attempters and how these changes may serve as predisposing factors for suicidal tendencies.


[Histologic studies on the effect of light coagulation of the retina on the vitreous body].
Up to 6 months after panretinal photocoagulation of rabbit eyes the subsequent changes in the vitreous body were examined histologically by means of a stereomicroscope. Marked changes were evident: severe exudation into all of the vitreous tissue during the early follow-up period, circumscribed areas of higher density or loss of normal density, membrane-like structures, confluent cavities and liquefaction of most of the tissue at the later postcoagulative stage.


[Changes in mitochondria density during oogenesis of loach].
The growth of loach oocytes is accompanied by an increase in the density of mitochondria. Simultaneously with the increase in density an acceleration of 14C-valine incorporation into mitochondrial proteins takes place. It is assumed that the increase in mitochondria density during oogenesis is due to an increase in the amount of membrane material per unit of mitochondria weight.


Current management of advanced and castration resistant prostate cancer.
Newer approaches to the management of advanced prostate cancer have rapidly evolved. While basic androgen deprivation remains as the first line in newly diagnosed hormone naïve metastatic prostate cancer, the agents used and strategies followed have undergone significant changes. Numerous new agents such as sipuleucel-T, abiraterone, enzalutamide, cabazitaxel and radium 223 have all been approved since 2010 to treat metastatic castration resistant prostate cancer (CRPC). New imaging techniques to detect advanced disease such as F-18 PET, 11 C-choline PET and other modalities are becoming available. The concepts of "bone health" and the management of side effects related to androgen deprivation therapy are also gaining attention as men are being treated with longer courses of androgen deprivation. Understanding the theory behind these new agents and management approaches while focusing on the practical clinical considerations are essential to improve outcomes in advanced prostate cancer. A review of the current state of the art in the management of advanced and castration resistant prostate cancer presented in this Canadian Journal of Urology International supplement was performed. Key findings are summarized and presented along with critical updates based on recent publications and meeting presentations. Key concepts identified in the management of advanced prostate cancer included the new understanding of prostate cancer based on translational discoveries, applications of various hormonally based strategies in advanced disease including traditional and recently approved agents. The use of new imaging modalities to identify metastatic disease, immunotherapy approaches and discussions of sequencing and which new agents are likely to be available in the future in the management of CRPC were identified. Bone targeted strategies are also addressed in the setting of androgen deprivation and metastatic disease. The management of men with advanced prostate cancer has become more multidisciplinary as treatment options have expanded. As the use of these agents and new strategies expand, urologists, medical oncologists and radiation oncologists must all become familiar with this rapidly changing field in order to maximize the outcome of patients with advanced and castration resistant prostate cancer.


A Sequential Process Model for Cognitive Diagnostic Assessment With Repeated Attempts.
When diagnostic assessments are administered to examinees, the mastery status of each examinee on a set of specified cognitive skills or attributes can be directly evaluated using cognitive diagnosis models (CDMs). Under certain circumstances, allowing the examinees to have at least one opportunity to correctly answer the questions and assessments, with repeated attempts on the items, provides many potential benefits. A sequential process model can be extended to model repeated attempts in diagnostic assessments. Two formulations of the sequential generalized deterministic-input noisy-"and"-gate (G-DINA) model were developed in this study. The first extension uses the latent transition analysis (LTA) approach to model changes in the attributes over attempts, and the second extension constructs a higher order structure of latent continuous variables and latent attributes to account for the dependences of the attributes over attempts. Accurate model parameter estimation and correct classifications of attributes were observed in a series of simulations using Bayesian estimation. The effectiveness of the developed sequential G-DINA model was demonstrated by fitting real data from a longitudinal mathematical test to the developed model and the longitudinal G-DINA model using the LTA approach. Finally, this article closes by discussing several important issues associated with the developed models and providing suggestions for future directions.


Salmonella isolates from wild birds and mammals in the Basque Country (Spain).
The authors investigated the prevalence of Salmonella spp. in 205 wild birds and mammals belonging to 45 species during the years 2001 and 2002 in the Basque Country (Spain). Salmonella was isolated from 16 (7.8%) animals. The prevalence was 8.5% (7/82) in birds, and 7.2% (9/123) in mammals. Nine serotypes, all of them belonging to the species Salmonella enterica, were identified: two isolates of Typhimurium (from 1/3 griffon vultures [Gyps fulvus], and 1/5 sparrowhawks [Accipiter nisus]); one of 6,14:z4, z23: (subsp. houtenae, 1/1 common kestrel [Falco tinnunculus]); one of Muenchen (1/1 captive Harris's hawk [Parabuteo unicinctus]); two of Enteritidis (1/5 tawny owls [Strix aluco], and 1/14 foxes [Vulpes vulpes]); one of Give, Newport and Umbilo and one untyped islolate (4/22 badgers [Meles meles]); two of Worthington and one of 38:IV:z35 (subsp. arizonae, 3/40 wild boars [Sus scrofa]); and three other untyped isolates (1/1 northern fulmar [Fulmarus glacialis], 1/11 buzzards [Buteo buteo], 1/4 genets [Genetta genetta]). Salmonella isolation was never associated with macroscopic or microscopic lesions. The results of this study confirm the importance of wildlife as a Salmonella reservoir and as a potential risk for humans and livestock.


Effect of vessel size on lipid content of coronary plaques assessed by integrated backscatter intravascular ultrasound.
Tissue characterization of coronary plaques is feasible using integrated backscatter intravascular ultrasound (IB-IVUS), and higher lipid content has been found in the target lesions of acute coronary syndrome (ACS). The present study was performed to identify clinical and IVUS parameters that correlate with plaque composition assessed by IB-IVUS. A total of 109 patients (age 60.0+/-9.7 years) were evaluated with IVUS and IB-IVUS prior to percutaneous coronary intervention. Patients with ACS had a larger vessel size and higher plaque burden in the target lesion than those with stable angina. Relative lipid content of the target lesion by IB-IVUS was also higher in ACS (43.6%+/-12.0% vs 29.9%+/-14.2%; P<0.001). The remodeling index (r=0.403, P<0.001), plaque burden (%) (r=0.495, P<0.001), and vessel size (r=0.572, P<0.001) significantly correlated with lipid content. In the multiple regression analysis, vessel size was the most important independent predictor of lipid content followed by presence of ACS and the remodeling index. ACS, positive remodeling, and larger plaque burden were associated with higher lipid content of coronary plaque. However, the lipid content on IB-IVUS was also significantly affected by vessel size. Therefore, qualitative, morphologic assessment of coronary plaque rather than simple quantitative analysis of tissue components seems to be more appropriate for the identification of vulnerable plaque using IB-IVUS.


Using social networks to scale up and sustain community-based programmes to improve physical activity and diet in low-income and middle-income countries: a scoping review protocol.
The World Health Organisation endorses community-based programmes as a cost-effective, feasible and a 'best buy' in the prevention and management of non-communicable diseases (NCDs). These programmes are particularly successful when the community actively participates in its design, implementation and evaluation. However, they may be only useful insofar as they can be scaled up and sustained in some meaningful way. Social network research may serve as an important tool for determining the underlying mechanisms that contribute to this process. The aim of this planned scoping review is to map and collate literature on the role of social networks in scaling-up and sustaining community-based physical activity and diet programmes in low-income and middle-income countries. This scoping review protocol has been planned around the Arksey and O'Malley framework and its enhancement. Inclusion criteria are peer-reviewed articles and grey literature exploring the role of social networks in the scale-up and/or sustainability of NCD prevention community-based programmes in adult populations. Studies must have been published since 2000, in English, and be based in a low-income or middle-income country. The following databases will be used for this review: PubMed, Cochrane, Scopus, Web of Science, CINAHL, SocIndex, the International Bibliography of the Social Sciences, Google and Google Scholar. Books, conference abstracts and research focused only on children will be excluded. Two reviewers will independently select and extract eligible studies. Included publications will be thematically analysed using the Framework Approach. Ethical approval will not be sought for this review as no individual-level data or human participants will be involved. This protocol is registered on the Open Science Framework (https://doi.org/10.17605/OSF.IO/KG7TX). The findings from the review will be published in an accredited journal. The Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews checklist will be used to support transparency and guide translation of the review.


Non-Invasive Isthmocele Treatment: A New Therapeutic Option During Assisted Reproductive Technology Cycles?
The objective of the study was to evaluate a new medical treatment strategy for infertile patients with isthmocele. This was a retrospective evaluation of the records of infertile patients with symptomatic isthmocele who received non-invasive isthmocele treatment (NIIT) before in vitro fertilization (IVF) treatment cycles. Isthmocele volumes were measured before and after NIIT. The IVF results and isthmocele-related complaints were also analyzed. The patients were treated with a depot gonadotropin-releasing hormone agonist for 3 months before frozen-thawed embryo transfer cycles. The mean isthmocele volume was 471.06 ± 182.81 mm3 (range: 289.43 - 765.4 mm3) in fresh cycles, but was reduced to 47.94 ± 29.48 mm3 (range: 18.70 - 105.6 mm3) in frozen-thawed cycles (P < 0.05). Intrauterine fluid was observed in two patients during fresh cycles, but was absent after NIIT during frozen-thawed cycles. There was no brown bloody discharge on the tip of the embryo transfer catheter in any case after NIIT. Two patients became pregnant and underwent term cesarean delivery (25%). NIIT can serve as an alternative pretreatment option for patients with isthmocele during IVF cycles.


Spatially informed knowledge translation: informing potential users of Canada's Compassionate Care Benefit.
Implemented in 2004 by the Canadian government, the Compassionate Care Benefit (CCB) program aims to provide income assistance and job security to caregivers who decide to take temporary leave from their employment to care for a terminally ill family member at risk of dying. Reports have cited numerous challenges with respect to the benefit's successful uptake, including the major obstacle of a general lack of awareness regarding the program's existence. Based on this knowledge, the present analysis aims to consider local contexts and potential barriers through engagement with the knowledge-to-action (KTA) cycle. Using an innovative and spatially informed three-step mixed-method analysis, we identify: (1) who likely CCB-eligible family caregivers are; (2) where these individuals' households are located; and (3) how best to get information about the CCB to them. Melding the findings from the three analytic steps generates a tailored path from which an information dissemination strategy can be guided (the intended action). Results indicate that targeted dissemination efforts undertaken outside of urban cores are likely to be most efficient in reaching potential or current CCB-eligible family caregivers. This strategy should be implemented through multiple formats and venues via two information pathways: (1) from key professionals to family caregivers and (2) from the community to the general public. Through employing a spatial perspective, these findings engage and usefully contribute to the KTA cycle process. Future involvement in the cycle will entail translating these findings for use in a decision-making context in order to implement an intervention. This approach can also be applied to other health and social programs where lack of awareness exists or for targeted interventions that require identifying specific populations.


The type III-dependent Hrp pilus is required for productive interaction of Xanthomonas campestris pv. vesicatoria with pepper host plants.
The plant pathogenic bacterium Xanthomonas campestris pv. vesicatoria expresses a type III secretion system that is necessary for both pathogenicity in susceptible hosts and the induction of the hypersensitive response in resistant plants. This specialized protein transport system is encoded by a 23-kb hrp (hypersensitive response and pathogenicity) gene cluster. Here we show that X. campestris pv. vesicatoria produces filamentous structures, the Hrp pili, at the cell surface under hrp-inducing conditions. Analysis of purified Hrp pili and immunoelectron microscopy revealed that the major component of the Hrp pilus is the HrpE protein which is encoded in the hrp gene cluster. Sequence homologues of hrpE are only found in other xanthomonads. However, hrpE is syntenic to the hrpY gene from another plant pathogen, Ralstonia solanacearum. Bioinformatic analyses suggest that all major Hrp pilus subunits from gram-negative plant pathogens may share the same structural organization, i.e., a predominant alpha-helical structure. Analysis of nonpolar mutants in hrpE demonstrated that the Hrp pilus is essential for the productive interaction of X. campestris pv. vesicatoria with pepper host plants. Furthermore, a functional Hrp pilus is required for type III-dependent protein secretion. Immunoelectron microscopy revealed that type III-secreted proteins, such as HrpF and AvrBs3, are in close contact with the Hrp pilus during and/or after their secretion. By systematic analysis of nonpolar hrp/hrc (hrp conserved) and hpa (hrp associated) mutants, we found that Hpa proteins as well as the translocon protein HrpF are dispensable for pilus assembly, while all other Hrp and Hrc proteins are required. Hence, there are no other conserved Hrp or Hrc proteins that act downstream of HrpE during type III-dependent protein translocation.


Diagnosis and management of pediatric brugada syndrome: a survey of pediatric electrophysiologists.
Brugada syndrome (BrS) can be difficult to diagnose and treat, especially in the young patient. As there is currently no consensus on the evaluation and treatment of BrS in the pediatric population, we sought to describe the current practice for the diagnosis and treatment of BrS among pediatric electrophysiologists. A web-based survey was distributed to 204 physician members (MDs) of The Pediatric and Adult Congenital Electrophysiology Society (PACES). Practice characteristics, BrS patient attributes, and diagnostic and therapeutic preferences were collected. Responses were obtained from 83 pediatric electrophysiologists. The most common initial presentation was family history. There is a large variation in testing, particularly in the use of electrophysiology (EP) studies, drug challenge testing, and genetic testing. Despite limited treatment options, there is only consensus in the therapeutic approach to the pediatric patient with symptomatic BrS with 97% of physicians recommending an implantable cardioverter defibrillator (ICD). In the asymptomatic patient, a wide variation in therapy was seen with only 27% of physicians recommending an ICD CONCLUSIONS: Significant practice variation exists among pediatric electrophysiologists with deviation from accepted diagnostic and therapeutic practices for adult BrS patients. Further studies are necessary to establish best practice guidelines for BrS in the pediatric EP community.


Two-photon calcium imaging of the medial prefrontal cortex and hippocampus without cortical invasion.
In vivo two-photon calcium imaging currently allows us to observe the activity of multiple neurons up to ~900 µm below the cortical surface without cortical invasion. However, many important brain areas are located deeper than this. Here, we used an 1100 nm laser that underfilled the back aperture of the objective together with red genetically encoded calcium indicators to establish two-photon calcium imaging of the intact mouse brain and detect neural activity up to 1200 μm from the cortical surface. This imaging was obtained from the medial prefrontal cortex (the prelimbic area) and the hippocampal CA1 region. We found that neural activity before water delivery repeated at a constant interval was higher in the prelimbic area than in layer 2/3 of the secondary motor area. Reducing the invasiveness of imaging is an important strategy to reveal the intact brain processes active in cognition and memory.


Insights into mobile health application market via a content analysis of marketplace data with machine learning.
Despite the benefits offered by an abundance of health applications promoted on app marketplaces (e.g., Google Play Store), the wide adoption of mobile health and e-health apps is yet to come. This study aims to investigate the current landscape of smartphone apps that focus on improving and sustaining health and wellbeing. Understanding the categories that popular apps focus on and the relevant features provided to users, which lead to higher user scores and downloads will offer insights to enable higher adoption in the general populace. This study on 1,000 mobile health applications aims to shed light on the reasons why particular apps are liked and adopted while many are not. User-generated data (i.e. review scores) and company-generated data (i.e. app descriptions) were collected from app marketplaces and manually coded and categorized by two researchers. For analysis, Artificial Neural Networks, Random Forest and Naïve Bayes Artificial Intelligence algorithms were used. The analysis led to features that attracted more download behavior and higher user scores. The findings suggest that apps that mention a privacy policy or provide videos in description lead to higher user scores, whereas free apps with in-app purchase possibilities, social networking and sharing features and feedback mechanisms lead to higher number of downloads. Moreover, differences in user scores and the total number of downloads are detected in distinct subcategories of mobile health apps. This study contributes to the current knowledge of m-health application use by reviewing mobile health applications using content analysis and machine learning algorithms. The content analysis adds significant value by providing classification, keywords and factors that influence download behavior and user scores in a m-health context.


Not on the menu: autophagy-independent clearance of prions.
A common feature of neurodegenerative diseases is the accumulation of disease-specific, aggregated protein species in the nervous system. Transmissible spongiform encephalopathies are universally fatal neurodegenerative diseases involving the transconformation and aggregation of prion proteins. At the cellular level macroautophagy has been identified as an efficient pathway for the clearance of these toxic protein aggregates. Hence, recent research has focused on the pharmacological manipulation of autophagy as a potential treatment for neurodegenerative diseases. Independent of their effects on the estrogen receptor, tamoxifen and its metabolite 4-hydroxytamoxifen are well known inducers of autophagy. However, we recently reported that the ability of 4-hydroxytamoxifen to clear prion infection is independent of autophagy. In contrast, we provide a model whereby perturbation of cholesterol metabolism, and not autophagy, is the main mechanism whereby 4-hydroxytamoxifen is able to exert its anti-prion effects. Thus, while tamoxifen, a widely available pharmaceutical, may have applications in prion therapy, prions may also represent a special case and may require different pharmacological interventions than other proteinopathies.


Acute renal failure after nonmyeloablative hematopoietic cell transplantation.
Acute renal failure (ARF) is a common life-threatening complication after myeloablative allogeneic hematopoietic cell transplantation (HCT). Nonmyeloablative HCT aims to eradicate the malignancy with graft-versus-tumor effect, rather than with high doses of chemoradiotherapy. It may be anticipated that a lower risk of ARF exists in nonmyeloablative HCT as a result of the milder preconditioning regimen. However, the patients who receive the nonmyeloablative HCT are older individuals who are not eligible for the more toxic allogeneic myeloablative procedure. The goal of this study was to evaluate ARF in a large group of patients who received nonmyeloablative HCT. This cohort study enrolled patients who were undergoing nonmyeloablative HCT at four major centers from 1998 to 2001. Conditioning therapy involved total body irradiation 2 Gy +/- fludarabine 30 mg/m2. Posttransplantation immunosuppression consisted of cyclosporine or tacrolimus and mycophenolate mofetil. ARF was classified into four grades, similar to previous studies in the literature. Collectively, 253 patients were recruited into this study. ARF (>50% decrease in GFR) occurred in 40.4% of patients over a 3-mo period, with 4.4% of patients requiring dialysis. The overall mortality in the study population was 34% at 1 yr. The mortality increased with worsening grade of ARF. The combined need for dialysis and artificial ventilation was associated with a mortality exceeding 80%. Although the number of patients who develop ARF is significant, the risk of developing ARF that requires dialysis after nonmyeloablative HCT is infrequent despite the older age of the patients. The data are also suggestive that ARF may contribute to mortality after nonmyeloablative HCT.


Defective glucagon secretion during sustained hypoglycemia following successful islet allo- and autotransplantation in humans.
Defective glucagon secretion during hypoglycemia is characteristic of long-standing type I diabetes. To determine whether this defect can be corrected by successful intrahepatic islet transplantation, we performed studies of hypoglycemia in four nondiabetic patients with chronic pancreatitis who had undergone total pancreatectomy and successful intrahepatic islet autotransplantation, in two type I diabetic recipients of successful intrahepatic islet allotransplantation, and in matched control subjects. We examined 1) whether intrahepatic islet autotransplantation provides glucagon secretion during prolonged periods of hypoglycemia and 2) whether intrahepatic islet allotransplantation in type I diabetic patients and consequent long-term normoglycemia reestablishes native alpha-cell responses to hypoglycemia. Glucagon secretion was assessed during 3-h hypoglycemic hyperinsulinemic clamp studies. The islet autograft recipients were studied 63 +/- 19 months posttransplant, and all were insulin-independent and normoglycemic (HbA(1c), 5.8 +/- 0.2%). Neither allograft recipient required exogenous insulin and maintained HbA(1c) levels of 5.7 and 6.4% 30 and 34 months posttransplant, respectively. All recipients were normoglycemic (fasting glucose: autograft recipients, 5.6 +/- 0.1 mmol/l; allograft recipient #1, 6.3 mmol/l; allograft recipient #2, 5.8 mmol/l) at the time of study. During hypoglycemia, no increase in glucagon secretion was observed in either the auto- or allotransplant recipients, whereas healthy control subjects and recipients of kidney transplantation had significant increases in glucagon. In contrast, both allo- and autograft recipients had glucagon responses to intravenous arginine. These data uniquely demonstrate that: 1) intrahepatic islet transplant grafts secrete glucagon in response to arginine, but fail to secrete glucagon in response to sustained hypoglycemia; and 2) the restoration of sustained normoglycemia for over 2 years in type I diabetic patients may not reestablish glucagon responses from the native pancreas during hypoglycemia. Transplantation sites other than the liver may be required to achieve normal glucagon secretion from the transplanted islets.


Analysis of postfire vegetation dynamics of Mediterranean shrub species based on terrestrial and NDVI data.
The present study offers an analysis of regeneration patterns and diversity dynamics after a wildfire, which occurred in 1993 and affected about 7000 ha in southern Spain. The aim of the work was to analyze the rule in the succession of shrub species after fire, relating it to the changes registered in the Normalized Difference Vegetation Index (NDVI). Fractional vegetation cover was recorded from permanent plots in 2000 and 2005. NDVI data related to each time were obtained from Landsat images. Both data sets, from fieldwork and remote sensing, were analyzed through statistical and quantitative analyses and then correlated. Results have permitted the description of the change in plant cover and species composition on a global and plot scale. It can be affirmed that, from the seventh to the twelfth year after the fire, the floristic composition within the burned area remained unchanged at a global level. However, on a smaller scale (plot level), the major shrub species, Ulex parviflorus, Rosmarinus officinalis, and Cistus clusii, underwent significant changes. The regeneration dynamics established by these species conditioned plant species composition and, consequently, diversity indexes such as Shannon (H) and Simpson (D). The changes recorded in the NDVI values corresponding to the surveyed plots were highly correlated with those found in the regrowth of the main species. Areas dominated by U. parviflorus in a senile phase were related to a decrease in NDVI values and an increase in the number of species. This result describes the successional dynamics; the dryness of the main colonizer shrub species is allowing the regrowth and re-establishment of other species. Within the study area, NDVI shows sensitivity to postfire plant cover changes and indirectly expresses the diversity dynamics.


Toxoplasma seroprevalence in animals in northern India.
In a serological survey of latent Toxoplasma prevalence on 3761 animals in northern India by the microtitre indirect haemagglutination test, 23.7 per cent were found to have antibody titres ranging from 1:4 to 1:1024. Seropositivity was recorded in 25.3 per cent of 1227 sheep, 30.3 per cent of 961 goats, 11.8 per cent of 603 horses, 19.3 per cent of 243 cattle, 15.7 per cent of 108 water buffaloes, 31.5 per cent of 178 pigs, 30.9 per cent of 175 dogs, 33.7 per cent of 80 cats and in 9.7 per cent of 186 bandicoot rats. Relevant epidemiological data has been furnished. High seropositivity in food animals and frequent isolations of Toxoplasma highlight the likely public health implications of the findings.


Bat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution.
In recognizing the host cellular receptor and mediating fusion of virus and cell membranes, the spike (S) glycoprotein of coronaviruses is the most critical viral protein for cross-species transmission and infection. Here we determined the cryo-EM structures of the spikes from bat (RaTG13) and pangolin (PCoV_GX) coronaviruses, which are closely related to SARS-CoV-2. All three receptor-binding domains (RBDs) of these two spike trimers are in the "down" conformation, indicating they are more prone to adopt the receptor-binding inactive state. However, we found that the PCoV_GX, but not the RaTG13, spike is comparable to the SARS-CoV-2 spike in binding the human ACE2 receptor and supporting pseudovirus cell entry. We further identified critical residues in the RBD underlying different activities of the RaTG13 and PCoV_GX/SARS-CoV-2 spikes. These results collectively indicate that tight RBD-ACE2 binding and efficient RBD conformational sampling are required for the evolution of SARS-CoV-2 to gain highly efficient infection.


Occurrence of Cruzia tentaculata Larvae in the Land Snail Megalobulimus abbreviatus-Influence of Natural Parasite Load on Snail Physiology.
The nematode Cruzia tentaculata is reported here for the first time in the land snail Megalobulimus abbreviatus in southern Brazil. The snails were infected with a high prevalence of larvae up to the L3 stage (68.6%). Cysts were located mainly in the mantle (pulmonary cavity) and the nerve ring. No other helminths were identified in the collected snails. Some physiological aspects were compared between snails infected with L3 larvae and non-infected snails and among infected animals with different parasite loads. No differences were found in hemolymph protein, glucose, or urea content between L3-infected and non-infected snails, nor among animals with different parasite loads. Discontinuous lesions in the rectum associated with the presence of encapsulated larvae were visible in animals with high parasite loads and were more frequent in adult animals. All analyses were carried out during the breeding season; however, the albumen glands of mature snails had a smaller volume in those with higher parasite loads. Ovotestis weight was also significantly negatively correlated with parasite load. Snail reproductive capacity could, therefore, be partially impaired but only for individuals with higher parasite loads. Considering only the measured parameters, natural infection by C. tentaculata does not appear to affect intermediary metabolism of M. abbreviatus. A greater number of larvae and greater severity of tissue injuries are more frequently observed in older snails.


In vivo antigenic modification of tumor cells. III. Metastatic thymic lymphoma specifically infected by thymotropic retrovirus.
Tissue distribution of radiation leukemia virus (RadLV) was examined after its inoculation into normal C57BL/6J (B6) mice, B6 mice bearing a transplantable, non-virus-producing thymic lymphoma (RL12-NP), and B6 mice bearing a transplanted non-virus producing, Harvey murine sarcoma virus-transformed fibrosarcoma. Virus expression was determined by competition radioimmunoassay for murine leukemia virus (MuLV) p30 (predominant group-reactive antigen of MuLV) and for RadLV p12 (a highly type-specific MuLV polypeptide) and by membrane immunofluorescence for cell surface gp71 (predominant envelope glycoprotein of MuLV). Normal adult B6 mice were given three sequential iv injections of RadLV and were examined several times up to 200 days later for the appearance of neoplastic disease or expression of virion antigens. No clinical abnormalities were noted, and animals remained healthy for greater than 200 days. Significant levels of MuLV p30 and RadLV p12 were detected only in the thymuses. Organs and tumors from RL12-NP-inoculated animals contained low or nondetectable levels of virion antigens. Inoculation of mice with RL12-Rad, a cell line derived by in vitro infection of RL12-NP cells with RadLV, produced widespread, discrete metastatic tumors and infiltrated the lymphoid organs of B6 mice in a pattern identical to that observed after administration of RL12-NP cells. Lymphoid organs of RL12-Rad-inoculated animals expressed variable levels of virion antigens reflecting differences in the extent of tumor cell infiltration as opposed to virus spread from tumor to host cells. Administration of infectious RadLV systemically into RL12-NP tumor-bearing animals converted these tumors to viron antigen expressors with levels in superinfected tumors equivalent to those found in RL12-Rad-induced tumors. Infection was highly selective, and host tissues were minimally contaminated by the inoculated virus. Part of this selectivity was explained by the thymotropic property of RadLV. A rapidly dividing murine fibrosarcoma was not infected by RadLV, but this same non-virus-expressing tumor could be infected by common fibrotropic MuLV isolates.


Increased Tuberculosis Patient Mortality Associated with Mycobacterium tuberculosis Mutations Conferring Resistance to Second-Line Antituberculous Drugs.
Rapid molecular diagnostics have great potential to limit the spread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) (M/XDR-TB). These technologies detect mutations in the Mycobacterium tuberculosis genome that confer phenotypic drug resistance. However, there have been few data published regarding the relationships between the detected M. tuberculosis resistance mutations and M/XDR-TB treatment outcomes, limiting our current ability to exploit the full potential of molecular diagnostics. We analyzed clinical, microbiological, and sequencing data for 451 patients and their clinical isolates collected in a multinational, observational cohort study to determine if there was an association between M. tuberculosis resistance mutations and patient mortality. The presence of an rrs 1401G mutation was associated with significantly higher odds of patient mortality (adjusted odds ratio [OR] = 5.72; 95% confidence interval [CI], 1.65 to 19.84]) after adjusting for relevant patient clinical characteristics and all other resistance mutations. Further analysis of mutations, categorized by the associated resistance level, indicated that the detection of mutations associated with high-level fluoroquinolone (OR, 3.99 [95% CI, 1.10 to 14.40]) and kanamycin (OR, 5.47 [95% CI, 1.64 to 18.24]) resistance was also significantly associated with higher odds of patient mortality, even after accounting for clinical site, patient age, reported smoking history, body mass index (BMI), diabetes, HIV, and all other resistance mutations. Specific gyrA and rrs resistance mutations, associated with high-level resistance, were associated with patient mortality as identified in clinical M. tuberculosis isolates from a diverse M/XDR-TB patient population at three high-burden clinical sites. These results have important implications for the interpretation of molecular diagnostics, including identifying patients at increased risk for mortality during treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT02170441.).


Cyclin-dependent kinase-mediated phosphorylation plays a critical role in the oncogenic functions of PELP1.
Estrogen receptor (ER) signaling plays an important role in breast cancer progression, and ER functions are influenced by coregulatory proteins. PELP1 (proline-, glutamic acid-, and leucine-rich protein 1) is a nuclear receptor coregulator that plays an important role in ER signaling. Its expression is deregulated in hormonal cancers. We identified PELP1 as a novel cyclin-dependent kinase (CDK) substrate. Using site-directed mutagenesis and in vitro kinase assays, we identified Ser(477) and Ser(991) of PELP1 as CDK phosphorylation sites. Using the PELP1 Ser(991) phospho-specific antibody, we show that PELP1 is hyperphosphorylated during cell cycle progression. Model cells stably expressing the PELP1 mutant that lack CDK sites had defects in estradiol (E2)-mediated cell cycle progression and significantly affected PELP1-mediated oncogenic functions in vivo. Mechanistic studies showed that PELP1 modulates transcription factor E2F1 transactivation functions, that PELP1 is recruited to pRb/E2F target genes, and that PELP1 facilitates ER signaling cross talk with cell cycle machinery. We conclude that PELP1 is a novel substrate of interphase CDKs and that its phosphorylation is important for the proper function of PELP1 in modulating hormone-driven cell cycle progression and also for optimal E2F transactivation function. Because the expression of both PELP1 and CDKs is deregulated in breast tumors, CDK-PELP1 interactions will have implications in breast cancer progression.


Medication adherence for persons with spinal cord injury and dysfunction from the perspectives of healthcare providers: A qualitative study.
Context: People with spinal cord injury and dysfunction (SCI/D) often take multiple medications (i.e. polypharmacy) to manage secondary health complications and multiple chronic conditions. Numerous healthcare providers are often involved in clinical care, increasing the risk of fragmented care, problematic polypharmacy, and conflicting health advice. These providers can play a crucial role in assisting patients with medication self-management to improve medication adherence. Design: A qualitative study involving telephone interviews, following a semi-structured guide that explored healthcare providers' conceptualization of factors impacting medication adherence for persons with SCI/D. The interviews were transcribed and analyzed descriptively and interpretively using a constant comparative process with the assistance of data display matrices. Analysis was guided by an ecological model of medication adherence. Setting and participants: Thirty-two healthcare providers from Canada, with varying clinical expertise. Intervention: Not Applicable. Outcome measures: Not Applicable. Results: Providers identified several factors that impact medication adherence for persons with SCI/D, which were grouped into micro (medication and patient-related), meso- (provider-related) and macro- (health system-related) factors. Medication-related factors included side effects, effectiveness, safety, and regimen complexity. Patient-specific factors included medication knowledge, preferences/expectations/goals, severity and type of injury, cognitive function/mental health, time since injury, and caregiver support. Provider-related factors included knowledge/confidence and trust. Health system-related factors included access to healthcare and access to medications. While providers were able to identify several factors influencing medication adherence, micro-level factors were the most frequently discussed. Conclusion: Findings from this study indicate that strategies to optimize medication adherence for persons with SCI/D should be multi-faceted.


A Shelter in the Storm - Acceptability and Feasibility of a Brief Clinical Intervention for Suicidal Crisis.
Background: People attending the emergency department (ED) for suicidal crisis are at significantly higher risk of taking their own lives in the week following discharge. Aims: We aimed to evaluate the acceptability and feasibility of implementing a brief clinical aftercare intervention provided through Allied Health Brief Therapies (AHBTs) Clinics. Method: Consecutive referrals (n = 149) to the clinics following assessment in the ED for suicidal crisis formed the study group. This article details participant engagement and retention, service provision, therapeutic alliance, and participant satisfaction with the program. Suicidal ideation and ED utilization 3 months pre-/postintervention were used to assess short-term impact. Results: The study supports the feasibility of implementing a brief aftercare intervention for those presenting to the ED for suicidal crisis. High rates of therapeutic alliance and satisfaction with the clinic intervention were reported by participants. Impact assessments pointed to a significant reduction in both suicidal ideation and ED utilization following the intervention. Limitations: A substantial number of participants had missing follow-up data. Given this and the absence of a control group, findings must be interpreted with caution. Conclusion: The study supports the acceptability and feasibility of implementing AHBT Clinics as a potential adjunct in the aftercare of people in suicidal crisis.


NestWatch: An open-access, long-term data set on avian reproductive success.
Long-term avian nesting data are valuable to researchers studying various aspects of avian ecology, conservation, and management. Administered by the Cornell Lab of Ornithology, NestWatch accepts nesting data from volunteers and professionals who agree to follow its protocol and submit data in a standardized form using either the website NestWatch.org, the mobile app, or a bulk upload template. These data (N = 574,288 nest records currently spanning 1874-2023) have been used to examine geographical and temporal variation in breeding success, clutch size, nesting phenology, and other metrics of interest to researchers. When combined with other data sets (e.g., climate, land cover, maps of environmental stressors), NestWatch data have been used to explore large-scale effects of anthropogenic change on nesting biology. These data can also be incorporated into investigations of status and trends for declining species and can potentially be aggregated with other large-scale nest-monitoring data sets to explore hemispheric or even global change. By committing these data to the public domain, we aim to increase their use among researchers and stimulate novel studies. The NestWatch Open Data Set by Cornell Lab of Ornithology is licensed under CC BY-NC 4.0 (creativecommons.org); users are free to copy, redistribute, remix, transform, and build upon the material in any medium or format, but must give appropriate credit, provide a link to the license, and indicate if changes were made. Users may do so in any reasonable manner, but not in any way that suggests the licensor endorses such use, and may not use the material for commercial purposes. This article is protected by copyright. All rights reserved.


[The local blood flow and oxygen tension in the brain of pigeons under high-altitude hypoxia].
The effect of barochamber hypoxia on the local blood flow in the pigeon neostriatum caudalum, hypostriatum accessorium, ectostriatum, cerebellum cortex was studied by means of the hydrogen clearance technique. The hypoxia was shown to decrease the oxygen available in the brain tissue and to increase the blood flow. The changes were different in different brain structures. The spectral analysis of the oxygen available fluctuations revealed no regular changes in the temporal pattern of the fluctuations.


Cannabinoids-Characteristics and Potential for Use in Food Production.
Scientific demonstrations of the beneficial effects of non-psychoactive cannabinoids on the human body have increased the interest in foods containing hemp components. This review systematizes the latest discoveries relating to the characteristics of cannabinoids from Cannabis sativa L. var. sativa, it also presents a characterization of the mentioned plant. In this review, we present data on the opportunities and limitations of cannabinoids in food production. This article systematizes the data on the legal aspects, mainly the limits of Δ9-THC in food, the most popular analytical techniques (LC-MS and GC-MS) applied to assay cannabinoids in finished products, and the available data on the stability of cannabinoids during heating, storage, and access to light and oxygen. This may constitute a major challenge to their common use in food processing, as well as the potential formation of undesirable degradation products. Hemp-containing foods have great potential to become commercially popular among functional foods, provided that our understanding of cannabinoid stability in different food matrices and cannabinoid interactions with particular food ingredients are expanded. There remains a need for more data on the effects of technological processes and storage on cannabinoid degradation.


Functional Specialization in the Attention Network.
Spatial attention is comprised of neural mechanisms that boost sensory processing at a behaviorally relevant location while filtering out competing information. The present review examines functional specialization in the network of brain regions that directs such preferential processing. This attention network includes both cortical (e.g., frontal and parietal cortices) and subcortical (e.g., the superior colliculus and the pulvinar nucleus of the thalamus) structures. Here, we piece together existing evidence that these various nodes of the attention network have dissociable functional roles by synthesizing results from electrophysiology and neuroimaging studies. We describe functional specialization across several dimensions (e.g., at different processing stages and within different behavioral contexts), while focusing on spatial attention as a dynamic process that unfolds over time. Functional contributions from each node of the attention network can change on a moment-to-moment timescale, providing the necessary cognitive flexibility for sampling from highly dynamic environments.


Molecular identification and differentiation of Staphylococcus species and strains of cheese origin.
Amplified Ribosomal-DNA Restriction Analysis (ARDRA) was used to differentiate among 12 species and 4 subspecies of the genus Staphylococcus. With a universal primer pair a 2.4 kbp PCR-product was amplified, including the 16S rDNA, the 16S-23S rDNA interspacer region, and about 500 bp of the 23S rDNA. Species-specific restriction patterns were found using the restriction enzymes HindIII and XmnI separately. Cheese related staphylococci were clearly differentiated. ARDRA results were in good agreement with results of partial sequencing of the 16S rDNA. ARDRA could fully replace the biochemical identification with ID32 Staph (BioMerieux) which was less reliable when staphylococci of cheese origin were analysed. Genomic restriction digests of cheese-related S. equorum strains by SmaI and SacI gave unique strain-specific restriction patterns which can be used to identify starter staphylococci in a complex microbial environment such as the surface of Red-Smear cheeses.


Immobilized molecular beacons: a new strategy using UV-activated poly(methyl methacrylate) surfaces to provide large fluorescence sensitivities for reporting on molecular association events.
We have designed appropriately prepared solid supports consisting of poly(methyl methacrylate) (PMMA) that provide enhanced performance levels for molecular beacons (MBs) that are used for recognizing and reporting on signature DNA sequences in solution. The attachment of primary amine-containing MBs to the PMMA surface was carried out by UV activating the PMMA to produce surface-confined carboxylate groups, which could then be readily coupled to the MBs using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) chemistry. The fluorescence properties of the MBs covalently attached onto this UV-activated PMMA surface were evaluated and compared with the same MBs immobilized onto glass supports. We observed improved limits of detection for the solution complement to the MBs when immobilized onto PMMA, and this was attributed to both the lower autofluorescence levels exhibited by PMMA at the detection wavelengths used and the improved quenching efficiency of the MBs when in their closed hairpin configuration when strapped to a PMMA surface as opposed to glass. As an example of the utility of the PMMA-based immobilization strategies developed for MBs, we report on the analysis of complementary DNAs specific for fruitless (fru) and Ods-site homeobox (OdsH) genes extracted from Drosophila melanogaster fruit flies. The fru gene functions in the central nervous system, where it is necessary for sex determination and male courtship behavior, whereas the OdsH gene is involved in the regulation of transcription.


Measurement of soil bacterial colony temperatures and isolation of a high heat-producing bacterium.
The cellular temperatures of microorganisms are considered to be the same as those of their surroundings because the cellular volume is too small to maintain a cellular temperature that is different from the ambient temperature. However, by forming a colony or a biofilm, microorganisms may be able to maintain a cellular temperature that is different from the ambient temperature. In this study, we measured the temperatures of bacterial colonies isolated from soils using an infrared imager and investigated the thermogenesis by a bacterium that increases its colony temperature. The temperatures of some colonies were higher or lower than that of the surrounding medium. A bacterial isolate with the highest colony temperature was identified as Pseudomonas putida. This bacterial isolate had an increased colony temperature when it grew at a temperature suboptimal for its growth. Measurements of heat production using a microcalorimeter showed that the temperature of this extraordinary, microcalorimetrically determined thermogenesis corresponded with the thermographically observed increase in bacterial colony temperature. When investigating the effects of the energy source on this thermal behavior, we found that heat production by this bacterium increased without additional biomass production at a temperature suboptimal for its growth. We found that heat production by bacteria affected the bacterial colony temperature and that a bacterium identified as Pseudomonas putida could maintain a cellular temperature different from the ambient temperature, particularly at a sub-optimal growth temperature. The bacterial isolate P. putida KT1401 increased its colony temperature by an energy-spilling reaction when the incubation temperature limited its growth.


Effect of Losartan on the Acute Response of Human Elderly Skeletal Muscle to Exercise.
To investigate the effect of blocking the angiotensin II Type I receptor (AT1R) upon the response to acute heavy-resistance exercise in elderly human skeletal muscle. The hypothesis was that AT1R blocking would result in a superior myogenic response accompanied by down-regulation of transforming growth factor-beta and up-regulation of insulin-like growth factor-1 signaling. Twenty-eight healthy elderly men (+64 yr) were randomized into two groups, consuming either AT1R blocker (losartan, 100 mg·d) or placebo for 18 d before exercise. Participants performed one bout of heavy-unilateral-resistance exercise. Six muscle biopsies were obtained from the vastus lateralis muscles of each subject: two before exercise and four after exercise (4.5 h and 1, 4, and 7 d). Blood pressure and blood samples were collected at the same time points. Biopsies were sectioned for immunohistochemistry to determine the number of satellite cells associated with Type I and Type II fibers. Gene expression levels of Notch, connective tissue, and myogenic signaling pathways were determined by real-time reverse transcription polymerase chain reaction. Changes over time were detected for circulating creatine kinase, the number of satellite cells per Type I fiber, and most of the gene targets, with no specific effect of losartan on these. However, when compared with placebo, losartan intake resulted in a greater suppression of myostatin messenger RNA. In general, there does not seem to be any effect of AT1R blocking on satellite cell number or myogenic pathways in elderly men in the days after one bout of heavy-resistance exercise. However, the greater suppression of myostatin may prove to be beneficial over a long-term intervention designed to induce hypertrophy.


Predictive Factors for Second-Line Therapy in Metastatic Renal Cell Carcinoma: A Retrospective Analysis.
Currently, about 50% of patients with metastatic renal cell carcinoma (mRCC) receive a second-line therapy. Therefore, the choice at each subsequent treatment line remains an important issue. In this retrospective study, we sought to identify pretreatment clinical parameters that could predict the likelihood of a patient receiving a second-line therapy. One hundred and sixty-one mRCC patients who received targeted therapy were evaluated. Descriptive statistics, Kaplan-Meier overall survival (OS), Cox regression, and binary logistic regression models were used for data analysis. Second-line therapy was given to 105 patients (65%). Patients with grade 1 tumor received second-line therapy more frequently than those with grade 2/3 tumors (P = 0.03). Only tumor grade was significantly different between patients receiving, or not receiving, second-line treatment. Median OS was significantly superior in patients receiving second-line therapy (32 versus 14 months; P = 0.007; hazard ratio [HR], 1.75; P = 0.008), patients with grade 1 tumors (130 versus 29 months in G2/3 tumors; HR, 3.85; P = 0.009), and in patients without early tumor progression (41 versus 11 months; HR, 5.04; 95% confidence interval [CI], 3.06-8.31; P < 0.001). In binary logistic regression, we identified early progression to be significantly associated with a higher probability of not receiving a second-line therapy (HR, 2.50; 95% CI, 1.01-6.21; P = 0.048). This study hypothesizes that pretreatment grade and early progression are predictive parameters for the selection of patients for second-line therapy.


The Application of Handheld Near-Infrared Spectroscopy and Raman Spectroscopic Imaging for the Identification and Quality Control of Food Products.
The following investigations describe the potential of handheld NIR spectroscopy and Raman imaging measurements for the identification and authentication of food products. On the one hand, during the last decade, handheld NIR spectroscopy has made the greatest progress among vibrational spectroscopic methods in terms of miniaturization and price/performance ratio, and on the other hand, the Raman spectroscopic imaging method can achieve the best lateral resolution when examining the heterogeneous composition of samples. The utilization of both methods is further enhanced via the combination with chemometric evaluation methods with respect to the detection, identification, and discrimination of illegal counterfeiting of food products. To demonstrate the solution to practical problems with these two spectroscopic techniques, the results of our recent investigations obtained for various industrial processes and customer-relevant product examples have been discussed in this article. Specifically, the monitoring of food extraction processes (e.g., ethanol extraction of clove and water extraction of wolfberry) and the identification of food quality (e.g., differentiation of cocoa nibs and cocoa beans) via handheld NIR spectroscopy, and the detection and quantification of adulterations in powdered dairy products via Raman imaging were outlined in some detail. Although the present work only demonstrates exemplary product and process examples, the applications provide a balanced overview of materials with different physical properties and manufacturing processes in order to be able to derive modified applications for other products or production processes.


Clinical and clinicopathologic features of transport tetany of feedlot lambs.
Clinical and clinicopathologic features of transport tetany in 9 feedlot lambs were investigated. The lambs became recumbent within 10 days after arrival in the feedlot. The mean serum calcium concentration, mean magnesium concentration, and calcium:phosphorus ratio were significantly (P less than 0.01) less in affected lambs than in 6 unaffected lambs from the same feedlot. The mean serum phosphorus concentration was significantly (P less than 0.05) greater in the group of affected lambs. High activities of serum glutamic oxalacetic transaminase, creatine kinase, and lactate dehydrogenase in the serum of affected lambs indicated muscle necrosis, which was confirmed by histologic examination. Blood pH, HCO-3, and total carbon dioxide were significantly greater in affected lambs (P less than 0.01) than in unaffected lambs.


Antidepressants plus benzodiazepines for adults with major depression.
Anxiety frequently coexists with depression and adding benzodiazepines to antidepressant treatment is common practice to treat people with major depression. However, more evidence is needed to determine whether this combined treatment is more effective and not any more harmful than antidepressants alone. It has been suggested that benzodiazepines may lose their efficacy with long-term administration and their chronic use carries risks of dependence.This is the 2019 updated version of a Cochrane Review first published in 2001, and previously updated in 2005. This update follows a new protocol to conform with the most recent Cochrane methodology guidelines, with the inclusion of 'Summary of findings' tables and GRADE evaluations for quality of evidence. To assess the effects of combining antidepressants with benzodiazepines compared with antidepressants alone for major depression in adults. We searched the Cochrane Common Mental Disorders Group's Controlled Trials Register (CCMDCTR), the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and PsycINFO to May 2019. We searched the World Health Organization (WHO) trials portal and ClinicalTrials.gov to identify any additional unpublished or ongoing studies. All randomised controlled trials that compared combined antidepressant plus benzodiazepine treatment with antidepressants alone for adults with major depression. We excluded studies administering psychosocial therapies targeted at depression and anxiety disorders concurrently. Antidepressants had to be prescribed, on average, at or above the minimum effective dose as presented by Hansen 2009 or according to the North American or European regulations. The combination therapy had to last at least four weeks. Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. We entered data into Review Manager 5. We used intention-to-treat data. We combined continuous outcome variables of depressive and anxiety severity using standardised mean differences (SMD) with 95% confidence intervals (CIs). For dichotomous efficacy outcomes, we calculated the risk ratio (RR) with 95% CI. Regarding the primary outcome of acceptability, only overall dropout rates were available for all studies. We identified 10 studies published between 1978 to 2002 involving 731 participants. Six studies used tricyclic antidepressants (TCAs), two studies used selective serotonin reuptake inhibitors (SSRIs), one study used another heterocyclic antidepressant and one study used TCA or heterocyclic antidepressant.Combined therapy of benzodiazepines plus antidepressants was more effective than antidepressants alone for depressive severity in the early phase (four weeks) (SMD -0.25, 95% CI -0.46 to -0.03; 10 studies, 598 participants; moderate-quality evidence), but there was no difference between treatments in the acute phase (five to 12 weeks) (SMD -0.18, 95% CI -0.40 to 0.03; 7 studies, 347 participants; low-quality evidence) or in the continuous phase (more than 12 weeks) (SMD -0.21, 95% CI -0.76 to 0.35; 1 study, 50 participants; low-quality evidence). For acceptability of treatment, there was no difference in the dropouts due to any reason between combined therapy and antidepressants alone (RR 0.76, 95% CI 0.54 to 1.07; 10 studies, 731 participants; moderate-quality evidence).For response in depression, combined therapy was more effective than antidepressants alone in the early phase (RR 1.34, 95% CI 1.13 to 1.58; 10 studies, 731 participants), but there was no evidence of a difference in the acute phase (RR 1.12, 95% CI 0.93 to 1.35; 7 studies, 383 participants) or in the continuous phase (RR 0.97, 95% CI 0.73 to 1.29; 1 study, 52 participants). For remission in depression, combined therapy was more effective than antidepressants alone in the early phase (RR 1.39, 95% CI 1.03 to 1.90, 10 studies, 731 participants), but there was no evidence of a difference in the acute phase (RR 1.27, 95% CI 0.99 to 1.63; 7 studies, 383 participants) or in the continuous phase (RR 1.31, 95% CI 0.80 to 2.16; 1 study, 52 participants). There was no evidence of a difference between combined therapy and antidepressants alone for anxiety severity in the early phase (SMD -0.76, 95% CI -1.67 to 0.14; 3 studies, 129 participants) or in the acute phase (SMD -0.48, 95% CI -1.06 to 0.10; 3 studies, 129 participants). No studies measured severity of insomnia. In terms of adverse effects, the dropout rates due to adverse events were lower for combined therapy than for antidepressants alone (RR 0.54, 95% CI 0.32 to 0.90; 10 studies, 731 participants; moderate-quality evidence). However, participants in the combined therapy group reported at least one adverse effect more often than participants who received antidepressants alone (RR 1.12, 95% CI 1.01 to 1.23; 7 studies, 510 participants; moderate-quality evidence).Most domains of risk of bias in the majority of the included studies were unclear. Random sequence generation, allocation concealment, blinding and selective outcome reporting were problematic due to insufficient details reported in most of the included studies and lack of availability of the study protocols. The greatest limitation in the quality of evidence was issues with attrition. Combined antidepressant plus benzodiazepine therapy was more effective than antidepressants alone in improving depression severity, response in depression and remission in depression in the early phase. However, these effects were not maintained in the acute or the continuous phase. Combined therapy resulted in fewer dropouts due to adverse events than antidepressants alone, but combined therapy was associated with a greater proportion of participants reporting at least one adverse effect.The moderate quality evidence of benefits of adding a benzodiazepine to an antidepressant in the early phase must be balanced judiciously against possible harms and consideration given to other alternative treatment strategies when antidepressant monotherapy may be considered inadequate. We need long-term, pragmatic randomised controlled trials to compare combination therapy against the monotherapy of antidepressant in major depression.


[Dysgerminoma-like lesion of the mediastinal and abdominal lymph nodes in a man].
Dysgerminoma-like lesion of mediastinal and abdominal lymph nodes without the involvement of the sex organs had been found in a young man and repeatedly confirmed throughout 23 years. High sensitivity of the tumor to X-ray therapy and cyclophosphamide made it possible to eliminate exacerbation periods.


Aberrant activity in an intact residual muscle is associated with phantom limb pain in above-knee amputees.
Many individuals who undergo limb amputation experience persistent phantom limb pain (PLP), but the underlying mechanisms of PLP are unknown. The traditional hypothesis was that PLP resulted from maladaptive plasticity in sensorimotor cortex that degrades the neural representation of the missing limb. However, a recent study of individuals with upper limb amputations has shown that PLP is correlated with aberrant electromyographic (EMG) activity in residual muscles, posited to reflect a retargeting of efferent projections from a preserved representation of a missing limb. Here, we assessed EMG activity in a residual thigh muscle (vastus lateralis, VL) in patients with transfemoral amputations during cyclical movements of a phantom foot. VL activity on the amputated side was compared to that recorded on patients' intact side while they moved both the phantom and intact feet synchronously. VL activity in the patient group was also compared to a sample of control participants with no amputation. We show that phantom foot movement is associated with greater VL activity in the amputated leg than that seen in the intact leg as well as that exhibited by controls. The magnitude of residual VL activity was also positively related to ratings of PLP. These results show that phantom limb movement is associated with aberrant activity in a residual muscle after lower-limb amputation and provide evidence of a positive relationship between this activity and phantom limb pain.NEW & NOTEWORTHY This study is the first to assess residual muscle activity during movement of a phantom limb in individuals with lower limb amputations. We find that phantom foot movement is associated with aberrant recruitment of a residual thigh muscle and that this aberrant activity is related to phantom limb pain.


Geographic and socioeconomic factors affecting delivery of bariatric surgery across high- and low-utilization healthcare systems.
In countries with universal health coverage, the delivery of care should be driven by need. However, other factors, such as proximity to local facilities or neighbourhood socioeconomic status, may be more important. The objective of this study was to evaluate which geographic and socioeconomic factors affect the delivery of bariatric care in Canada. This was a national retrospective cohort study of all adult patients undergoing bariatric surgery between April 2008 and March 2015 in Canada (excluding Quebec). The main outcome was neighbourhood rate of bariatric surgery per 1000 obese individuals (BMI over 30 kg/m2 ). Geographic cluster analysis and multilevel ordinal logistic regression were used to identify high-use clusters, and to evaluate the effect of geographic and socioeconomic factors on care delivery. Having a bariatric facility within the same public health unit as the neighbourhood was associated with a 6·6 times higher odds of being in a bariatric high-use cluster (odds ratio (OR) 6·60, 95 per cent c.i. 1·90 to 22·88; P = 0·003). This finding was consistent across provinces after adjusting for utilization rates. Neighbourhoods with higher obesity rates were also more likely to be within high-use clusters (OR per 5 per cent increase: 2·95, 1·54 to 5·66; P = 0·001), whereas neighbourhoods closer to bariatric centres were less likely to be (OR per 50 km: 0·91, 0·82 to 1·00; P = 0·048). In this study, across provincial healthcare systems with high and low utilization, the delivery of care was driven by the presence of local facilities and neighbourhood obesity rates. Increasing distance to bariatric centres substantially influenced care delivery.


The association of overweight and obesity with blood pressure among Chinese children and adolescents.
To examine the association between obesity and high blood pressure (BP) in Chinese children and adolescents. Body mass index (BMI) and blood pressure measurements of 197 191 children aged 7-17 years were obtained from a Chinese national survey in 2010. Obesity and high BP were defined according to the reference values for Chinese children. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of different BMI categories for high BP, as well as the population attributable risk percent (PAR%), were also calculated. The prevalence of high BP was 16.1% for boys and 12.9% for girls in 2010. Overweight and obese children had a significantly higher prevalence of high BP than non-overweight children in both boys and girls in each age group. ORs (95% CI) for high BP were 4.1 (3.9, 4.4) in obese boys and 4.0 (3.7, 4.3) in obese girls. The overall PAR% for high BP due to overweight and obesity was 14.4%. Overweight and obese children have a significantly higher risk of high BP than non-overweight children. Eliminating overweight and obesity could reduce 14.4% of high BP cases.


Bowel Angiodysplasia and Myocardial Infarction secondary to an ischaemic imbalance: a case report.
Angiodysplasia, defined as a vascular ectasia or arteriovenous malformation, is the most frequent cause of occult bleeding in patients older than 60 years and a significant association with several cardiac condition is described. Patients with anemia and negative findings on upper endoscopy and colonoscopy should be referred for further investigation of the small bowel. The investigation of choice, when available, is wireless capsule endoscopy. Several therapeutic options are available in this cases, as we reviewed in this report. We report a case of 78-year old man admitted to our Intensive Coronary Unit for dyspnea and chest pain. A diagnosis of non-ST-segment elevation acute coronary syndrome was made and a concomintant, significant anemia was found (hemoglobin 8.2 g/dl). No cororary disease was found by an angiography though the past medical history revealed systemic hypertension, chronic kidney disease (KDOQY stage III), and diabetes mellitus type II on insuline therapy. A Wireless Video capsule examination was positive for jejunum angiodysplasia and an argon plasma coagulation was chosen as terapeutic option. No subsequent supportive therapy and interventions were required in subsequent one year of follow-up.


Listening Effort and Speech Recognition with Frequency Compression Amplification for Children and Adults with Hearing Loss.
Nonlinear frequency compression (NFC) can improve the audibility of high-frequency sounds by lowering them to a frequency where audibility is better; however, this lowering results in spectral distortion. Consequently, performance is a combination of the effects of increased access to high-frequency sounds and the detrimental effects of spectral distortion. Previous work has demonstrated positive benefits of NFC on speech recognition when NFC is set to improve audibility while minimizing distortion. However, the extent to which NFC impacts listening effort is not well understood, especially for children with sensorineural hearing loss (SNHL). To examine the impact of NFC on recognition and listening effort for speech in adults and children with SNHL. Within-subject, quasi-experimental study. Participants listened to amplified nonsense words that were (1) frequency-lowered using NFC, (2) low-pass filtered at 5 kHz to simulate the restricted bandwidth (RBW) of conventional hearing aid processing, or (3) low-pass filtered at 10 kHz to simulate extended bandwidth (EBW) amplification. Fourteen children (8-16 yr) and 14 adults (19-65 yr) with mild-to-severe SNHL. Participants listened to speech processed by a hearing aid simulator that amplified input signals to fit a prescriptive target fitting procedure. Participants were blinded to the type of processing. Participants' responses to each nonsense word were analyzed for accuracy and verbal-response time (VRT; listening effort). A multivariate analysis of variance and linear mixed model were used to determine the effect of hearing-aid signal processing on nonsense word recognition and VRT. Both children and adults identified the nonsense words and initial consonants better with EBW and NFC than with RBW. The type of processing did not affect the identification of the vowels or final consonants. There was no effect of age on recognition of the nonsense words, initial consonants, medial vowels, or final consonants. VRT did not change significantly with the type of processing or age. Both adults and children demonstrated improved speech recognition with access to the high-frequency sounds in speech. Listening effort as measured by VRT was not affected by access to high-frequency sounds.


A graph-Laplacian-based feature extraction algorithm for neural spike sorting.
Analysis of extracellular neural spike recordings is highly dependent upon the accuracy of neural waveform classification, commonly referred to as spike sorting. Feature extraction is an important stage of this process because it can limit the quality of clustering which is performed in the feature space. This paper proposes a new feature extraction method (which we call Graph Laplacian Features, GLF) based on minimizing the graph Laplacian and maximizing the weighted variance. The algorithm is compared with Principal Components Analysis (PCA, the most commonly-used feature extraction method) using simulated neural data. The results show that the proposed algorithm produces more compact and well-separated clusters compared to PCA. As an added benefit, tentative cluster centers are output which can be used to initialize a subsequent clustering stage.


[Subjective health and rehabilitation needs of LVA insured patients currently applying for medical rehabilitation].
Unlike services paid through the Federal German Health Insurance, applications for medical rehabilitation are granted based on defined criteria. In some cases, rehabilitation is granted without apparent reason. Seeking to minimize this problem, this study integrates information on the subjective health status into the decision-making process of medical examiners. The return rate of the postal questionnaire (87%) as well as the evaluation of the examiners documented the practicability of the approach. The interviewed applicants described themselves as more limited in their abilities on several health dimensions (ICIDH) compared to a population of prestationary interviewed rehabilitation patients, whereby the standard deviations in both populations were similar. Furthermore, the applicants rarely utilized complementary treatments and sociomedical/legal advice. A surprising result lies in the mostly non-existent association between the subjective health status and the medical decisions. This constitutes a significant difficulty in legitimizing the decision-making process of the medical examiners.


Serum lipid parameters and the prevalence of corneal arcus in a dyslipidaemic patient population.
To determine whether an association exists between plasma lipoprotein constituents and the prevalence of corneal arcus in dyslipidaemic patients. Adult patients (n = 115) were included if their fasting total serum cholesterol concentrations exceeded the 95th percentile or their serum low-density lipoprotein (LDL) : high density lipoprotein (HDL) ratios exceeded 5. Slit-lamp assessment of the corneas was performed. The study group divided into a subgroup with arcus 37% (43) and a subgroup without arcus 63% (72). Total serum cholesterol and triglyceride levels were not associated with corneal arcus. A significant difference was found (p < 0.05) between the mean levels of LDL cholesterol (LDL-C) in the group without arcus (5.61 +/- 1.74 mmol/l) and the group with arcus (5.96 +/- 1.71 mmol/l). The mean serum HDL-cholesterol (HDL-C) in the group with corneal arcus was 1.04 +/- 0.30 mmol/l as opposed to 1.31 +/- 0.38 mmol/l in the group without arcus (p < 0.005 for difference). The mean LDL-C : HDL-C ratio in the group without arcus was 4.28 (SD: 1.99), and 5.73 (SD: 2.09) in the group with a corneal arcus (p < 0.05). Low HDL-C levels, high LDL-C levels and LDL-C : HDL-C ratios > 5 have been implicated as risk factors of numerous circulatory diseases. The observations in this study suggest that the presence of corneal arcus in the dyslipidaemic patient correlates strongly with these same risk indicators.


Accessing health information during the COVID-19 pandemic: the experience of NHS maternity service users.
The COVID-19 pandemic caused various disruptions to NHS maternity services in England. Changes were made to antenatal and postnatal care and the way that information was shared with maternity service users during these times. Fewer face-to-face appointments, increased virtual appointments and changes in guidance about the suitability of the COVID-19 vaccine without appropriate information sharing and evidence caused concern. This study took a blended inductive-deductive approach to secondary data analysis using a population subset of 16 from a wider study that sought to understand the impact of COVID-19 on maternity services in England. Participants of this study were aged 28-44 and gave birth using NHS maternity services in England. The data were collected and coded using Rapid Analysis Procedure sheets, which generated key themes, which are used here to structure the results. Four main themes were generated from the analysis: 1) service restrictions to antenatal and postnatal appointments 2) access to information and changes to antenatal and postnatal care 3) inconsistencies in the implementation of government and NHS policy and 4) limited information about COVID-19 vaccine provided by NHS trusts and hesitancy in vaccine acceptance. Participants experienced poor communication that affected their understanding of maternity service changes and there was limited general and maternal health information provided. Vaccine information was also inadequate, and participants expressed a desire for clearer guidance. The UK Government, Royal College of Obstetricians and Gynaecologists, and NHS must collaborate with maternity service users to ensure that there are evidence-based guidelines and policies that can be understood and standardised across all NHS maternity trusts.


Long-term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus-related cirrhosis.
The effect of viral suppression on long-term disease outcome after decompensation in patients with hepatitis B virus (HBV)-related cirrhosis has not been established. The aim of this study was to determine the long-term effect of antiviral therapy (AVT) in patients with HBV-related decompensated cirrhosis. This was a multicenter, prospective, inception cohort study of 707 patients who presented with first-onset decompensated complications, including 284 untreated and 423 antiviral-treated patients (58 previously treated, 253 with early treatment, and 112 with delayed treatment). The primary endpoint was 5-year liver transplantation (LT)-free survival. Secondary endpoints included virological response (VR) and serological response and improvement in liver function. Despite baseline high HBV activity and worse liver function, antiviral-treated patients had significantly better transplant-free survival than untreated patients (5-year survival rates of 59.7% vs. 46.0%, respectively), with more apparent benefits from antivirals in Child-Turcotte-Pugh class B/C and high-viremia groups. The rate of VR and hepatitis B e antigen seroconversion at 5 years in antiviral-treated patients was 14.2% and 49.1%, respectively. A significant improvement in liver function was observed in treated versus untreated patients, with 33.9% of treated patients delisted for LT. Patients with early treatment had better clinical outcomes than those with delayed treatment. Survival was dependent on antiviral response, being significantly better in responders than in nonresponders or untreated cases. The initial benefit of AVT was negated over time in nonresponders. Antiviral treatment and maintained VR remained independently predictive of survival. The study results were corroborated by propensity score-matching analysis. AVT significantly modifies the natural history of decompensated cirrhosis, improving liver function and increasing survival. The results underscore the importance of promptly administering potent antiviral drugs to patients under consideration for LT.


Real-World Adherence and Persistence to Oral Disease-Modifying Therapies in Multiple Sclerosis Patients Over 1 Year.
Disease-modifying therapies (DMTs) are indicated to reduce relapse rates and slow disease progression for relapsing-remitting multiple sclerosis (MS) patients when taken as prescribed. Nonadherence or non-persistence in the real-world setting can lead to greater risk for negative clinical outcomes. Although previous research has demonstrated greater adherence and persistence to oral DMTs compared with injectable DMTs, comparisons among oral DMTs are lacking. To compare adherence, persistence, and time to discontinuation among MS patients newly prescribed the oral DMTs fingolimod, dimethyl fumarate, or teriflunomide. This retrospective study used MarketScan Commercial and Medicare Supplemental claims databases. MS patients with ≥ 1 claim for specified DMTs from April 1, 2013, to June 30, 2013, were identified. The index drug was defined as the first oral DMT within this period. To capture patients newly initiating index DMTs, patients could not have a claim for their index drugs in the previous 12 months. Baseline characteristics were described for patients in each treatment cohort. Adherence, as measured by medication possession ratio (MPR) and proportion of days covered (PDC); persistence (30-day gap allowed); and time to discontinuation over a 12-month follow-up period were compared across treatment cohorts. Adjusted logistic regression models were used to examine adherence, and Cox regression models estimated risk of discontinuation. 1,498 patients newly initiated oral DMTs and met study inclusion criteria: fingolimod (n = 185), dimethyl fumarate (n = 1,160), and teriflunomide (n = 143). Patients were similar across most baseline characteristics, including region, relapse history, and health care resource utilization. Statistically significant differences were observed across the treatment cohorts for age, gender, previous injectable/infused DMT use, and comorbidities. Adherence and time to discontinuation were adjusted for age, gender, region, previous oral and injectable/infused DMT use, relapse history, and Charlson Comorbidity Index score. Relative to fingolimod patients, dimethyl fumarate and teriflunomide patients were significantly less likely to have an MPR ≥ 80% (OR = 0.18; 95% CI = 0.09-0.36; P < 0.001 and OR = 0.19; 95% CI = 0.08-0.42; P < 0.001, respectively). Similarly, relative to fingolimod patients, dimethyl fumarate and teriflunomide patients were significantly less likely to have PDC ≥ 80% (OR = 0.47; 95% CI = 0.33-0.67; P < 0.001 and OR = 0.37; 95% CI = 0.23-0.59; P < 0.001, respectively). Additionally, the HR for discontinuation was about 2 times greater for dimethyl fumarate (HR = 1.93; 95% CI = 1.44-2.59; P < 0.001) and teriflunomide patients (HR = 2.27; 95% CI = 1.57-3.28; P < 0.001) compared with fingolimod. In a real-world setting, patients taking fingolimod had better adherence and persistence compared with patients taking other oral DMTs over 12 months. Coupled with clinical factors, medication adherence and persistence should be important considerations when determining coverage decisions for MS patients. This research was funded by Novartis Pharmaceuticals. Johnson, Lin, Ko, and Herrera are employed by Novartis Pharmaceuticals and own Novartis stock. Huanxue Zhou is employed by KMK Consulting, which provides consulting services to Novartis. Study concept and design were contributed by Johnson, Lin, Ko, and Herrera. Zhou collected the data, and data interpretation was performed by Johnson, Lin, Ko, and Herrera. All authors were involved in manuscript revision. The abstract for this study was presented at the AMCP Nexus 2015; October 26-29, 2015; Orlando, Florida.


[Communicating with elderly patients].
As with other adults, communication with elderly patients will be based on the three pillars of the person-centered approach, on motivational interviewing and on the Calgary Cambridge guide. The particularity of communication with the elderly lies in the consideration of obstacles such as visual, auditory and cognitive deficits. In addition, caregivers who accompany the patient sometimes monopolize the discussion, which could prevent him from expressing himself or even making decisions about his health. Humanity and Validation are a set of tools for communicating more effectively with the very elderly or those suffering from dementia.


[Development of guidelines for rehabilitation of patients with stroke: analysis of therapeutic procedures].
The Federal Insurance Institute for Salaried Employees (BfA, Bundesversicherungsanstalt für Angestellte) in Berlin took the initiative to develop evidence-based guidelines for rehabilitation including stroke rehabilitation. In the present study we performed a systematic survey of the scientific literature on stroke rehabilitation and deduced 8 evidence-based therapeutic modules. They were supplemented by 5 practice-based modules to cover the full range of interventions currently applied in stroke rehabilitation. Modules are clusters of various interventions which were aggregated according to the rehabilitative goal they have in common. Data were analysed from 8,876 BfA patients, the total population of "neuro"-patients in 2001 and 2002 with 142,951 interventions and 1,071,885 appointments. Stroke diagnoses covered ICD-10 codes I60, I61, I62, I63, I64 or were coded by G45, G81 and one of these I-codes. Stroke rehabilitation as provided in daily practice was found to be a complex multimodal treatment programme in all hospitals which were studied. On average, patients receive treatments from 7.3 therapeutic modules. A dominating role is played by "motor modules". Obviously, they play a major role in acute stroke rehabilitation in all hospitals compared to cognitive retraining, language therapy and especially improvement of psychic functions, which were significantly less applied. A dramatic variation could be shown to exist between the rehabilitation hospitals (1) with respect to the number of patients who were treated with a given module (e. g., some modules showed variations between 18 % and 100 %), and (2) with respect to treatment intensity and treatment duration per week. Several factors can be taken into account for interpretation of this high variance. Intrinsically, the high variation in symptomatology after stroke can play a major role, as both the deficit profile and the level of severity of a given deficit and the combined severity level can vary from patient to patient. On the other hand, extrinsic factors such as lack of staff may also account for some of the differences. In any case, the results show the necessity to optimize stroke rehabilitation by development and implementation of guidelines. Yet, they also point to a need for further research into rehabilitation interventions and procedures to yield evidence for the approximately 30 % of "only" practice-based interventions.