Play in the reading room: Utilizing soft modeling compound to teach musculoskeletal anatomy and pathology.
Musculoskeletal (MSK) anatomy and pathology from a radiology perspective can be difficult to conceptualize and understand due to the challenge of visualizing 3D structures in stacks of 2D imaging. Consequently, trainees may benefit from inexpensive methods that can help trainees better visualize MSK anatomy and pathology. The purpose of this study is to provide proof of concept for inexpensive methodology to help learners such as radiology residents quickly and inexpensively understand musculoskeletal anatomy and pathology. This can help trainees become better at applying musculoskeletal knowledge to clinical practice. Soft-modeling compounds such as Play-Doh® was utilized in a variety of colors with pottery tools to recreate 3D models of challenging MSK anatomy and pathology for trainees. Qualitative feedback from the residents was collected. Eighteen different pathological conditions across six major bone structures were modeled with a soft modeling compound. Residents qualitatively identified the experience as educational in terms of helping them better understand MSK pathology and positive in terms of making learning fun, less stressful, and memorable due to uniqueness of the learning modality. Residents report challenges modeling complex anatomical features and pathology via this methodology. Radiology residents and other learners can enhance their knowledge of musculoskeletal anatomy and pathology via utilization of inexpensive soft modeling compounds. This may offer a cheaper and more time sensitive alternative to current 3-dimensional hardware and software technologies being developed for educational purposes. Additional work needs to be done to examine the utility of this methodology across larger and diverse groups of learners.


Unguiculin A and Ptilomycalins E-H, Antimalarial Guanidine Alkaloids from the Marine Sponge Monanchora unguiculata.
Chemical study of the CH2Cl2-MeOH (1:1) extract from the sponge Monanchora unguiculata collected in Madagascar highlighted five new compounds, one acyclic guanidine alkaloid, unguiculin A (1) and four pentacyclic alkaloids, ptilomycalins E-H (2-5), along with four known compounds: crambescidin 800 (6) and crambescidin 359 (7), crambescidic acid (8), and fromiamycalin (9). Their structures were elucidated by 1D and 2D NMR spectra and HRESIMS data. All compounds were evaluated for their cytotoxicity against KB cells and their antiplasmodial activity. The new ptilomycalin E (2) and the mixture of the new ptilomycalins G (4) and H (5) showed promising cytotoxicity against KB cells with IC50 values of 0.85 and 0.92 μM, respectively. Ptilomycalin F (3) and fromiamycalin (9) exhibited promising activity against Plasmodium falciparum with IC50 values of 0.23 and 0.24 μM, respectively.


TRAIL: at the center of drugable anti-tumor pathways.
Molecular analysis, in vivo and in vitro has identified TRAIL as a central component of anti-cancer networks in the cell. More recently, TRAIL has been shown to be involved in the selective apoptosis of AML cells by histone deacetylase inhibitors (HDACi). Here we summarize findings that the TRAIL pathway is a key factor in the apoptotic action of HDACi, as well as, retinoids and retinoid-combinations.


Improved membrane filter method for fecal coliform analysis.
A two-layer agar method has been developed which consistently yields higher recovery of fecal coliforms on membrane filters when compared to the existing membrane fecal coliform procedure. This method has been evaluated by three laboratories using samples of raw and chlorinated waste water, and reservoir, river, and marine waters. Verification of 1,013 fecal coliform colonies isolated from 61 water samples averaged 92% on this proposed procedure. Comparison with the Standard Methods membrane fecal coliform procedure revealed the two-layer agar method had an overall increased sensitivity to fecal coliform detection in these waters. It is therefore proposed that this procedure be evaluated as an alternative to the Standard Methods fecal coliform membrane Filter test in the examination of chlorinated secondary effluents, marine waters, and any natural waters that may contain pollutants with heavy metal ions.


Task sharing in rural Haiti: Qualitative assessment of a brief, structured training with and without apprenticeship supervision for community health workers.
Despite growing support for supervision after task sharing trainings in humanitarian settings, there is limited research on the experience of trainees in apprenticeship and other supervision approaches. Studying apprenticeships from trainees' perspectives is crucial to refine supervision and enhance motivation for service implementation. The authors implemented a multi-stage, transcultural adaptation for a pilot task sharing training in Haiti entailing three phases: 1) literature review and qualitative research to adapt a mental health and psychosocial support training; 2) implementation and qualitative process evaluation of a brief, structured group training; and 3) implementation and qualitative evaluation of an apprenticeship training, including a two year follow-up of trainees. Structured group training revealed limited knowledge acquisition, low motivation, time and resource constraints on mastery, and limited incorporation of skills into practice. Adding an apprenticeship component was associated with subjective clinical competency, increased confidence regarding utilising skills, and career advancement. Qualitative findings support the added value of apprenticeship according to trainees.


Inflammatory bowel disease patient profiles are related to specific information needs: A nationwide survey.
Inflammatory bowel diseases (IBD) is a heterogenous, lifelong disease, with an unpredictable and potentially progressive course, that may impose negative psychosocial impact on patients. While informed patients with chronic illness have improved adherence and outcomes, previous research showed that the majority of IBD patients receive insufficient information regarding their disease. The large heterogeneity of IBD and the wide range of information topics makes a one-size fits all knowledge resource overwhelming and cumbersome. We hypothesized that different patient profiles may have different and specific information needs, the identification of which will allow building personalized computer-based information resources in the future. To evaluate the scope of disease-related knowledge among IBD patients and determine whether different patient profiles drive unique information needs. We conducted a nationwide survey addressing hospital-based IBD clinics. A Total of 571 patients completed a 28-item questionnaire, rating the amount of information received at time of diagnosis and the importance of information, as perceived by participants, for a newly diagnosed patient, and for the participants themselves, at current time. We performed an exploratory factor analysis of the crude responses aiming to create a number of representative knowledge domains (factors), and analyzed the responses of a set of 15 real-life patient profiles generated by the study team. Participants gave low ratings for the amount of information received at disease onset (averaging 0.9/5) and high ratings for importance, both for the newly diagnosed patients (mean 4.2/5) and for the participants themselves at current time (mean 3.5/5). Factor analysis grouped responses into six information-domains. The responses of selected profiles, compared with the rest of the participants, yielded significant associations (defined as a difference in rating of > 0.5 points with a P < 0.05). Patients with active disease showed a higher interest in work-disability, stress-coping, and therapy-complications. Patients newly diagnosed at age > 50, and patients with long-standing disease (> 10 years) showed less interest in work-disability. Patients in remission with mesalamine or no therapy showed less interest in all domains except for nutrition and long-term complications. We demonstrate unmet patient information needs. Analysis of various patient profiles revealed associations with specific information topics, paving the way for building patient-tailored information resources.


Pseudotumor cerebri associated with cyclosporine use in severe atopic dermatitis.
Cyclosporine use can cause neurologic complications in 0.5% to 35% of cases, although the appearance of pseudotumor cerebri (PC) is exceptional. PC secondary to the use of cyclosporine is described mainly in individuals who have received a bone marrow transplant. We report the first case, to our knowledge, of PC secondary to the use of cyclosporine in a child with severe atopic dermatitis, with satisfactory resolution and without vision sequelae.


Cryptococcal meningoencephalitis.
A patient was admitted to hospital with an apparent psychiatric disturbance. When she became stuporous the cerebrospinal fluid was cultured but proved sterile. The latex test showed that serum was positive for cryptococcal antigens, and cryptococcal meningoencephalitis was diagnosed. Amphotericin B was given but when she developed a toxic reaction it was replaced by flucytosine. She responded well to flucytosine alone and no side effects appeared on continued treatment. Cryptococcal meningitis may present as a psychiatric disturbance, and serological tests are invaluable aids to diagnosis.


Inhibition of cholesterol synthesis reduces low-density-lipoprotein apoprotein B production without decreasing very-low-density-lipoprotein apoprotein B synthesis in rabbits.
The kinetics of the apoprotein B (apo B) of very-low-density (VLDL; d less than 1.006) and low-density (LDL; d 1.019-1.063) lipoproteins were studied in six rabbits by using radioiodinated homologous lipoproteins, before and during oral administration of mevinolin (5 mg/kg per day), a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 220.127.116.11), to explore the mechanism by which the drug reduces LDL synthesis. Before treatment LDL-apo B production greatly exceeded VLDL-apo B production in all animals, indicating that a large proportion of plasma LDL was derived from a VLDL-independent pathway. Five animals responded to mevinolin with a fall in plasma cholesterol (mean change - 53%; P less than 0.01). This was associated with a 66% decrease in LDL-apo B synthesis (P less than 0.05). In contrast, VLDL-apo B synthesis was unaffected by mevinolin. Furthermore, in all but one animal the decrement in LDL-apo B synthesis was greater than the rate of VLDL-apo B synthesis before treatment, demonstrating that mevinolin had reduced the VLDL-independent production of LDL.


A dysbiosis index to assess microbial changes in fecal samples of dogs with chronic inflammatory enteropathy.
Recent studies have identified various bacterial groups that are altered in dogs with chronic inflammatory enteropathies (CE) compared to healthy dogs. The study aim was to use quantitative PCR (qPCR) assays to confirm these findings in a larger number of dogs, and to build a mathematical algorithm to report these microbiota changes as a dysbiosis index (DI). Fecal DNA from 95 healthy dogs and 106 dogs with histologically confirmed CE was analyzed. Samples were grouped into a training set and a validation set. Various mathematical models and combination of qPCR assays were evaluated to find a model with highest discriminatory power. The final qPCR panel consisted of eight bacterial groups: total bacteria, Faecalibacterium, Turicibacter, Escherichia coli, Streptococcus, Blautia, Fusobacterium and Clostridium hiranonis. The qPCR-based DI was built based on the nearest centroid classifier, and reports the degree of dysbiosis in a single numerical value that measures the closeness in the l2 - norm of the test sample to the mean prototype of each class. A negative DI indicates normobiosis, whereas a positive DI indicates dysbiosis. For a threshold of 0, the DI based on the combined dataset achieved 74% sensitivity and 95% specificity to separate healthy and CE dogs.


Effect of intravenous immunoglobulin therapy on anti-NT5C1A antibody-positive inclusion body myositis after successful treatment of hepatitis C: A case report.
Inclusion body myositis (IBM) is the commonest idiopathic inflammatory myopathy of older persons. Pathophysiological mechanism of IBM remains unknown; however, an association of IBM with chronic hepatitis C virus (HCV) infection and serum autoantibodies against skeletal muscle protein 5'-nucleotidase 1A (NT5C1A) has recently been reported. No effective treatment for IBM has yet been developed. We here present a 70-year-old man who was anti-NT5C1A antibody-positive in association with IBM and chronic hepatitis C. The initial treatment of ombitasvir/paritaprevir/ritonavir for his chronic hepatitis C was successful; however, his symptoms of IBM did not improve. On the contrary, his quadriplegic paralysis became more severe and he developed dysphagia. Next, steroid pulse therapy was initiated for IBM and, although his hyper-creatine phosphokinase-emia improved, his symptoms did not; indeed, they worsened. Subsequent intravenous immunoglobulin therapy (IVIg) resulted in obvious improvement in his dysphagia. Thereafter IVIg therapy was repeated at approximately 2-monthly intervals. His dysphagia remained improved for more than 1 year; however, his quadriplegia continued to progress slowly. Although IBM can reportedly be associated with hepatitis C, we inferred that there was no direct relationship between these conditions in our patient because his IBM did not improve after treatment of his hepatitis C. Although his IBM-associated quadriplegia did not improve, IVIg therapy did result in improvement in his dysphagia.


Particulate matter exposure induces persistent lung inflammation and endothelial dysfunction.
Epidemiologic and animal studies have shown that exposure to particulate matter air pollution (PM) is a risk factor for the development of atherosclerosis. Whether PM-induced lung and systemic inflammation is involved in this process is not clear. We hypothesized that PM exposure causes lung and systemic inflammation, which in turn leads to vascular endothelial dysfunction, a key step in the initiation and progression of atherosclerosis. New Zealand White rabbits were exposed for 5 days (acute, total dose 8 mg) and 4 wk (chronic, total dose 16 mg) to either PM smaller than 10 mum (PM(10)) or saline intratracheally. Lung inflammation was quantified by morphometry; systemic inflammation was assessed by white blood cell and platelet counts and serum interleukin (IL)-6, nitric oxide, and endothelin levels. Endothelial dysfunction was assessed by vascular response to acetylcholine (ACh) and sodium nitroprusside (SNP). PM(10) exposure increased lung macrophages (P<0.02), macrophages containing particles (P<0.001), and activated macrophages (P<0.006). PM(10) increased serum IL-6 levels in the first 2 wk of exposure (P<0.05) but not in weeks 3 or 4. PM(10) exposure reduced ACh-related relaxation of the carotid artery with both acute and chronic exposure, with no effect on SNP-induced vasodilatation. Serum IL-6 levels correlated with macrophages containing particles (P=0.043) and ACh-induced vasodilatation (P=0.014 at week 1, P=0.021 at week 2). Exposure to PM(10) caused lung and systemic inflammation that were both associated with vascular endothelial dysfunction. This suggests that PM-induced lung and systemic inflammatory responses contribute to the adverse vascular events associated with exposure to air pollution.


Staining the Germline in Live Caenorhabditis elegans: Overcoming Challenges by Applying a Fluorescent-dye Feeding Strategy.
C. elegans provides a tractable model organism for studying germline cell biology. Microscopy experiments are relatively facile, as this worm is transparent and germline development can be observed in real-time using DIC microscopy and/or fluorescent transgenes. Despite these many tools, robust staining techniques for imaging germ cells in live worms have been more elusive, due to the tough outer cuticle of the worm, which impairs staining efficiency. This limitation has restricted the spectrum of probes that can be used to investigate reproductive cell biology in C. elegans. Building on previous approaches, I recently applied a fluorescent-dye feeding strategy to reproducibly label organelles and monitor physiological changes in germlines of living C. elegans. In this approach, fluorescent dyes are initially introduced into the agar plates and bacterial lawns on which worms are subsequently cultured. After worms are grown on the dyed plates, oocytes show staining patterns consistent with verified transgenic markers. Thus, this approach offers an effective solution for labeling difficult-to-stain tissues in live worms, and establishes an entry point for incorporating new probes and sensors into analyses of C. elegans germline biology.


Ketamine and norketamine stability in whole blood at ambient and 4°C conditions.
A study was implemented to describe the pharmacokinetics (PK) of ketamine (K) and its metabolite norketamine (NK) in critically ill adults. Conducting studies in these subjects is hindered by the immediate need to process and freeze samples obtained in a busy intensive care setting. The ability to store unprocessed samples at room temperature for an extended time period would overcome this barrier. Stability and blood to plasma partitioning of K and NK were investigated in whole blood for up to 120 h at room temperature and 4°C. Whole blood was spiked with K and NK (1000 ng/mL each). Blood samples were aliquoted at different time points (0-120 h), extracted and analyzed using a validated high-performance liquid chromatography tandem mass spectrometry assay. The study demonstrated the stability of both K and NK in whole blood up to 120 h. These in vitro studies suggest that the concentrations of K and NK measured in the PK samples are reliable. The established stability results were successfully employed to investigate K and NK pharmacology studies in critically ill adults.


On the origin of the chordate central nervous system: expression of onecut in the sea urchin embryo.
We identified a transcription factor of the onecut class in the sea urchin Strongylocentrotus purpuratus that represents an ortholog of the mammalian gene HNF6, the founding member of the onecut class of proteins. The isolated sea urchin gene, named SpOnecut, encodes a protein of 483 amino acids with one cut domain and a homeodomain. Phylogenetic analysis clearly places the sea urchin gene into this family, most closely related to the ascidian onecut gene HNF-6. Nevertheless, phylogenetic analysis reveals a difficult phylogeny indicating that certain members of the family evolve more rapidly than others and also that the cut domain and homeodomain evolve at a different pace. In fly, worm, ascidian, and teleost fish, the onecut genes isolated so far are exclusively expressed in cells of the central nervous system (CNS), whereas in mammals the two copies of the gene have acquired additional functions in liver and pancreas development. In the sea urchin embryo, expression is first detected in the emerging ciliary band at the late blastula stage. During the gastrula stage, expression is limited to the ciliary band. In the early pluteus stage, SpOnecut is expressed at the apical organ and the elongating arms but continues most prominently in the ciliary band. This is the first gene known that exclusively marks the ciliary band and therein the apical organ in a pluteus larva, whereas chordate orthologs execute essential functions in dorsal CNS development. The significance of this finding for the hypothesis that the ciliary bands and apical organs of the hypothetical "dipleurula"-like chordate ancestor and the chordate/vertebrate CNS are of common origin is discussed.


The sonoanatomy of lumbar erector spinae and its iliac attachment - the potential substrate of the iliac crest pain syndrome, an ultrasound study in healthy subjects.
Iliac crest pain syndrome is a regional pain syndrome that has been identified in many patients with low back pain. Based on anatomical studies, it was suggested that the potential substrate of this syndrome might be the enthesis of the erector spinae muscle at the posterior medial iliac crest. As there have been no imaging studies of this important enthesis, our aim was to assess its characteristics by ultrasound. Erector spinae enthesis was first studied in a cadaver. Then its characteristics were recorded in 25 healthy volunteers (median age: 28.92, SD: 5.31, mean Body Mass Index 22.61, SD: 3.38), with Esaote My Lab 7 machine using linear transducer (4-13 MHz). The cadaver study confirmed the attachment of a substantial part of erector spinae to a well-defined region on the medial posterior iliac crest. The US study in the volunteers consistently showed the entheses as typical hyperechoic fibrillar structures, slightly oblique to the skin in the longitudinal plane and attaching to the iliac crest. In the transverse plane, the entheses were seen as oval, densely dotted structures in contact with the superior edge of posterior superior iliac spine. Their mean thickness (4.9 ± 0.6 and 5.2 ± 0.7 mm longitudinally; 4.3 ± 0.6 and 4.4 ± 0.7 mm transversely), maximum width (16.3 ± 2.8 and 15.7 ± 2.3 mm) and depth (10.8 ± 7.3 and 10.6 ± 6.2 mm) on the left and right side, respectively, as well as their echostructure were recorded and described. The erector spinae entheses could be assessed in detail by ultrasound, thus their pathological transformation associated with iliac crest pain syndrome could be identified.


Topological equivalence of optical crossover networks and modified data manipulator networks.
The crossover network is a multistage interconnection network that shows potential for use in optical computing and photonic switching applications. In this paper, a proof of topological equivalence between the crossover network and the modified data manipulator network is presented. It is shown that the Gray Code can be used as the mapping function between the crossover network and a network which is equivalent to the modified data manipulator network. Given the results of this proof, the optical crossover network can then be proposed as the optical interconnection fabric for many switching and computing applications.


Silymarin Ameliorates Oxidative Stress and Enhances Antioxidant Defense System Capacity in Cadmium-Treated Mice.
Cadmium is an environmental pollutant which induces oxidative stress while silymarin as an antioxidant is able to scavenge free radicals. The aim of the present study was to investigate the effect of silymarin on oxidative stress markers and antioxidant defense system capacity in mice treated with cadmium chloride. In this experimental study, adult mice were divided into four groups as follow: i. Control, ii. Cadmium chloride (5 mg/kg b.w., s.c.), iii. Silymarin+cadmium chloride, and iv. Silymarin (100 mg/kg b.w., i.p.). Mice were treated with cadmium chloride for 24 hours and silymarin was administered 24 hours before the cadmium. Blood samples were then collected from the experimental groups and their sera were prepared. To investigate oxidative stress markers in the serum, the amount of malondialdehyde (MDA) and thiol groups (-SH) were evaluated. To measure the total antioxidant power in the serum, Ferric Reducing/ Antioxidant Power (FRAP) method was used. In addition, the activity of enzymes including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) was assessed to evaluate serum antioxidant defense power. In the cadmium-treated group, the amount of MDA significantly increased as compared to the control group. In silymarin+cadmium group, silymarin significantly ameliorated the level of MDA compared to the cadmium group. In addition, cadmium significantly reduced serum FRAP, the activity of antioxidant defense system enzymes and thiol groups compared to the control. In silymarin+cadmium group, silymarin could significantly reverse the reduction of these markers compared to the cadmium group. Administration of silymarin alone caused a significant increase in serum FRAP, the activity of antioxidant defense system enzymes and thiol groups compared to the control group. Silymarin as a powerful antioxidant reverses the toxic effect of cadmium on the serum levels of lipid peroxidation, total antioxidant power, antioxidant defense system enzymes activity and thiol groups.


Novel concepts in nontypeable Haemophilus influenzae biofilm formation.
Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative microbe that frequently colonizes the human host without obvious signs of inflammation, but is also a frequent cause of otitis media in children and exacerbations in chronic obstructive pulmonary disease patients. Accumulating data suggest that NTHi can reside in biofilms during both colonization and infection. Recent literature proposes roles for phosphorylcholine, sialic acid, bacterial DNA, but also eukaryotic DNA in the development of NTHi biofilms. However, many questions remain. Until now, there are insufficient data to explain how NTHi forms biofilms. Here, we review the recent advances in NTHi biofilm formation with particular focus on the role that neutrophils may play in this process. We propose that recruitment of neutrophils facilitates NTHi biofilm formation on mucosal sites by the initiation of neutrophil extracellular traps.


Intraoperative Death During Cervical Spinal Surgery: A Retrospective Multicenter Study.
A retrospective multicenter study. Routine cervical spine surgeries are typically associated with low complication rates, but serious complications can occur. Intraoperative death is a very rare complication and there is no literature on its incidence. The purpose of this study was to determine the intraoperative mortality rates and associated risk factors in patients undergoing cervical spine surgery. Twenty-one surgical centers from the AOSpine North America Clinical Research Network participated in the study. Medical records of patients who received cervical spine surgery from January 1, 2005, to December 31, 2011, were reviewed to identify occurrence of intraoperative death. A total of 258 patients across 21 centers met the inclusion criteria. Most of the surgeries were done using the anterior approach (53.9%), followed by posterior (39.1%) and circumferential (7%). Average patient age was 57.1 ± 13.2 years, and there were more male patients (54.7% male and 45.3% female). There was no case of intraoperative death. Death during cervical spine surgery is a very rare complication. In our multicenter study, there was a 0% mortality rate. Using an adequate surgical approach for patient diagnosis and comorbidities may be the reason how the occurrence of this catastrophic adverse event was prevented in our patient population.


The peroxidase-catalysed oxidation of a chalcone and its possible physiological significance.
1. Crystalline horseradish peroxidase catalysed the oxidation of 2',4,4'-trihydroxychalcone (isoliquiritigenin) in the presence of trace amounts of hydrogen peroxide under aerobic conditions. One atom of oxygen was consumed for each molecule of substrate. 2. The reaction course comprised a lag phase and a linear phase. The optimum pH for the linear phase of the reaction was about 7.5. The length of the lag phase decreased with increasing pH. It is suggested that the chalcone anion is the actual substrate for the reaction. 3. No evidence for the production of reducing free radicals or perhydroxyl radicals during the reaction could be found. 4. 4',7-Dihydroxyflavonol and 4',6-dihydroxyaurone were isolated from the reaction mixture. The immediate products of the reaction may have included 3,4',7-trihydroxyflavanone and 4',6-dihydroxy-2-(alpha-hydroxybenzyl)coumaran-one, which can be readily converted non-enzymically into the flavonol and aurone respectively. 5. A similar reaction was catalysed by cell-free extracts of hypocotyls of Phaseolus vulgaris. 6. The physiological significance of the reaction is discussed in terms of a possible free-radical mechanism. An analogy may exist between flavonoid biosynthesis and lignin formation.


An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm.
Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9-MALAT1-BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.


Comparative Study of Artificial Intelligence Techniques for the Diagnosis of Chronic Nerve Diseases.
Farming is essential to the long-term viability of any economy. It differs in each country, but it is essential for long-term economic success. Only a few of the agricultural industry's issues include a lack of suitable irrigation systems, weeds, and plant monitoring concerns as a consequence of efficient management in distinct open and closed zones for crop and plant treatment. The objective of this work is to carry out a study on the use of artificial intelligence and computer vision methods for diagnosis of diseases in agro sectors in the context of agribusiness, demonstrating the feasibility of using these techniques as tools to support automation and obtain productivity gains in this sector. During the literary analysis, it was determined that technology could improve efficiency, hence decreasing these types of concerns. Given the consequences of a wrong diagnosis, diagnosis is work that requires a high level of precision. Fuzzy cognitive maps were shown to be the most efficient method of utilizing bibliographically reviewed preferences, which led to the consideration of neural networks as a second option because this technique is the most robust in terms of the qualifying criteria of the data stored in databases.


Evaluation of Correlation between Psychomotor Vigilance Task Scores and Drowsiness Estimation Levels Obtained from Facial Videos.
This paper reports the results of an experiment to evaluate the relationship between results obtained with a drowsiness estimation system we have developed using facial videos and those obtained with the Psychomotor Vigilance Task (PVT), which is a standard index of sleepiness used in sleep medicine. The correlation between PVT scores and the output of the drowsiness estimation system, which outputs drowsiness levels from assigned facial expressions, was calculated using data from 30 subjects. The Spearman's correlation coefficients between the drowsiness estimation results and the PVT mean response time, the slowest 10% response time, and the number of lapses were 0.36 (p <0.001), 0.43 (p <0.001), and 0.40 (p <0.001), respectively. Since this experiment showed a correlation between the drowsiness estimation results and those with PVT, it would seem possible to make specific interventions based on drowsiness estimation results learned from ground-truth drowsiness levels. Such estimation results could help prevent accidents resulting from drowsiness or insufficient vigilance while driving or working.


Molecular cloning of the murine adenosine deaminase gene from a genetically enriched source: identification and characterization of the promoter region.
A genomic library was prepared with DNA from a genetically enriched mouse cell line in which amplified copies of the adenosine deaminase (ADA) gene account for over 5% of the genome. Overlapping cosmid clones encompassing the entire ADA structural gene were isolated from this genomic library and used for subsequent structural and functional analyses. Nuclease protection and primer extension analyses served to identify the location of multiple transcription initiation sites at the 5' end of the structural gene. Promoter activity was found by functional analyses to reside within a 240-base-pair fragment which contains the transcription initiation sites. Sequences upstream of the transcription initiation sites are very G + C rich (77%) and include a 22 nucleotide stretch of deoxyguanylate residues and two potential Sp1 transcription factor-binding sites. Comparison of the mouse and human ADA gene promoters revealed the presence of several regions that are highly conserved with regard to both sequence content and location and may represent genetic elements which are involved in ADA gene expression.


Prevalence and characteristics of hypoxic hepatitis in the largest single-centre cohort of avian influenza A(H7N9) virus-infected patients with severe liver impairment in the intensive care unit.
Avian influenza A(H7N9) virus (A(H7N9)) emerged in February 2013. Liver impairment of unknown cause is present in 29% of patients with A(H7N9) infection, some of whom experience severe liver injury. Hypoxic hepatitis (HH) is a type of acute severe liver injury characterized by an abrupt, massive increase in serum aminotransferases resulting from anoxic centrilobular necrosis of liver cells. In the intensive care unit (ICU), the prevalence of HH is ∼1%-2%. Here, we report a 1.8% (2/112) incidence of HH in the largest single-centre cohort of ICU patients with A(H7N9) infection. Both HH patients presented with multiple organ failure (MOF) involving respiratory, cardiac, circulatory and renal failure and had a history of chronic heart disease. On admission, severe liver impairment was found. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were 937 and 1281 U/L, and 3117 and 3029 U/L, respectively, in the two patients. Unfortunately, both patients died due to deterioration of MOF. A post-mortem biopsy in case 1 confirmed the presence of centrilobular necrosis of the liver, and real-time reverse transcription polymerase chain reaction of A(H7N9)-specific genes was negative, which excluded A(H7N9)-related hepatitis. The incidence of HH in A(H7N9) patients is similar to that in ICU patients with other aetiologies. It seems that patients with A(H7N9) infection and a history of chronic heart disease with a low left ventricular ejection fraction on admission are susceptible to HH, which presents as a marked elevation in ALT at the time of admission.


Inhibiting interspecies coaggregation of plaque bacteria with a cranberry juice constituent [published erratam appear in J Am Dent Assoc 1999 Jan;130(1):36 and 1999 Mar;130(3):332].
Dental plaque stability depends on bacterial adhesion to acquired pellicle, and on interspecies adhesion (or coaggregation). A high-molecular-weight cranberry constituent at 0.6 to 2.5 milligrams per milliliter reversed the coaggregation of 49 (58 percent) of 84 coaggregating bacterial pairs tested. It acted preferentially on pairs in which one or both members are gram-negative anaerobes frequently involved in periodontal diseases. Thus, the anticoaggregating cranberry constituent has the potential for altering the subgingival microbiota, resulting in conservative control of gingival and periodontal diseases. However, the high dextrose and fructose content of the commercially available cranberry juice makes it unsuitable for oral hygiene use, and the beneficial effect of the high-molecular-weight constituent requires animal and clinical studies.


Association between total body muscle percentage and prevalence of non-alcoholic fatty liver disease in Korean adults findings from an 18-year follow-up: a prospective cohort study.
This study aimed to elucidate the association between total lean muscle mass and the incidence of non-alcoholic fatty liver disease (NAFLD) in the adult Korean population. Utilizing data derived from the 18-year prospective cohort of the Korean Genome and Epidemiology Study, NAFLD was diagnosed via the hepatic steatosis index with an established cutoff value of 36. Lean muscle mass was assessed via bioelectrical impedance analysis and subsequently divided into tertiles. A generalized mixed model with a logit link was employed for repeated measures data analysis, accounting for potential confounders. Analysis encompassed 7,794 participants yielding 49,177 measurements. The findings revealed a markedly increased incidence of NAFLD in the lower tertiles of muscle mass, specifically, tertile 1 (odds ratio [OR], 20.65; 95% confidence interval [CI], 9.66-44.11) and tertile 2 (OR, 4.57; 95% CI, 2.11-9.91), in comparison to tertile 3. Age-dependent decreases in the OR were observed within the tertile 1 group, with ORs of 10.12 at age of 40 years and 4.96 at age of 80 years. Moreover, each 1%-point increment in total muscle mass corresponded with an estimated OR of 0.87 (95% CI, 0.82-0.93) for NAFLD resolution. The study demonstrates a significant association between total muscle mass and NAFLD prevalence among Korean adults. Given the potential endocrine role of muscle mass in NAFLD pathogenesis, interventions aimed at enhancing muscle mass might serve as an effective public health strategy for mitigating NAFLD prevalence.


Bronchogenic carcinoma and the acquired immunodeficiency syndrome.
The majority of patients with the acquired immunodeficiency syndrome will develop clinical and radiographic pulmonary involvement during the course of their disease. Although opportunistic pathogens account for the majority of these intrathoracic abnormalities, pulmonary neoplasms are being encountered more often than would be expected for the age group under consideration. Clinicians need to be vigilant for the possibility of the early appearance of bronchogenic carcinoma in this subset of patients.


Ion channels in axon and Schwann cell membranes at paranodes of mammalian myelinated fibers studied with patch clamp.
While recent studies have established the presence of voltage-gated ion channels on Schwann cells in culture and on freshly isolated fibers from mature mammals, an important issue not yet explored is whether Schwann cell channels are regionally specialized. In the nodal region, the intimate association between the Schwann cell and its axon suggests that this is a likely site for functional specialization. Here, we examine whether there is a localized expression of channels in the Schwann cell paranodal regions, in a manner similar to that already shown for the nodal axon. Cell-attached and outside-out patch-clamp recordings were made from paranodal regions of rat myelinated sciatic nerve fibers where the myelin on both sides of the node was retracted by enzymatic treatment. Even though no myelin was visible on the surface of the retracted paranode, significant portions of this surface were found to stain positively with a marker (anti-galactocerebroside) for Schwann cell membranes, suggesting that part of the axon still was covered by glial membranes. Using Lucifer yellow in the recording pipettes, we observed that the dye diffused into either axons or Schwann cells when the membrane under the tip was ruptured. Using this as a criterion to identify membranes obtained from retracted paranodes, we found delayed and inwardly rectifying potassium channels on both axon- and Schwann-derived patches. However, sodium channels were detected only in axon patches. This is the first report that voltage-gated glial channels are present in immediate vicinity to axons of the PNS. This finding, coupled with earlier reports that functional channels are absent in soma of mature myelinating Schwann cells, suggests that ion channels in these cells are regionally specialized for functional interaction with axons.


A Deep Learning Method for Foot Progression Angle Detection in Plantar Pressure Images.
Foot progression angle (FPA) analysis is one of the core methods to detect gait pathologies as basic information to prevent foot injury from excessive in-toeing and out-toeing. Deep learning-based object detection can assist in measuring the FPA through plantar pressure images. This study aims to establish a precision model for determining the FPA. The precision detection of FPA can provide information with in-toeing, out-toeing, and rearfoot kinematics to evaluate the effect of physical therapy programs on knee pain and knee osteoarthritis. We analyzed a total of 1424 plantar images with three different You Only Look Once (YOLO) networks: YOLO v3, v4, and v5x, to obtain a suitable model for FPA detection. YOLOv4 showed higher performance of the profile-box, with average precision in the left foot of 100.00% and the right foot of 99.78%, respectively. Besides, in detecting the foot angle-box, the ground-truth has similar results with YOLOv4 (5.58 ± 0.10° vs. 5.86 ± 0.09°, p = 0.013). In contrast, there was a significant difference in FPA between ground-truth vs. YOLOv3 (5.58 ± 0.10° vs. 6.07 ± 0.06°, p < 0.001), and ground-truth vs. YOLOv5x (5.58 ± 0.10° vs. 6.75 ± 0.06°, p < 0.001). This result implies that deep learning with YOLOv4 can enhance the detection of FPA.


Simple plunge freezing applied to plant tissues for capturing the ultrastructure close to the living state.
In order to observe the ultrastructure close to the living state, simple plunge freezing in liquid propane was applied to plant tissues. The method yielded a well-preserved ultrastructure to a depth of up to 40 microm from the surface of the young pea leaves, which were used as the specimen. Within the well-frozen area all membranes appeared smooth and the ultrastructural details of each organelle were similar to those obtained by high-pressure freezing. Several physical connections between the membranes were visualized. The relative simplicity and the satisfactory freezing performance of the method render it suitable for capturing the features of actively functioning cells in routine ultrastructural studies.


A molecularly defined D1 medium spiny neuron subtype negatively regulates cocaine addiction.
The striatum plays a critical role in regulating addiction-related behaviors. The conventional dichotomy model suggests that striatal D1/D2 medium spiny neurons (MSNs) positively/negatively regulate addiction-related behaviors. However, this model does not account for the neuronal heterogeneity and functional diversity of the striatum, and whether MSN subtypes beyond the pan-D1/D2 populations play distinct roles in drug addiction remains unknown. We characterized the role of a tachykinin 2-expressing D1 MSN subtype (Tac2+), present in both rodent and primate striatum, using cocaine addiction mouse models. We found that acute cocaine administration reduces Tac2 neuronal activity, and cocaine conditioning alters neuronal response related to cocaine reward contextual associations. In addition, activation/inhibition of Tac2+ neurons attenuates/promotes cocaine-induced conditioned place preference and cocaine intravenous self-administration. Furthermore, stimulation of the NAc-to-lateral hypothalamic projection of Tac2+ neurons suppresses cocaine reward behavior. Our study reveals an unconventional negative regulatory function of D1 MSNs in drug addiction that operates in a subtype- and projection-specific manner.


Integrated chromosome 19 transcriptomic and proteomic data sets derived from glioma cancer stem-cell lines.
One subproject within the global Chromosome 19 Consortium is to define chromosome 19 gene and protein expression in glioma-derived cancer stem cells (GSCs). Chromosome 19 is notoriously linked to glioma by 1p/19q codeletions, and clinical tests are established to detect that specific aberration. GSCs are tumor-initiating cells and are hypothesized to provide a repository of cells in tumors that can self-replicate and be refractory to radiation and chemotherapeutic agents developed for the treatment of tumors. In this pilot study, we performed RNA-Seq, label-free quantitative protein measurements in six GSC lines, and targeted transcriptomic analysis using a chromosome 19-specific microarray in an additional six GSC lines. The data have been deposited to the ProteomeXchange with identifier PXD000563. Here we present insights into differences in GSC gene and protein expression, including the identification of proteins listed as having no or low evidence at the protein level in the Human Protein Atlas, as correlated to chromosome 19 and GSC subtype. Furthermore, the upregulation of proteins downstream of adenovirus-associated viral integration site 1 (AAVS1) in GSC11 in response to oncolytic adenovirus treatment was demonstrated. Taken together, our results may indicate new roles for chromosome 19, beyond the 1p/19q codeletion, in the future of personalized medicine for glioma patients.


Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto)antigen-specific T cells.
TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in susceptible cells, which can be both malignant and nontransformed. Despite homologies among the death ligands, there are great differences between the TRAIL system on the one hand and the TNF and CD95 systems on the other hand. In particular, TRAIL-induced apoptosis differs between rodents and man. Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector functions. Because we previously demonstrated that TRAIL does not induce apoptosis in human (auto)antigen-specific T cells, we now asked whether TRAIL exhibits other immunoregulatory properties in these cells. Active TRAIL inhibited calcium influx through store-operated calcium release-activated calcium channels, IFN-gamma/IL-4 production, and proliferation. These effects were independent of APC, Ag specificity, and Th differentiation, and no differences were detected between healthy donors and multiple sclerosis patients. TRAIL affected neither the expression of the cell cycling inhibitor p27(Kip1) nor the capacity of T cells to produce IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor does not induce T cell anergy. Instead, the TRAIL-induced hypoproliferation could be attributed to the down-regulation of the cyclin-dependent kinase 4, indicating a G(1) arrest of the cell cycle. Thus, although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx.


Rat brain endothelial cells are a target of manganese toxicity.
Manganese (Mn) is an essential trace metal; however, exposure to high Mn levels can result in neurodegenerative changes resembling Parkinson's disease (PD). Information on Mn's effects on endothelial cells of the blood-brain barrier (BBB) is lacking. Accordingly, we tested the hypothesis that BBB endothelial cells are a primary target for Mn-induced neurotoxicity. The studies were conducted in an in vitro BBB model of immortalized rat brain endothelial (RBE4) cells. ROS production was determined by F(2)-isoprostane (F(2)-IsoPs) measurement. The relationship between Mn toxicity and redox status was investigated upon intracellular glutathione (GSH) depletion with diethylmaleate (DEM) or L-buthionine sulfoximine (BSO). Mn exposure (200 or 800 microM MnCl(2) or MnSO(4)) for 4 or 24h led to significant decrease in cell viability vs. controls. DEM or BSO pre-treatment led to further enhancement in cytotoxicity vs. exposure to Mn alone, with more pronounced cell death after 24-h DEM pre-treatment. F(2)-IsoPs levels in cells exposed to MnCl(2) (200 or 800 microM) were significantly increased after 4h and remained elevated 24h after exposure compared with controls. Consistent with the effects on cell viability and F(2)-IsoPs, treatment with MnCl(2) (200 or 800 microM) was also associated with a significant decrease in membrane potential. This effect was more pronounced in cells exposed to DEM plus MnCl(2) vs. cells exposed to Mn alone. We conclude that Mn induces direct injury to mitochondria in RBE4 cells. The ensuing impairment in energy metabolism and redox status may modify the restrictive properties of the BBB compromising its function.


Exploration of New Sites in Adenovirus Hexon for Foreign Peptides Insertion.
Adenoviral vectors are now being explored as vaccine carriers to prevent infectious diseases in humans and animals. There are two strategies aimed at the expression of a vaccine antigen by adenoviral vectors. The first includes an insertion of the foreign gene expression cassette into the E1 region. The second strategy is antigen incorporation into the viral capsid proteins. To extend this methodology, we have searched for new sites at the human adenovirus serotype 5 major capsid protein hexon for a vaccine antigen insertion. To this end, we utilized sites in the hexon hypervariable region (HVR) 7, 8 and 9 to display a 15-mer peptide containing the main neutralizing epitope of porcine reproductive and respiratory syndrome virus. However, we could not rescue the viruses with the insertions of the peptide into HVR 8 and 9, consistent with the viruses being unable to tolerate insertions at these sites. In contrast, the virus with the insertion of the peptide in HVR 7 was viable - growing well in cell culture and the inserted peptide was exposed on the virion surface.


National practice guidelines for mental health care: a comparative policy analysis of the United kingdom and the United States.
Mental disorders are the leading cause of disability worldwide, according to the World Health Organization (WHO, 1996). In a report on health indicators of premature death and disability, the World Bank concluded that mental health problems account for 8.1% of the global burden of disease (GBD). Industrialized nations have taken different approaches in applying innovations to mental health care and mental health care policy. This paper uses the K. McInnis-Dittrich model of policy analysis (Ginsberg, 1994) to analyze the approaches of the United Kingdom (U.K.) and the United States (U.S.) to mental health treatment, specifically examining the effects of the U.K.'s national practice guidelines and the U.S.'s lack of similar guidelines. Recommendations for changes in current U.S. mental health policy are presented.


Improved pharmacy department workflow with new method of order entry for single-agent, high-dose methotrexate.
To determine whether a process change impacted the proportion of orders for single-agent, high-dose methotrexate entered by chemotherapy pharmacists instead of general pharmacy staff. Coordination of antiemetic premedication and leucovorin rescue with the new method of order entry was evaluated. Adults treated with single-agent, high-dose methotrexate were identified retrospectively. Order entry of methotrexate and ancillary medications was examined to determine whether the old or new method was used and whether it was performed by a chemotherapy pharmacist. The fundamental difference between the old and new methods for order entry is use of the "unscheduled" frequency of medication administration to replace the administration frequency of "once" with a specified date and time. Timing of antiemetic premedication and leucovorin rescue relative to methotrexate administration were tallied for the new method. Chi-square analysis was performed for the primary objective. Observational statistics were performed otherwise. The number of evaluable encounters identified was 158. A chemotherapy pharmacist entered a greater proportion of orders when the new method was utilized (P < .0001). The proportion of orders entered by a chemotherapy pharmacist increased during the hours of 0700 and 2259 with the new method. Appropriate coordination of antiemetic and leucovorin administration was documented for 96% and 100% of cases with the new method of order entry. The proportion of orders for single-agent, high-dose methotrexate entered by a chemotherapy pharmacist was significantly greater with the use of the new method. Administration of antiemetic premedication and leucovorin rescue were appropriately coordinated with the use of the new method for order entry of single-agent, high-dose methotrexate.


Ultrahigh resolution mass spectrometry-based metabolic characterization reveals cerebellum as a disturbed region in two animal models.
In the previous reports about cognitive dysfunction, cerebellum was thought to be a less affected tissue by genetic or environmental alterations in comparison to other tissues in the brain including hippocampus under the same conditions. In this work, we investigated two types of metabolomic alterations inside the cerebellum tissue. The first one addressed the differences in the metabolomics profiles between Transgenic (Tg) CRND8 of Alzheimer's disease mice and non-transgenic (non-Tg) littermates. The second one addressed the metabolic differences between wild type mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and wild type mice which are not exposed to this toxic compound. For these two investigations, ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR/MS) was implemented. As a result, the significant changes of each comparison were tentatively annotated by the high mass accuracy generated from the measurements in the negative ion mode. The biosynthesis of amino acids was also enhanced pronouncedly, and perturbation of purine metabolism was also observed in Tg mice compared to non-Tg littermates. In another animal model, the reduced levels of amino acids were found whereas the intermediate levels in purine metabolism and fatty acids including fatty acid conjugated metabolites were elevated in cerebellar tissues of mice exposed to TCDD compared to control group. Collectively, it was demonstrated that FT-ICR/MS was a powerful tool for interpretation of the elemental compositions of the peaks, revealing that the metabolic perturbations in cerebellar tissues of mice were induced by either genetic manipulation or environmental factor. Therefore, the non-targeted approach, alternatively, provides various metabolic phenotypes for the systems-level mirror of the complex etiology of neurotoxicity in the cerebellum.


Statistical strategies for constructing health risk models with multiple pollutants and their interactions: possible choices and comparisons.
As public awareness of consequences of environmental exposures has grown, estimating the adverse health effects due to simultaneous exposure to multiple pollutants is an important topic to explore. The challenges of evaluating the health impacts of environmental factors in a multipollutant model include, but are not limited to: identification of the most critical components of the pollutant mixture, examination of potential interaction effects, and attribution of health effects to individual pollutants in the presence of multicollinearity. In this paper, we reviewed five methods available in the statistical literature that are potentially helpful for constructing multipollutant models. We conducted a simulation study and presented two data examples to assess the performance of these methods on feature selection, effect estimation and interaction identification using both cross-sectional and time-series designs. We also proposed and evaluated a two-step strategy employing an initial screening by a tree-based method followed by further dimension reduction/variable selection by the aforementioned five approaches at the second step. Among the five methods, least absolute shrinkage and selection operator regression performs well in general for identifying important exposures, but will yield biased estimates and slightly larger model dimension given many correlated candidate exposures and modest sample size. Bayesian model averaging, and supervised principal component analysis are also useful in variable selection when there is a moderately strong exposure-response association. Substantial improvements on reducing model dimension and identifying important variables have been observed for all the five statistical methods using the two-step modeling strategy when the number of candidate variables is large. There is no uniform dominance of one method across all simulation scenarios and all criteria. The performances differ according to the nature of the response variable, the sample size, the number of pollutants involved, and the strength of exposure-response association/interaction. However, the two-step modeling strategy proposed here is potentially applicable under a multipollutant framework with many covariates by taking advantage of both the screening feature of an initial tree-based method and dimension reduction/variable selection property of the subsequent method. The choice of the method should also depend on the goal of the study: risk prediction, effect estimation or screening for important predictors and their interactions.


Effects of pimobendan in cats with hypertrophic cardiomyopathy and recent congestive heart failure: Results of a prospective, double-blind, randomized, nonpivotal, exploratory field study.
The benefits of pimobendan in the treatment of congestive heart failure (CHF) in cats with hypertrophic cardiomyopathy (HCM) have not been evaluated prospectively. To investigate the effects of pimobendan in cats with HCM and recent CHF and to identify possible endpoints for a pivotal study. We hypothesized that pimobendan would be well-tolerated and associated with improved outcome. Eighty-three cats with HCM and recently controlled CHF: 30 with and 53 without left ventricular outflow tract obstruction. Prospective randomized placebo-controlled double-blind multicenter nonpivotal field study. Cats received either pimobendan (0.30 mg/kg q12h, n = 43), placebo (n = 39), or no medication (n = 1) together with furosemide (<10 mg/kg/d) with or without clopidogrel. The primary endpoint was a successful outcome (ie, completing the 180-day study period without a dose escalation of furosemide). The proportion of cats in the full analysis set population with a successful outcome was not different between treatment groups (P = .75). For nonobstructive cats, the success rate was 32% in pimobendan-treated cats versus 18.2% in the placebo group (odds ratio [OR], 2.12; 95% confidence interval [CI], 0.54-8.34). For obstructive cats, the success rate was 28.6% and 60% in the pimobendan and placebo groups, respectively (OR, 0.27; 95% CI, 0.06-1.26). No difference was found between treatments for the secondary endpoints of time to furosemide dose escalation or death (P = .89). Results were similar in the per-protocol sets. Adverse events in both treatment groups were similar. In this study of cats with HCM and recent CHF, no benefit of pimobendan on 180-day outcome was identified.


Primary care research from a health system perspective.
Vertically integrated systems of health care share a set of interests with academic health services researchers. These interests include questions about: the appropriate size and scope of the various system components; mechanisms for coordinating care across component parts; and "what works" in terms of clinical effectiveness within components. Primary care is a key system component in which all of these questions apply. Traditional research designs, however, are often difficult to apply in a health system context. The problems are (1) the rapid pace at which organizational change occurs, which renders some research findings obsolete before they are published, and (2) the difficulty in generalizing across a complex set of local environmental factors that vary from system to system. Useful research from a system perspective will either focus on problems of wide generalizability over place and time or be conducted according to new methodologies that offer much faster "cycle time" from design to findings.


Vitamin D and 1,25(OH)2D regulation of T cells.
Vitamin D is a direct and indirect regulator of T cells. The mechanisms by which vitamin D directly regulates T cells are reviewed and new primary data on the effects of 1,25 dihydroxyvitamin D (1,25(OH)2D) on human invariant natural killer (iNK)T cells is presented. The in vivo effects of vitamin D on murine T cells include inhibition of T cell proliferation, inhibition of IFN-γ, IL-17 and induction of IL-4. Experiments in mice demonstrate that the effectiveness of 1,25(OH)2D requires NKT cells, IL-10, the IL-10R and IL-4. Comparisons of mouse and human T cells show that 1,25(OH)2D inhibits IL-17 and IFN-γ, and induces T regulatory cells and IL-4. IL-4 was induced by 1,25(OH)2D in mouse and human iNKT cells. Activation for 72 h was required for optimal expression of the vitamin D receptor (VDR) in human and mouse T and iNKT cells. In addition, T cells are potential autocrine sources of 1,25(OH)2D but again only 48-72 h after activation. Together the data support the late effects of vitamin D on diseases like inflammatory bowel disease and multiple sclerosis where reducing IL-17 and IFN-γ, while inducing IL-4 and IL-10, would be beneficial.


Gating of cx46 gap junction hemichannels by calcium and voltage.
Connexin 46 (cx46), when expressed in Xenopus oocytes, not only forms typical gap junction channels between paired cells but also forms open gap junction hemichannels in the plasma membrane of single cells. The gap junction hemichannels share properties with complete gap junction channels in terms of permeability and gating. Here we characterize the gate that closes hemichannels in response to increased calcium concentration with whole-cell and single-channel records. The channels close within a narrow range of extracellular calcium concentrations (1-2 mM) which includes the calcium concentration prevailing in the primary site of cx46 expression, the lens. The effect of calcium on the channels is determined by voltage. A cysteine mutant of cx46, cx46L35C, was used to determine the localization of the gate. Experimental evidence suggests that position 35 is pore lining. The localization protocol tests the accessibility of position 35 for thiol reagents applied extra- or intracellularly to the channel closed by calcium. Channel closure by calcium excluded the thiol reagent from the outside but not from the inside. Consequently, the gate results in a regional closure of the pore and it is located extracellular to the position 35 of cx46. The present data also suggest that the cx46 gap junction hemichannel may exert a physiological function in the lens. Considering the association of calcium with cataract formation, it is feasible that misregulation of cx46 gap junction hemichannels could be a cause for cataract.


Quantitative microbial risk assessment for Escherichia coli O157 on lettuce, based on survival data from controlled studies in a climate chamber.
The aims of the study were to determine the survival of Escherichia coli O157 on lettuce as a function of temperature and light intensity, and to use that information in a screening-level quantitative microbial risk assessment (QMRA) in order to evaluate risk-reducing strategies including irrigation water quality guidelines, rinsing, and holding time between last irrigation and harvest. Iceberg lettuce was grown in a climate chamber and inoculated with E. coli O157. Bacterial numbers were determined with the standard plate count method after inoculation and 1, 2, 4, and 7 day(s) postinoculation. The experiments were carried out at 11, 18, and 25°C in light intensities of 0, 400, and 600 mmol (m(2))(-1) s(-1). There was a significant effect of temperature and light intensity on survival, with less bacteria isolated from lettuce incubated at 25 and 18°C compared with 11°C (P < 0.0001), and in light intensities of 400 and 600 mmol (m(2))(-1) s(-1) compared with 0 mmol (m(2))(-1) s(-1) (P < 0.001). The average log reductions after 1, 2, 4, and 7 day(s) were 1.14, 1.71, 2.04, and 3.0, respectively. The QMRA compared the relative risk with lettuce consumption from 20 scenarios. A stricter water quality guideline gave a mean fivefold risk reduction. Holding times of 1, 2, 4, and 7 day(s) reduced the risk 3, 8, 8, and 18 times, respectively, compared with harvest the same day as the last irrigation. Finally, rinsing lettuce for 15 s in cold tap water prior to consumption gave a sixfold risk reduction compared with eating unrinsed lettuce. Sensitivity analyses indicated that variation in bacterial inactivation had the most significant effect on the risk outcome. A QMRA determining the relative risks between scenarios reduces uncertainty and can provide risk managers with decision support.


An expert consensus on the most effective components of cognitive behavioural therapy for adults with depression: a modified Delphi study.
Designing new approaches to delivering cognitive behavioural therapy (CBT) requires an understanding of the key components. This study aimed to establish an expert consensus on the effective components of CBT for depressed adults. An international panel of 120 CBT experts was invited to participate in a modified Delphi study. Thirty-two experts participated in round 1; 21 also provided data in round 2. In round 1, experts rated the effectiveness of 35 content and process components. A priori rules identified components carried forward to round 2, in which experts re-rated items and final consensus items were identified. Consensus was achieved for nine content components (ensuring understanding; developing and maintaining a good therapeutic alliance; explaining the rationale for CBT; eliciting feedback; identifying and challenging avoidant behaviour; activity monitoring; undertaking an initial assessment; relapse prevention methods; homework assignments); and three process components (ensuring therapist competence; scheduling sessions flexibly; scheduling sessions for 45-60 mins). Five of the twelve components identified were generic therapeutic competences rather than specific CBT items. There was less agreement about the effectiveness of cognitive components of CBT. This is an important first step in the development of novel approaches to delivering CBT that may increase access to treatment for patients.


Molecular mechanisms of biomineralization in marine invertebrates.
Much recent marine research has been directed towards understanding the effects of anthropogenic-induced environmental change on marine biodiversity, particularly for those animals with heavily calcified exoskeletons, such as corals, molluscs and urchins. This is because life in our oceans is becoming more challenging for these animals with changes in temperature, pH and salinity. In the future, it will be more energetically expensive to make marine skeletons and the increasingly corrosive conditions in seawater are expected to result in the dissolution of these external skeletons. However, initial predictions of wide-scale sensitivity are changing as we understand more about the mechanisms underpinning skeletal production (biomineralization). These studies demonstrate the complexity of calcification pathways and the cellular responses of animals to these altered conditions. Factors including parental conditioning, phenotypic plasticity and epigenetics can significantly impact the production of skeletons and thus future population success. This understanding is paralleled by an increase in our knowledge of the genes and proteins involved in biomineralization, particularly in some phyla, such as urchins, molluscs and corals. This Review will provide a broad overview of our current understanding of the factors affecting skeletal production in marine invertebrates. It will focus on the molecular mechanisms underpinning biomineralization and how knowledge of these processes affects experimental design and our ability to predict responses to climate change. Understanding marine biomineralization has many tangible benefits in our changing world, including improvements in conservation and aquaculture and exploitation of natural calcified structure design using biomimicry approaches that are aimed at producing novel biocomposites.


Metabolic syndrome: clinical and angiographic impact on patients with acute coronary syndrome.
Metabolic syndrome (MetS) is represented by a cluster of various risk factors and is one of the most important public health problems of the 21st century. The aim of this study was to identify the impact of this syndrome in patients with acute coronary syndrome (ACS). We included patients with ST and non-ST segment elevation ACS. We divided patients into two groups: A) patients with MetS criteria and B) patients without MetS criteria. We compared the incidence of major cardiovascular events, severity of coronary artery disease (CAD), need for urgent revascularization and in-hospital mortality between groups. Among 917 patients with ACS, 421 (43.4%) fulfilled criteria of MetS. Age of patients in this group was 63.37 +/- 9.95 years (compared with 61.77 +/- 12.20 years in group B), 66.7% vs. 72.8% males, diabetes 70.3% vs. 33.3%, hypertension 87.6% vs. 40.5% and dyslipidemia 70.5% vs. 26.9%, respectively. ST-elevation ACS was more frequent in group A. We observed more severe CAD, and major cardiovascular events were more frequent in group A. Multivariate analysis demonstrated that hyperfibrinogenemia, hyperglycemia and MetS were independent predictors of heart failure and combined end point. Incidence of MetS was high in patients with ACS, presented with more comorbidities and older patients, and was associated with poorer in-hospital outcome. It may be probable that the high inflammatory and prothrombotic response and more severe CAD in these patients increase the incidence of major cardiovascular events.


Telbivudine in liver transplant recipients: Renal protection does not overcome the risk of polyneuropathy and myopathy.
The recently reported benefit of telbivudine for renal function has not been systematically studied in long-term liver transplantation (LT) recipients who are at high risk for renal impairment. We aimed to examine whether switching lamivudine therapy to telbivudine could improve renal function in LT recipients who have impaired renal function. This single-center, prospective cohort study enrolled LT recipients who were on lamivudine for hepatitis B virus (HBV) prophylaxis and who had renal impairment for at least 1 year. Lamivudine was switched to telbivudine. The primary outcome was to evaluate the change in renal function at weeks 12, 24, 36, and 48. The secondary outcomes were to assess the efficacy of telbivudine for HBV prophylaxis and the safety profile of telbivudine in the posttransplant setting. After 45 patients were enrolled, the study was terminated early because of increased rates of polyneuropathy/myopathy. During telbivudine treatment (median, 64 weeks), estimated glomerular filtration rate (eGFR) increased in 34 patients (76%). The improvement in renal function was prominent after 24 weeks of telbivudine treatment. Telbivudine was effective as prophylaxis against HBV recurrence. Twenty-six patients (58%) developed polyneuropathy and/or myopathy. The 1-year estimated incidence of polyneuropathy/myopathy was 28%. Diabetes was the strongest predictor of polyneuropathy/myopathy (hazard ratio, 4.13; 95% confidence interval, 1.49-11.50; P = 0.007). In conclusion, although it seems to have a favorable effect in the improvement of renal function and seems to be effective in the prevention of HBV recurrence, the high risk of polyneuropathy and myopathy hampers the use of telbivudine in LT recipients.


Potential Air Pollutant Emissions and Permitting Classifications for Two Biorefinery Process Designs in the United States.
Advanced biofuel production facilities (biorefineries), such as those envisioned by the United States (U.S.) Renewable Fuel Standard and U.S. Department of Energy's research and development programs, often lack historical air pollutant emissions data, which can pose challenges for obtaining air emission permits that are required for construction and operation. To help fill this knowledge gap, we perform a thorough regulatory analysis and use engineering process designs to assess the applicability of federal air regulations and quantify air pollutant emissions for two feasibility-level biorefinery designs. We find that without additional emission-control technologies both biorefineries would likely be required to obtain major source permits under the Clean Air Act's New Source Review program. The permitting classification (so-called "major" or "minor") has implications for the time and effort required for permitting and therefore affects the cost of capital and the fuel selling price. Consequently, we explore additional technically feasible emission-control technologies and process modifications that have the potential to reduce emissions to achieve a minor source permitting classification. Our analysis of air pollutant emissions and controls can assist biorefinery developers with the air permitting process and inform regulatory agencies about potential permitting pathways for novel biorefinery designs.


Impact of the Royal Australasian College of Physicians' clinical examination preparation on basic physician trainee assessment of jugular venous pressure.
Australian internal medicine trainees undergo intensive training in preparation for the Royal Australasian College of Physicians (RACP) clinical examination. Trainees preparing for the 2013 RACP clinical examination assessed the jugular venous pressure (JVP) of patients, with central venous pressure monitoring in the intensive care unit before and after the exam. RACP clinical examination preparation was associated with improvements of trainees' ability to identify JVP that were not elevated, although the JVP examination was performed marginally as a diagnostic test. Ongoing training might further improve this skill.


Ground-cover measurements: assessing correlation among aerial and ground-based methods.
Wyoming's Green Mountain Common Allotment is public land providing livestock forage, wildlife habitat, and unfenced solitude, amid other ecological services. It is also the center of ongoing debate over USDI Bureau of Land Management's (BLM) adjudication of land uses. Monitoring resource use is a BLM responsibility, but conventional monitoring is inadequate for the vast areas encompassed in this and other public-land units. New monitoring methods are needed that will reduce monitoring costs. An understanding of data-set relationships among old and new methods is also needed. This study compared two conventional methods with two remote sensing methods using images captured from two meters and 100 meters above ground level from a camera stand (a ground, image-based method) and a light airplane (an aerial, image-based method). Image analysis used SamplePoint or VegMeasure software. Aerial methods allowed for increased sampling intensity at low cost relative to the time and travel required by ground methods. Costs to acquire the aerial imagery and measure ground cover on 162 aerial samples representing 9000 ha were less than $3000. The four highest correlations among data sets for bare ground--the ground-cover characteristic yielding the highest correlations (r)--ranged from 0.76 to 0.85 and included ground with ground, ground with aerial, and aerial with aerial data-set associations. We conclude that our aerial surveys are a cost-effective monitoring method, that ground with aerial data-set correlations can be equal to, or greater than those among ground-based data sets, and that bare ground should continue to be investigated and tested for use as a key indicator of rangeland health.


A scoping review of the unassisted physical exam conducted over synchronous audio-video telemedicine.
This scoping review aims to provide a broad overview of the research on the unassisted virtual physical exam performed over synchronous audio-video telemedicine to identify gaps in knowledge and guide future research. Searches for studies on the unassisted virtual physical exam were conducted in 3 databases. We included primary research studies in English on the virtual physical exam conducted via patient-to-provider synchronous, audio-video telemedicine in the absence of assistive technology or personnel. Screening and data extraction were performed by 2 independent reviewers. Seventy-four studies met inclusion criteria. The most common components of the physical exam performed over telemedicine were neurologic (38/74, 51%), musculoskeletal (10/74, 14%), multi-system (6/74, 8%), neuropsychologic (5/74, 7%), and skin (5/74, 7%). The majority of the literature focuses on the telemedicine physical exam in the adult population, with only 5% of studies conducted specifically in a pediatric population. During the telemedicine exam, the patients were most commonly located in outpatient offices (28/74, 38%) and homes and other non-clinical settings (25/74, 34%). Both patients and providers in the included studies most frequently used computers for the telemedicine encounter. Research evaluating the unassisted virtual physical exam is at an early stage of maturity and is skewed toward the neurologic, musculoskeletal, neuropsychologic, and skin exam components. Future research should focus on expanding the range of telemedicine exam maneuvers studied and evaluating the exam in the most relevant settings, which for telemedicine is trending toward exams conducted through mobile devices and in patients' homes.


The distal elements, OCT and SPH, stimulate the formation of preinitiation complexes on a human U6 snRNA gene promoter in vitro.
The distal control region of a human U6 small nuclear RNA (snRNA) gene promoter contains two separable elements, octamer (OCT) and SPH, found in many vertebrate snRNA genes. Complete distal regions generally account for a 4- to 100-fold stimulation of snRNA gene promoters. We examined the mechanism of transcriptional stimulation by each element when linked to the proximal U6 promoter. Multimers of either OCT or SPH did not increase transcriptional levels above that with a single copy, either in transfected human cells or after in vitro transcription in a HeLa S100 extract. The orientation of a single SPH element differentially stimulated transcription in transfected cells, whereas the orientation of an octamer element was not important. Using Sarkosyl to limit transcription to a single-round, we concluded that promoters containing either OCT or SPH elements supported an increased number of preinitiation complexes in vitro. Furthermore, the rate of formation of U6 promoter preinitiation complexes resistant to low (0.015%) concentrations of Sarkosyl was accelerated on templates containing either OCT or SPH. However, neither element had a significant effect on the number of rounds of reinitiation in the S100 extract.


Randomized comparison between interscalene and costoclavicular blocks for arthroscopic shoulder surgery.
This randomized trial compared ultrasound-guided interscalene block (ISB) and costoclavicular brachial plexus block (CCB) for arthroscopic shoulder surgery. We hypothesized that CCB would provide equivalent analgesia to ISB 30 min after surgery without the risk of hemidiaphragmatic paralysis. All 44 patients received an ultrasound-guided block of the intermediate cervical plexus. Subsequently, they were randomized to ISB or CCB. The local anesthetic agent (20 mL of levobupivacaine 0.5% and epinephrine 5 µg/mL) and pharmacological block adjunct (4 mg of intravenous dexamethasone) were identical for all study participants. After the block performance, a blinded investigator assessed ISBs and CCBs every 5 min until 30 min using a composite scale that encompassed the sensory function of the supraclavicular nerves, the sensorimotor function of the axillary nerve and the motor function of the suprascapular nerve. A complete block was defined as one displaying a minimal score of six points (out of a maximum of eight points) at 30 min. Onset time was defined as the time required to reach the six-point minimal composite score. The blinded investigator also assessed the presence of hemidiaphragmatic paralysis at 30 min with ultrasonography.Subsequently, all patients underwent general anesthesia. Postoperatively, a blinded investigator recorded pain scores at rest at 0.5, 1, 2, 3, 6, 12, and 24 hours. Patient satisfaction at 24 hours, consumption of intraoperative and postoperative narcotics, and opioid-related side effects (eg, nausea/vomiting, pruritus) were also tabulated. Both groups displayed equivalent postoperative pain scores at 0.5, 1, 2, 3, 6, 12, and 24 hours. ISB resulted in a higher incidence of hemidiaphragmatic paralysis (100% vs 0%; P < 0.001) as well as a shorter onset time (14.0 (5.0) vs 21.6 (6.4) minutes; p<0.001). However, no intergroup differences were found in terms of proportion of patients with minimal composite scores of 6 points at 30 min, intraoperative/postoperative opioid consumption, side effects, and patient satisfaction at 24 hours. Compared to ISB, CCB results in equivalent postoperative analgesia while circumventing the risk of hemidiaphragmatic paralysis. Further confirmatory trials are required. Future studies should also investigate if CCB can provide surgical anesthesia for arthroscopic shoulder surgery. NCT03411343.


The presence of PHOSPHO1 in matrix vesicles and its developmental expression prior to skeletal mineralization.
PHOSPHO1 is a phosphoethanolamine/phosphocholine phosphatase that has previously been implicated in generating inorganic phosphate (P(i)) for matrix mineralization. In this study, we have investigated PHOSPHO1 mRNA expression during embryonic development in the chick. Whole-mount in situ hybridization indicated that PHOSPHO1 expression occurred prior to E6.5 and was initially restricted to the bone collar within the mid-shaft of the diaphysis of long bones but by E11.5 expression was observed over the entire length of the diaphysis. Alcian blue/alizarin red staining revealed that PHOSPHO1 expression seen in the primary regions of ossification preceded the deposition of mineral, suggesting that it is involved in the initial events of mineral formation. We isolated MVs from growth plate chondrocytes and confirmed the presence of high levels of PHOSPHO1 by immunoblotting. Expression of PHOSPHO1, like TNAP activity, was found to be up-regulated in MVs isolated from chondrocytes induced to differentiate by the addition of ascorbic acid. This suggests that both enzymes may be regulated by similar mechanisms. These studies provide for the first time direct evidence that PHOSPHO1 is present in MVs, and its developmental expression pattern is consistent with a role in the early stages of matrix mineralization.


Endocrine control of benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is the most common benign proliferative disease among aging men. Androgens play a key role in the development and growth of the male genital tract favoring differentiation and proliferation of stromal and epithelial cells of the prostate gland. It is known that growth factors play a crucial role in the cross-talk between stromal cells and epithelial cells. These factors, mainly secreted by stromal cells, act in an autocrine/paracrine manner to maintain prostate cellular homeostasis. A number of experimental studies support the interdependence between growth factors (IGF, FGF, TGF) and the steroid hormone milieu of the prostate. Alterations of these interactions may alter the balance between proliferation and cell death leading to the development of BPH. The onset of BPH is closely related to an inflammatory microenvironment. Chronic inflammation, which generally follows the acute inflammation because of infectious agents, is favored by hormonal or metabolic abnormalities. However, a close correlation between these mechanisms and metabolic or sexual hormones (androgen/estrogen ratio) alteration has been shown suggesting a key role of hypogonadism in the development of prostate inflammation. This review clear shows that the BPH pathogenesis and the subsequent onset of the lower urinary tract symptoms (LUTS) depends from different etio-pathogenetic factors whose mechanism of action remains to be evaluated.


Heterokaryosis and parasexuality in Pyricularia oryzae Cavara.
Auxotrophs in three different races of Pyricularia oryzae were obtained following ultraviolet mutagenesis, and tested for complementarity on minimal medium. Prototrophic growth resulted between combinations of different auxotrophs of single strains, but not between strains. The growth did not result form crossfeeding, but required at least transitory heterokaryosis. Putative diploids, i.e., large prototrophic conidia, were readily isolated from the heterokaryons. In addition, conidia with nearly every possible combination of parental markers were found, showing that P. oryzae does indeed complete the parasexual cycle. The degree of genetic recombination found here may help to explain the extreme variability of this organism.


Reconstitution of the multiprotein complex of pp60src, hsp90, and p50 in a cell-free system.
A rabbit reticulocyte lysate system that has been used to reconstitute functional complexes between steroid receptors and the 90-kDa heat shock protein (hsp90) has been used here to form complexes between the pp60src tyrosine kinase and hsp90. Reticulocyte lysate forms complexes between hsp90 and a temperature-sensitive mutant of Rous sarcoma virus pp60v-src, which is normally present in cytosol virtually entirely in the multiprotein complex form. In addition, hsp90 in the lysate complexes with wild-type pp60v-src, of which only a small portion is normally recovered in cytosol in the native multiprotein complex, and with the cellular homolog, pp60c-src, which has never been recovered in cytosol in the form of a native multiprotein complex with hsp90. Moreover, the reticulocyte lysate-reconstituted complex also contains the 50-kDa phosphoprotein component of the native pp60v-src multiprotein complex. The native and reconstituted pp60src-hsp90 complexes have similar thermal stability and, like steroid receptor heterocomplexes, they are stabilized by molybdate. As previously shown with reticulocyte lysate-reconstituted steroid receptor heteroprotein complexes, the reconstituted pp60src multiprotein complex contains hsp70, which is a major candidate for providing the protein unfoldase activity required for hsp90 association.


Assessment of haematopoietic progenitor cell counting with the Sysmex® XN-1000 to guide timing of apheresis of peripheral blood stem cells.
Successful peripheral blood stem cell (PBSC) collection depends on optimal timing of apheresis, as usually determined by flow cytometry CD34-positive (+) cell count in peripheral blood (PB). Since this method is costly and labour-intensive, we evaluated the use of the Hematopoietic Progenitor Cell count programme on a Sysmex® XN haematologic analyser (XN-HPC) as a rapid and inexpensive alternative for predicting CD34+ cell count in PB samples. Haematopoietic progenitor cell and CD34+ cell counts were compared using 273 PB samples collected from 78 healthy donors and 72 patients who underwent PBSC transplantation. We assessed the effectiveness of the XN-HPC in safely predicting pre-harvest CD34+ counts. The most efficient cut-off values of XNHPC were identified. We also evaluated the imprecision (coefficient of variation, CV) and functional sensitivity. Imprecision of the XN-HPC count was <6.3% on daily measurement of three levels of quality control material. Functional sensitivity was 8.9×106/L. A cut-off value of ≥62×106/L XN-HPC for multiple myeloma (MM) patients and ≥30×106/L for all other subjects had both 100% specificity and 100% positive predictive value for identifying samples with CD34+ cells ≥20×106/L. An XN-HPC threshold of <13×106/L identified preharvest CD34+ cell count <10×106/L with 100% sensitivity and 100% negative predictive value. The XN-HPC is a fast, easy and inexpensive test that can safely improve apheresis workflow thus possibly replacing other more expensive CD34 counts currently performed and promoting optimal timing of PBSC collection.


Yosprala: A Fixed Dose Combination of Aspirin and Omeprazole.
Cardiovascular disease is the leading cause of morbidity and mortality in the United States. Patients who survive a primary cerebrovascular or cardiovascular event are at increased risk of a subsequent occurrence. Antiplatelet therapy plays an essential role for secondary prevention in individuals with stroke, transient ischemic attack, acute or chronic artery disease, or peripheral arterial disease. Maintaining high-risk patients on low-dose aspirin therapy is a fundamental component of management. However, poor adherence, secondary to the drug's gastrointestinal side effects, has been associated with negative cardiovascular outcomes. Numerous studies have indicated that proton-pump inhibitors significantly reduce the risk of upper gastrointestinal adverse events in aspirin-treated patients. The US Food and Drug Administration approved Yosprala (Aralez Pharmaceuticals), a fixed-dose combination of delayed-release aspirin and immediate-release omeprazole, on September 15, 2016. It is the first product to become available in the United States that combines these 2 pharmacologic drug classes, and represents a new therapeutic option for patients and healthcare providers who strive to improve adherence to daily aspirin therapy.


On the unraveling of 'revitalization of local health traditions' in India: an ethnographic inquiry.
India has recently renewed emphasis on non-allopathic systems of medicine as a means to address the health needs of its populace. Earlier in 2002, its national health policy had sought to 'revitalize' community-based health knowledge and practices - jointly christened 'local health traditions'. Yet policy texts remain silent on the actual means by which 'revitalization of local health traditions' should take place. Our research sought to understand the policy lessons of and for revitalization of local health traditions in the three Southern Indian states through an ethnographic inquiry in 2014-2016. Our inquiry included a narrative synthesis of policy texts tracing the history of governance processes and mechanisms pertaining to traditional medicine, including local health traditions, linking this to the activities of non-governmental organizations (NGOs) and networks involved in "revitalization". Through in-depth interviews, observations and case studies, we sought to understand the life worlds of local health tradition practitioners and what revitalization meant to them. Our method revealed that beyond a purely academic inquiry, we needed an (inter)action that would give greater voice to these perspectives and views leading to hosting an interactive dialogue among practitioners, NGO representatives, academics, and government officials. Our ethnographic inquiry unraveled the problematic of a litotic approach to local health traditions as those which are non- institutionalized, non-certified, non-documented; assuming the state to be the only source of power and legitimacy. Revitalization discussions were restricted (and often misled) by such an approach. Local health practitioners and others directed us to interesting possibilities of revitalization either through participatory modes of documentation of traditional health knowledge, strengthening existing collective forums for formal social recognition, and building pedagogical institutions that promote experiential learning. Were we not enabled by ethnography as a method that changes its shape apace with emerging findings, we would have not been able to comprehensively answer our questions. This is critical because not only was this already a marginalized area of inquiry, but with any other method we risked reinforcing inequities by imposing epistemological and other hierarchies on our participants- whom we would argue were partners - in arriving at our conclusions.


Machine learning based local recurrence prediction in colorectal cancer using polarized light imaging.
Current treatment for stage III colorectal cancer (CRC) patients involves surgery that may not be sufficient in many cases, requiring additional adjuvant systemic therapy. Identification of this latter cohort that is likely to recur following surgery is key to better personalized therapy selection, but there is a lack of proper quantitative assessment tools for potential clinical adoption. The purpose of this study is to employ Mueller matrix (MM) polarized light microscopy in combination with supervised machine learning (ML) to quantitatively analyze the prognostic value of peri-tumoral collagen in CRC in relation to 5-year local recurrence (LR). A simple MM microscope setup was used to image surgical resection samples acquired from stage III CRC patients. Various potential biomarkers of LR were derived from MM elements via decomposition and transformation operations. These were used as features by different supervised ML models to distinguish samples from patients that locally recurred 5 years later from those that did not. Using the top five most prognostic polarimetric biomarkers ranked by their relevant feature importances, the best-performing XGBoost model achieved a patient-level accuracy of 86%. When the patient pool was further stratified, 96% accuracy was achieved within a tumor-stage-III sub-cohort. ML-aided polarimetric analysis of collagenous stroma may provide prognostic value toward improving the clinical management of CRC patients.


Lithium for schizophrenia.
Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, among them lithium. To review the effects of lithium for the treatment of schizophrenia and schizophrenia-like psychoses. We searched the Cochrane Schizophrenia Group's register (November 2006). This register is compiled by methodical searches of BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile, supplemented with hand searching of relevant journals and numerous conference proceedings. We also contacted pharmaceutical companies and authors of relevant studies to identify further trials and to obtain original patient data. We included all randomised controlled trials comparing lithium to antipsychotics or to placebo (or no intervention), whether as sole treatment or as an adjunct to antipsychotic medication for the treatment of schizophrenia and/or schizophrenia-like psychoses. We extracted data independently. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). The update search in 2006 did not detect further studies that met our inclusion criteria. The review thus still includes 20 studies with a total of 611 participants. Most studies were small, of short duration and incompletely reported, but a number of authors were willing to share their data with us. Three studies comparing lithium with placebo as the sole treatment showed no difference in any of the outcomes we analysed. In eight studies comparing lithium with antipsychotic drugs as the sole treatment, more participants in the lithium group left the studies early (n=270, RR 1.8, CI 1.2 to 2.9, NNT 9, CI 5 to 33). Several of the outcomes relating to these studies suggested that lithium is less effective than antipsychotic drugs, but it was difficult to summarise the data because a variety of rating scales were used in the studies. Eleven studies examined whether the augmentation of antipsychotic drugs with lithium salts is more effective than antipsychotic drugs alone. More participants who received lithium augmentation had a clinically significant response (n=244, RR 0.8, CI 0.7 to 0.96, NNT 8, CI 4 to 33). However, statistical significance became borderline when participants with schizoaffective disorders were excluded in a sensitivity analysis (n=120, RR 0.8, CI 0.6 to 1.0, p=0.07). Furthermore, more participants in the lithium augmentation groups left the studies early (n=320, RR 2.0 CI 1.3 to 3.1, NNT 7, CI 4 to 14), suggesting a lower acceptability of lithium augmentation compared to those on antipsychotics alone. No superior efficacy of lithium augmentation in any specific aspect of the mental state was found. While based on very little data, there were no differences between groups for adverse events. There is no randomised trial-based evidence that lithium on its own is an effective treatment for people with schizophrenia. The evidence available on augmentation of antipsychotics with lithium is inconclusive, but does justify further, large, simple and well-designed trials. These should concentrate on two target groups: 1) people with no affective symptoms, so that trialists can determine whether lithium has an effect on the core symptoms of schizophrenia, 2) people with schizoaffective disorders for whom lithium is widely used in clinical practice, although there is no evidence to support this use.


Respiratory dysfunction in chronic neck pain patients. A pilot study.
The aim of this pilot study was to add weight to a hypothesis according to which patients presenting with chronic neck pain could have a predisposition towards respiratory dysfunction. Twelve patients with chronic neck pain and 12 matched controls participated in this study. Spirometric values, maximal static pressures, forward head posture and functional tests were examined in all subjects. According to the results, chronic neck patients presented with a statistically significant decreased maximal voluntary ventilation (P = 0.042) and respiratory muscle strength (Pimax and Pemax), (P = 0.001 and P = 0.002, respectively). Furthermore, the current study demonstrated a strong association between an increased forward head posture and decreased respiratory muscle strength in neck pateits. The connection of neck pain and respiratory function could be an important consideration in relation to patient assessment, rehabilitation and consumption of pharmacological agents.