Management of patients who are receiving warfarin or a new oral anticoagulant and require urgent or emergency surgery.
An increasing number of patients are receiving long‑term oral anticoagulant therapy and the availability of new oral anticoagulants (OACs), which are easier to use than warfarin, will further expand the population of anticoagulated patients. As a consequence, an increasing number of patients will need perioperative anticoagulant management because of elective or nonelective surgery or procedures. The perioperative management of such patients is pertinent to a broad spectrum of physicians, including anesthesiologists, internists, and surgeons. The objectives of this review are to provide a clinically‑focused background on the pharmacology of warfarin and the new OACs and to suggest perioperative anticoagulant management strategies. This review will focus on the perioperative management of warfarin and new OACs who require urgent or emergent surgery or who require rapid anticoagulant reversal because of ongoing bleeding or high bleeding risk.


Enhancer Connectome Nominates Target Genes of Inherited Risk Variants from Inflammatory Skin Disorders.
The vast majority of polymorphisms for human dermatologic diseases fall in noncoding DNA regions, leading to difficulty interpreting their functional significance. Recent work using chromosome conformation capture technology in combination with chromatin immunoprecipitation (ChIP) has provided a systematic means of linking noncoding variants in active enhancer loci to putative gene targets. Here, we apply H3K27ac HiChIP high-resolution contact maps, generated from primary human T-cell subsets (CD4+ naïve, T helper type 17, and regulatory T cells), to 21 dermatologic conditions associated with single nucleotide polymorphisms from 106 genome-wide association studies. This "enhancer connectome" identified 1,492 HiChIP gene targets from 542 noncoding SNPs (P ≤ 5.0 × 10-8). SNP-containing enhancers from inflammatory skin conditions were significantly enriched at the HLA locus and also targeted several key factors from the JAK-STAT signaling pathway, but nonimmune conditions were not. A focused profiling of systemic lupus erythematosus HiChIP genes identified enhancer interactions with factors important for effector CD4+ T-cell differentiation and function, including IRF8 and members of the Ikaros family of zinc-finger proteins. Our results show the ability of the enhancer connectome to nominate functionally relevant candidates from genome-wide association study-identified variants, representing a powerful tool to guide future studies into the genomic regulatory mechanisms underlying dermatologic diseases.


Evidence-based guidelines for the management of large hemispheric infarction : a statement for health care professionals from the Neurocritical Care Society and the German Society for Neuro-intensive Care and Emergency Medicine.
Large hemispheric infarction (LHI), also known as malignant middle cerebral infarction, is a devastating disease associated with significant disability and mortality. Clinicians and family members are often faced with a paucity of high quality clinical data as they attempt to determine the most appropriate course of treatment for patients with LHI, and current stroke guidelines do not provide a detailed approach regarding the day-to-day management of these complicated patients. To address this need, the Neurocritical Care Society organized an international multidisciplinary consensus conference on the critical care management of LHI. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. The panel devised a series of clinical questions related to LHI, and assessed the quality of data related to these questions using the Grading of Recommendation Assessment, Development and Evaluation guideline system. They then developed recommendations (denoted as strong or weak) based on the quality of the evidence, as well as the balance of benefits and harms of the studied interventions, the values and preferences of patients, and resource considerations.


Testicular varicocele: an overview.
Testicular varicocele or varicocele is one of the common causes of scrotal swelling. It is predominantly found in the adolescent and young adult age group and it can adversely affect testicular function in a variety of ways. There is a considerable debate about the effects of varicoceles on future fertility, but the current evidence suggests that varicoceles are found in a higher percentage among males attending the infertility clinics and that treatment of varicoceles is associated with increased spontaneous conception rates among infertile couples. In this article we give an overall view on the aetiology, adverse effects and management of varicoceles.


In vitro cytotoxicity testing of airborne formaldehyde collected in serum-free culture media.
The purpose of this study was to identify a suitable sampling model for on-site toxicity assessment of soluble air contaminants such as formaldehyde, a well known industrial and indoor air contaminant. The in vitro cytotoxicity of formaldehyde, the selected model for soluble air contaminants, was studied using the MTS (tetrazolium salt) assay in two carcinoma cell lines, A549 epithelial lung and HepG2 hepatocarcinoma, and in skin fibroblasts. The cytotoxic effects of airborne formaldehyde were evaluated using test atmospheres in concentrations below 10 ppm (12.3 mg/m3), generated by a dynamic diffusion method and bubbled (0.3 L/min) through serum-free culture media for one or four hours. Human cells were treated with formaldehyde air samples, and cell viability was determined after four hours incubation. In parallel, the concentration of airborne formaldehyde was monitored, using the 3500 NIOSH method. Cell viability of the HepG2 cells exposed to formaldehyde air samples (8.75 ppm x 4 h) was reduced to less than 50% (31.6 +/- 1.24%). The HepG2 cell lines were found to be more sensitive (IC50 = 103.79 +/- 23.55 mg/L) to formaldehyde than both A549 cell lines (IC50= 198.36 +/- 9.54 mg/L) and skin fibroblasts (IC50 = 196.68 +/- 36.73 mg/L) (P < 0.01). An average of 96.8% was determined for collection efficiency of formaldehyde in serum-free culture media. The results of this study suggest that absorption of soluble air contaminants, such as formaldehyde, in serum-free culture media can be used as a suitable sampling model for on-site toxicity assessments.


[Antenatally detected hydronephrosis: practical approach for the pediatrician].
Approximately 1% of the fetuses present some dilatation of their urinary tract in utero. More than 50% of these antenatally detected hydronephrosis will disappear spontaneously after birth. The other 50% comprises ureteropelvic junction obstruction, vesico-ureteral reflux and primary megaureters. Postnatal radiological evaluation (renal ultrasonography and VCUG) is performed in every infant with a significantly dilated renal pelvis (> 8 mm between 20 and 30 weeks or > 10 mm after 30 weeks in utero). Renal nuclear scan should be done in every child with significant/worsening post-natal hydronephrosis. Antibioprophylaxis will be started from birth to prevent urinary tract infection. Medical or surgical approach will be chosen in the light of the uroradiological exam results and the clinical progress.


Crystal structure of (E)-1-[4-({4-[(4-meth-oxy-benzyl-idene)amino]-phen-yl}sulfan-yl)phen-yl]ethan-1-one.
The title Schiff base compound, C22H19NO2S, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. Both mol-ecules have an E conformation about the C=N bond. The two mol-ecules differ in the orientation of the aromatic rings with respect to each other. The outer 4-meth-oxy-benzene ring is inclined to the central benzene ring and the outer 4-acetyl-benzene ring by 1.80 (19) and 63.73 (19)°, respectively, in mol-ecule A, and by 6.72 (18) and 68.53 (19)°, respectively, in mol-ecule B. The two outer benzene rings are inclined to one another by 63.77 (18) and 63.19 (18)° in mol-ecules A and B, respectively. In the crystal, the individual mol-ecules stack in columns along [010], and are linked by a number of C-H⋯π inter-actions, forming slabs lying parallel to (001).


CALCIPHYLAXIS: PASSIVE TRANSFER.
Rats were sensitized by mouth with dihydrotachysterol and subsequently challenged by a subcutaneous injection of ferric dextran. Mineralization at the injection site is barely detectable 17 hours after challenge. If, at this time, the challenged skin is transplanted onto a normal recipient, mineralization continues in the nonsensitized host. Sensitization is indispensable only for the initiation of the calciphylactic response and, once "triggered," the mechanism for this type of mineralization is transferable.


Expectations for dog ownership: Perceived physical, mental and psychosocial health consequences among prospective adopters.
Dog ownership is popular worldwide, with most human-dog dyads forming successful attachment bonds. However, millions of dogs are surrendered to animal shelters annually, possibly due to mismatches between owner expectations and the realities of dog ownership. The aim of the current study was to explore the benefits and challenges people expect from dog ownership and how these expectations vary with previous ownership history. An Australian-wide sample of 3465 prospective adopters completed a self-administered online questionnaire about the physical, mental and psychosocial health benefits and challenges they associated with dog ownership. Among the potential benefits, respondents expected increased walking (89%), happiness (89%) and companionship (61%) and decreased stress (74%) and loneliness (61%). Among the challenges, they expected increased responsibility (64%) and dog training (62%). Ownership history influenced respondents' expectations, with previous/current dog owners having consistently greater odds of expecting benefits and reduced odds of expecting challenges than non-owners. A possible explanation is that previous/current dog owners' exhibit bias when considering dog ownership by selectively recalling positive experiences from previous ownership. Our findings support the need for education of prospective dog owners to ensure their expectations align with the reality of ownership, based on current scientific evidence.


Inhibition of the pro-inflammatory NF-κB pathway by a grape seed and grape marc meal extract in intestinal epithelial cells.
In pigs and other monogastric animal, the weaning phase is commonly accompanied by an increased susceptibility to gut disorders such as diarrhoea owing to the induction of an inflammatory process in the intestine during weaning. Given the unfavourable effects of intestinal inflammation on feed consumption, digestive capacity of the intestine and growth of animals, controlling intestinal inflammation is a reasonable approach for the maintenance of performance characteristics of livestock animals. Therefore, this study aimed to study the anti-inflammatory potential of a commercial polyphenol-rich grape seed (GS) and grape marc (GM) meal-based feed additive in a well-established in vitro intestinal epithelium model (polarized Caco-2 cells). The anti-inflammatory potential was evaluated by studying the effect of an ethanolic extract obtained from the GS and GM meal-based feed additive (GSGME) on the pro-inflammatory transcription factor NF-κB, which is considered to play a key role in the induction of weaning-associated intestinal inflammation. The highest non-cytotoxic concentrations of the ethanolic GSGME dose dependently reduced TNFα-induced NF-κB transactivation and decreased TNFα-induced mRNA levels of the NF-κB target genes IL-1β, IL-8, MCP-1 and CXCL1 in Caco-2 intestinal cells (p < 0.05). No effect of the ethanolic GSGME was observed on the cytoprotective Nrf2 pathway in Caco-2 cells as evidenced by an unaltered Nrf2 transactivation and unchanged mRNA levels of Nrf2 target genes, such as GPX-2, NQO1, CYP1A1 and UGT1A1. In conclusion, this study shows that an ethanolic GSGME exerts anti-inflammatory effects in intestinal cells under in vitro conditions. Thus, polyphenol-rich GSGM meal-based feed additives may be useful for the inhibition or prevention of inflammatory processes in the intestine of livestock animals, in particular during states with inappropriate NF-κB activation in the intestinal tissue, such as the weaning phase. Future studies are warranted to prove the in vivo anti-inflammatory potential of GSGM meal-based feed additives.


The effects of di(2-ethylhexyl)phthalate exposure and selenium nutrition on sertoli cell vimentin structure and germ-cell apoptosis in rat testis.
This study aimed to investigate the effects of di(2-ethylhexyl)phthalate (DEHP) on Sertoli-cell vimentin filaments and germ-cell apoptosis in testes of pubertal rats at different selenium (Se) status. Se deficiency was produced in 3-weeks old Sprague-Dawley rats by feeding them ≤ 0.05 Se mg/kg diet for 5 weeks, Se supplementation group was on 1 mg Se/kg diet, and DEHP was applied at 1000 mg/kg dose by gavage during the last 10 days of the feeding period. The diet with excess Se did not cause any appreciable alteration in vimentin staining and apoptosis of germ cells, but Se deficiency caused a mild decrease in the intensity of vimentin immunoreactivity and enhanced germ-cell apoptosis significantly (approximately 3-fold, p <0.0033). DEHP exposure caused disruption and collapse of vimentin filaments and significantly induced apoptotic death of germ cells (approximately 8-fold, p <0.0033). In DEHP-exposed Se-deficient animals, compared with the control, collapse of vimentin filaments was more prominent; there was serious damage to the seminiferous epithelium; and a high increment (approximately 25-fold, p <0.0033) in apoptotic germ cells was observed. Thus, Se deficiency exacerbated the toxicity of DEHP on Sertoli cells and spermatogenesis, whereas Se supplementation provided protection. These results put forward the critical role of Se in the modulation of redox status of testicular cells and emphasize the importance of Se status for reproductive health.


[B-scan sonography of the carotid artery. Technique, results and indications (author's transl)].
Three hundred and forty-six carotid arteries were examined with a two-dimensional 3.5 MHz real time scanner in 173 patients with evidence of cerebral ischaemia; 62 carotid arteries were investigated by selective trans-femoral angiography in 36 of these patients at the same time. Sonography and angiography agreed in 20 (91%) of 22 angiographically normal cases, in all cases (10) with haemodynamically insignificant plaques, in eight (66%) of 12 stenosis of less than 50%, in nine (90%) of ten stenosis of more than 50% and in four (44%) of nine total occlusions. Sensitivity of carotid sonography varied with the severity of the lesion from 44 to 100%. Its specificity was 91%. B-scan sonography of the carotid artery, in the presence of cerebro-vascular lesions (transitory ischaemia, cerebral infarcts) and in the presence of non-specific symptoms and of asymptomatic vascular murmurs, may provide indications for the use of angiography. Its values as a screening procedure remains to be assessed.


Cytomegalovirus disease as a risk factor for graft loss and death after orthotopic liver transplantation.
To determine whether cytomegalovirus (CMV) disease is an independent risk factor for graft loss and death after orthotopic liver transplantation, we performed a 3-year follow-up study of 143 consecutive liver transplant recipients and six patients who underwent retransplantation. Thirty-seven patients (25%) had had CMV disease and were alive after treatment. Fifty-two deaths and eight graft losses occurred. The cumulative incidence of graft failure at 1 and 3 years of follow-up were 40% and 63%, respectively, for patients with CMV disease, compared with 22% and 33%, respectively, for those without CMV disease (P < .05, logrank test). Cumulative probabilities of survival for patients with and without CMV disease were 64% and 82%, respectively, at 1 year and 46% and 69%, respectively, after 3 years (P < .05, logrank test). Multivariate analysis with use of a time-dependent Cox model showed that previous CMV disease was an independent risk factor for graft loss at 1 and 3 years of follow-up (P = .04 and P = .007) and for patient survival (P = .04 and P = .01). Our results indicate that CMV disease is a significant independent risk factor for graft loss and patient survival after liver transplantation.


Localized encapsulating peritoneal sclerosis constricting the terminal ileum--an unusual appearance requiring surgical intervention.
Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD). It is characterized by encapsulation of the bowel, causing symptoms of intestinal obstruction. Exclusive involvement of parts of the bowel may occur and may be more common than previously thought. Our main objective was to investigate and report on patients with localized EPS. Between July 2002 and December 2011, 9 of 17 EPS patients were referred to our department of surgery for a diagnostic laparotomy. Three of the 9 cases showed localized encapsulation of the small bowel and were selected for the purpose of this study. All 3 patients presented with an acute inflammatory state and symptoms of bowel obstruction. In 2 patients, EPS became clinically overt after kidney transplantation; the third patient was diagnosed while on hemodialysis. All shared a history of PD ranging from 31 to 101 months. In none of the patients was radiologic examination conclusive, although 2 showed peritoneal thickening and ascites. Each patient underwent laparotomy, confirming EPS. In all cases, a thickened peritoneal membrane became apparent, predominantly covering the ileocecal region of the intestine. In addition, a constrictive membrane at the level of the terminal ileum was noted. In 2 cases, the patients underwent enterolysis and dissection of the constricting fibrotic peritoneal membrane (peritonectomy) without bowel resection. The 3rd patient was managed with parenteral nutrition and tamoxifen. The postoperative course in 1 patient was complicated by infected ascites that resolved with antibiotic treatment. Eventually, all patients were doing well, with adequate oral intake and without the need for repeat surgery. Localized EPS may be more common than previously thought. It has a predilection for the level of the terminal ileum. We believe that an elective diagnostic laparotomy should be considered early, because this procedure offers both diagnostic opportunities and therapeutic options. Localized EPS cases may benefit most from enterolysis and peritonectomy.


Semantic and affective priming as a function of stimulation of the subthalamic nucleus in Parkinson's disease.
Lexical-semantic and emotional processing deficits have been associated with Parkinson's disease. This study investigated automatic and controlled lexical-semantic processing, the automatic activation of emotional evaluations, and the processing of words conveying negative and neutral emotional connotations in a combined affective and semantic priming paradigm. Eighteen participants with Parkinson's disease who had undergone surgery for deep brain stimulation (DBS) of the subthalamic nucleus (STN) completed a lexical decision task at short and long stimulus onset asynchronies (SOAs), during on and off stimulation conditions. Nineteen non-neurologically impaired participants acted as controls. The results indicated that automatic lexical-semantic and emotional evaluative processes are unimpaired in Parkinson's disease as reflected in the presence of comparable semantic and affective priming effects at the short SOA in on and off stimulation conditions compared with healthy controls. In contrast, participants with Parkinson's disease in the off stimulation condition showed a pattern of aberrant controlled lexical-semantic processing as evidenced by a lack of semantic priming effects at the long SOA condition. Controlled semantic priming was present, however, when the participants with Parkinson's disease were receiving stimulation of the STN, suggesting that STN stimulation modulates basal ganglia-thalamocortical circuits involved in such processes. Finally, delayed reaction times for negatively valenced targets compared with neutrally valenced targets was evident in participants with Parkinson's disease in the on stimulation condition and control participants, but not for participants with Parkinson's disease in the off stimulation condition, suggesting that the incidental evaluation of negatively versus neutrally valenced words in Parkinson's disease is modulated by basal ganglia-thalamocortical circuits.


Allele-specific and heritable chromatin signatures in humans.
Next-generation sequencing-based assays to detect gene regulatory elements are enabling the analysis of individual-to-individual and allele-specific variation of chromatin status and transcription factor binding in humans. Recently, a number of studies have explored this area, using lymphoblastoid cell lines. Around 10% of chromatin sites show either individual-level differences or allele-specific behavior. Future studies are likely to be limited by cell line accessibility, meaning that white-bloodcell-based studies are likely to continue to be the main source of samples. A detailed understanding of the relationship between normal genetic variation and chromatin variation can shed light on how polymorphisms in non-coding regions in the human genome might underlie phenotypic variation and disease.


Microdiffusion and fluoride-specific electrode determination of fluoride in infant foods: collaborative study.
Twelve laboratories analyzed (1 replicate) 12 samples of infant foods--milk, pears, and peas--containing 0.2-5 ppm F. There was one laboratory outlier. Mean coefficients of variation were 7.06% for intralaboratory determination of 3 sets of blind duplicates and 21.6% for interlaboratory determination of 12 samples. Variance analysis for all samples yielded a reproducibility standard deviation of 0.41 ppm; for 3 sets of blind duplicates, repeatability standard deviation was 0.26 ppm and reproducibility standard deviation was 0.32 ppm.


Water Structures Reveal Local Hydrophobicity on the In2O3(111) Surface.
Clean oxide surfaces are generally hydrophilic. Water molecules anchor at undercoordinated surface metal atoms that act as Lewis acid sites, and they are stabilized by H bonds to undercoordinated surface oxygens. The large unit cell of In2O3(111) provides surface atoms in various configurations, which leads to chemical heterogeneity and a local deviation from this general rule. Experiments (TPD, XPS, nc-AFM) agree quantitatively with DFT calculations and show a series of distinct phases. The first three water molecules dissociate at one specific area of the unit cell and desorb above room temperature. The next three adsorb as molecules in the adjacent region. Three more water molecules rearrange this structure and an additional nine pile up above the OH groups. Despite offering undercoordinated In and O sites, the rest of the unit cell is unfavorable for adsorption and remains water-free. The first water layer thus shows ordering into nanoscopic 3D water clusters separated by hydrophobic pockets.


Effect of c-Met inhibitor SU11274 on hepatocellular carcinoma cell growth.
c-Met, a type of receptor tyrosine kinase, may be significantly associated with the progression of hepatocellular carcinoma (HCC). In addition, des-γ-carboxyprothrombin (DCP) has been found to interact with c-Met and activate HCC cell growth. Therefore, the functional inhibition of c-Met expressed on HCC cells should arrest HCC cell growth. The present study found that the c-Met inhibitor SU11274 suppressed HCC cell growth by inhibiting the activation of c-Met. Furthermore, this inhibitor also neutralized the activation of HCC cell growth resulting from the addition of DCP. These results suggest that the functional inhibition of c-Met might be a target for the development of chemotherapeutic agents for HCC, and especially those that are positive for expression of DCP.


Breeder reactors in france.
France relies on nuclear power as an important part of her energy program. Anticipating problems with the availability of natural uranium before the year 2020, the French have been pursuing a three-stage program of development of breeder reactors. The third reactor in this program, the near-commercial plant Super Phenix Mark I, is expected to reach power operation in 1983. Although there are still some uncertainties, particularly about the date when the breeder will become competitive with other energy sources, the outlook is considered favorable and preliminary designs for commercial plants are under way.


Second and Outer Coordination Sphere Effects in Nitrogenase, Hydrogenase, Formate Dehydrogenase, and CO Dehydrogenase.
Gases like H2, N2, CO2, and CO are increasingly recognized as critical feedstock in "green" energy conversion and as sources of nitrogen and carbon for the agricultural and chemical sectors. However, the industrial transformation of N2, CO2, and CO and the production of H2 require significant energy input, which renders processes like steam reforming and the Haber-Bosch reaction economically and environmentally unviable. Nature, on the other hand, performs similar tasks efficiently at ambient temperature and pressure, exploiting gas-processing metalloenzymes (GPMs) that bind low-valent metal cofactors based on iron, nickel, molybdenum, tungsten, and sulfur. Such systems are studied to understand the biocatalytic principles of gas conversion including N2 fixation by nitrogenase and H2 production by hydrogenase as well as CO2 and CO conversion by formate dehydrogenase, carbon monoxide dehydrogenase, and nitrogenase. In this review, we emphasize the importance of the cofactor/protein interface, discussing how second and outer coordination sphere effects determine, modulate, and optimize the catalytic activity of GPMs. These may comprise ionic interactions in the second coordination sphere that shape the electron density distribution across the cofactor, hydrogen bonding changes, and allosteric effects. In the outer coordination sphere, proton transfer and electron transfer are discussed, alongside the role of hydrophobic substrate channels and protein structural changes. Combining the information gained from structural biology, enzyme kinetics, and various spectroscopic techniques, we aim toward a comprehensive understanding of catalysis beyond the first coordination sphere.


Use of immediate dermal fat graft for scalp contour defect following resection of arteriovenous malformation.
Arterial venous malformations (AVMs) are rare conditions that are difficult to manage. Therapeutic options include selective embolization with or without surgical excision. Recurrence, however, is high despite correction of the primary abnormality. Cosmetic concern is among the indications for treatment, particularly if the AVM occurs on the face or scalp. Historically, AVM excision and the residual defect correction have been performed separately. We present the first case reported of a successful embolization and interval excision with immediate reconstruction using a dermal fat graft, as a novel approach to correct soft tissue defect following the resection of an AVM. A 35-year-old man presented with a 20-year history of a nonpulsating mass posterior to the hairline in the right frontoparietal region, measuring 4.0 cm on its longest axis. Embolization of the AVM was achieved by injecting N-butyl cyanoacrylic acid and ethiodol. One month after embolization, surgical excision of the mass was performed. The resulting disfiguring contour defect was immediately corrected using a dermal fat graft harvested from the groin. At 4 months' follow-up, the graft was viable with no evidence of resorption or epidermal cyst formation. In addition, there was no recurrence of the AVM and no complications at the donor site. This case demonstrates the utility of a dermal fat grafts in correcting the impending defect in 1 stage avoiding a second-stage procedure and significant period of cosmetic disfigurement. This method should be considered as a treatment option for patients requiring moderately sized AVM excisions in cosmetically sensitive areas.


Evaluation of Selected Culinary-Medicinal Mushrooms for Antioxidant and ACE Inhibitory Activities.
Considering the importance of diet in prevention of oxidative stress-related diseases including hypertension, this study was undertaken to evaluate the in vitro antioxidant and ACE inhibitory activities of selected culinary-medicinal mushrooms extracted by boiling in water for 30 min. Antioxidant capacity was measured using the following assays: DPPH free radical scavenging activity, β-carotene bleaching, inhibition of lipid peroxidation, reducing power ability, and cupric ion reducing antioxidant capacity (CUPRAC). Antioxidant potential of each mushroom species was calculated based on the average percentages relative to quercetin and summarized as Antioxidant Index (AI). Ganoderma lucidum (30.1%), Schizophyllum commune (27.6%), and Hericium erinaceus (17.7%) showed relatively high AI. Total phenolics in these mushrooms varied between 6.19 to 63.51 mg GAE/g extract. In the ACE inhibitory assay, G. lucidum was shown to be the most potent species (IC(50) = 50 μg/mL). Based on our findings, culinary-medicinal mushrooms can be considered as potential source of dietary antioxidant and ACE inhibitory agents.


A human killer inhibitory receptor specific for HLA-A1,2.
Killer inhibitory receptors (KIRs) are transmembrane glycoproteins, expressed on NK cells and a small subset of T cells, that inhibit cell-mediated cytotoxicity upon binding to polymorphic MHC class I determinants on target cells. Although human KIRs specific for HLA-C and HLA-B molecules have been characterized, none have been shown to interact with HLA-A. Here we demonstrate that a member of the KIR cDNA family, designated NKAT4, encodes a 70-kDa receptor specific for HLA-A3.


[Diversity and relative abundance of corals, octocorals and sponges at Jaragua National Park, Dominican Republic].
The Jaragua National Park is located in a remote area to the SW coast of the Dominican Republic. Fishing and mining are the major human activities. The main reef formations of the Park include: (a) long bank reefs (spur and groove) growing as bands over the platform and running in a SW-NW direction at 12-25 m depth, (b) well developed, deep, fringing reefs at the platform edge (drop-off) areas which could extend from 10 to 45 m depth, and (c) small patch reefs and poorly developed coral-octocoral-sponge-algal communities in shallow platforms near shore, rocky bottoms, and over the submerged walls of the uplifted reef. Nine reef localities were surveyed between Cabo Beata and Bahia Honda using Scuba diving to inventory the diversity and relative abundance of scleractinian corals, octocorals and sponges. Fringing reefs were surveyed starting at the bottom (30 m) and swimming in a zig-zag pattern (50 m on each side) to shallower areas. Bank reefs were surveyed by swimming in zig-zag across the spur-groove formation along 500 m. Sponges were the most diverse group with 83 species in 50 genera followed by the scleractinian corals with 56 species in 26 genera and the octocorals with 47 species in 15 genera. New records included eight coral species, 29 octocoral species and 59 sponges. The diversity, species composition and abundance of particular groups varied across the different localities. Northern reefs within the park and the Los Frailes Island offshore had the highest live cover, relative abundance and diversity for the three groups. In general, the Jaragua National Park had the highest diversity of corals, octocorals and sponges reported for the Dominican Republic and rank amongst the highest reported for the northern Caribbean. It is recommended that the area be protected and that fishing activities be regulated or eliminated altogether.


Devolution. Separate ways.
Devolution will bring health policy under the democratic control of the directly elected Scottish parliament and Welsh assembly. Some fear that members of these bodies may wish to interfere in service delivery, rather than concentrating on strategy. Devolution could highlight anomalies in health spending. Many professionals fear that devolution will fragment UK-wide policy networks.


Response to Tsuda et al. "demonstrating the undermining of science and health policy after the Fukushima nuclear accident by applying the toolkit for detecting misused epidemiological methods".
The SHAMISEN (Nuclear Emergency Situations - Improvement of Medical And Health Surveillance) European project was conducted in 2015-2017 to review the lessons learned from the experience of past nuclear accidents and develop recommendations for preparedness and health surveillance of populations affected by a nuclear accident. Using a toolkit approach, Tsuda et al. recently published a critical review of the article by Cléro et al. derived from the SHAMISEN project on thyroid cancer screening after nuclear accident. We address the main points of criticism of our publication on the SHAMISEN European project. We disagree with some of the arguments and criticisms mentioned by Tsuda et al. We continue to support the conclusions and recommendations of the SHAMISEN consortium, including the recommendation not to launch a mass thyroid cancer screening after a nuclear accident, but rather to make it available (with appropriate information counselling) to those who request it.


Clinical spectrum of the pentanucleotide repeat expansion in the RFC1 gene in ataxia syndromes.
To determine the clinical significance of an intronic biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) in patients with late-onset cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), in patients with other ataxias, and in healthy controls by comprehensive genetic analyses. In this case-control study, we included 457 individuals comprising 26 patients with complete or incomplete CANVAS, 70 patients with late-onset cerebellar ataxia, 208 healthy controls, and 153 individuals from 39 multigenerational families without ataxia to determine repeat stability. All 96 patients were screened for the repeat expansion by duplex PCR. To further characterize the repeat type and lengths, we used fragment length analysis, repeat-primed PCR, Sanger sequencing, and Southern blotting. Expression of RFC1 and the neighboring gene WDR19 were determined by quantitative PCR. Massive biallelic pentanucleotide expansions were found in 15/17 patients with complete CANVAS (88%), in 2/9 patients with incomplete CANVAS (22%), in 4/70 patients with unspecified, late-onset cerebellar ataxia (6%), but not in controls. In patients, the expansion comprised 800-1,000 mostly AAGGG repeats. Nonmassively expanded repeat numbers were in the range of 7-137 repeats and relatively stable during transmission. Expression of RFC1 and WDR19 were unchanged and RFC1 intron retention was not found. A biallelic pentanucleotide repeat expansion is a frequent cause of CANVAS and found in a considerable number of patients with an incomplete clinical presentation or other forms of cerebellar ataxia. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations.


Role of Thymoquinone in Cardiac Damage Caused by Sepsis from BALB/c Mice.
Sepsis is a major health complication causing patient mortality and increased healthcare costs. Cardiac dysfunction, an important consequence of sepsis, affects mortality. We previously reported that thymoquinone (TQ) protected against hyperlipidemia and doxorubicin-induced cardiac damage. This study investigated the possible protective effects of TQ against cardiac damage in septic BALB/c mice. Eight-week-old male BALB/c mice were divided into four groups: control, TQ, cecal ligation and puncture (CLP), and TQ + CLP. CLP was performed after 2-week TQ gavage. After 48 h, we measured the histopathological alterations of the cardiac tissue and the plasma levels of troponin-T (cTnT) and ATP. We evaluated autophagy (p62 and beclin 1), pyroptosis (NLRP3, caspase-1, interleukin [IL]-1β, and IL-18) at the gene and protein levels and IL-6 and tumor necrosis factor-α (TNF-α) at the gene level. Our results demonstrated that TQ administration significantly reduced intestinal histological alterations. TQ inhibited plasma cTnT levels; improved ATP; significantly inhibited p62, NLRP3, caspase-1, IL-1β, IL-18, IL-6, TNF-α, and MCP-1expressions; and increased beclin 1 and IL-10 level. The phosphatidylinositide 3-kinase level was significantly decreased in the TQ + CLP group versus the CLP group. These results suggest that TQ effectively modulates autophagy, pyroptosis, and pro-inflammatory, making it important in the treatment of sepsis-induced cardiac damage.


Susceptibility to melanoma: influence of skin type and polymorphism in the melanocyte stimulating hormone receptor gene.
Allelic variation at the melanocyte stimulating hormone receptor (MC1R) gene has been linked with sun-sensitive skin types, suggesting it is a susceptibility candidate for melanoma. We determined the frequency of the val92met, asp294his, and asp84glu MC1R alleles in 190 Caucasian controls and 306 melanoma cases and studied their association with skin type and hair color. The percentage of controls with at least one val92met, asp294his, or asp84glu allele was 17.3%, 6.8%, and 3.5%, respectively. Individually, frequencies of the val92met, asp294his, or asp84glu alleles in the controls with skin types 3 and 4 were similar to those with skin types 1 and 2. Trend analysis, however, did identify an association (exact p = 0.048, two-sided test) between skin type and MC1R variants in the group comprising all controls with any one or more of these alleles. There was no association between MC1R alleles and hair color. Allele frequencies were not different in melanoma cases and controls. There were no associations between skin types and the proportion of cases with the asp294his or asp84glu alleles, though the association between skin type and the val92met allele approached significance (exact p = 0.09, two-sided test). Unexpectedly, in the group comprising all cases with one or more variant alleles, the proportion of subjects with variant alleles increased with skin types associated with tanning rather than burning, although trend analysis showed that this association did not quite reach statistical significance (exact p = 0.08, two-sided test). Asp84glu (but not val92met or asp294his) variant alleles were more common in subjects with blonde hair, although the relationship between the asp84glu allele and hair color did not achieve statistical significance (chi(2)3 = 6.16, exact p = 0.10). We interpret the data presented as indicating that polymorphism at MC1R does not appear a major determinant of skin type, at least in terms of these allelic variants. Furthermore, considered alone, these alleles are not susceptibility candidates for malignant melanoma.


Opioids for chronic pain: a knowledge assessment of nonpain specialty providers.
Although the majority of opioids in the US are prescribed by nonpain specialists, these providers often report inadequate training in chronic pain management and opioid prescribing. The extent of health care providers' knowledge of opioid prescribing for chronic pain has not been well established. The purpose of this study was to assess knowledge about the use of opioids for chronic pain among health care providers seeking pain-focused continuing medical education. The study participants (n=131) were recruited at a pain-focused continuing medical education conference for nonpain specialists. Upon commencement of the conference, the KnowPain-50 survey was completed. The survey comprised 50 questions, and 18 questions were related to opioid management. The focus of each opioid question was further categorized as either medicolegal (n=7) or clinical (n=11). The majority of study participants were male physicians with a mean age of 51.8 years. The proportion of correct responses to the 50-item survey was 72%. The proportion of correct responses to the 32 nonopioid questions was 74%, and the proportion of correct responses to the 18 opioid questions was 69% (P<0.001). Similarly, the proportion of correct responses to the seven medicolegal opioid questions was 74%, and the proportion of correct responses to the eleven clinical opioid questions was 67% (P<0.001). Health care providers demonstrated gaps in knowledge about the use of opioids for chronic pain. Lower scores on clinically based opioid questions may indicate an opportunity to provide focused educational content about this area of practice. This information could be helpful in designing future educational modules for nonpain providers.


Effect of age and activity on knee joint proprioception.
Falls lead to significant morbidity and mortality in persons older than 65 years of age. Impaired proprioception may be a contributing factor to falls, and this may be influenced by the level of habitual physical activity. The primary purpose of this study was to investigate knee joint proprioception among young volunteers and active and sedentary elderly volunteers. Knee joint proprioception was measured through reproduction of static knee angles using a Penny and Giles electrogoniometer. The secondary purpose of this investigation was to test the reproducibility of the Penny and Giles electrogoniometer in measuring static knee angles. Sixteen young subjects (age range, 19-27 years) and 24 elderly subjects (age range, 60-86 years) participated. Subjects were given a screening history and physical examination to exclude neuromuscular or vestibular disorders or lower limb injuries. Knee joint proprioception was measured two times during one week. The elderly group was separated into active and sedentary subgroups based on their level of activity during the past year. The electrogoniometer was placed laterally across the dominant knee joint. From the prone position each subject attained one of ten randomly predetermined knee joint angles from 10 degrees to 60 degrees. The subject then returned to the starting position and reproduced the test angle. The absolute angular error (the absolute difference between the test angle and subject perceived angle of knee flexion) was determined. A positive correlation was found between control visits for all subjects (r = 0.88), and significant differences were observed between young (mean, 2.01 +/- 0.46 degrees) and active-fold (mean, 3.12 +/- 1.12 degrees; P < 0.001), young and sedentary-old (mean, 4.58 +/- 1.93 degrees; P < 0.001), and active-old and sedentary-old (P < 0.03). These findings demonstrate that the Penny and Giles electrogoniometer is a reproducible device for measuring knee joint angles in both young and elderly subjects. Furthermore, we found that proprioception is diminished with age and that regular activity may attenuate this decline. One strategy to reduce the incidence of poor proprioception and fall with ageing may be regular exercise.


Rapid and quantitative detection of homologous and non-homologous recombination events using three oligonucleotide MLPA.
Embryonic stem (ES) cell technology allows modification of the mouse germline from large deletions and insertions to single nucleotide substitutions by homologous recombination. Identification of these rare events demands an accurate and fast detection method. Current methods for detection rely on Southern blotting and/or conventional PCR. Both the techniques have major drawbacks, Southern blotting is time-consuming and PCR can generate false positives. As an alternative, we here demonstrate a novel approach of Multiplex Ligation-dependent Probe Amplification (MLPA) as a quick, quantitative and reliable method for the detection of homologous, non-homologous and incomplete recombination events in ES cell clones. We have adapted MLPA to detect homologous recombinants in ES cell clones targeted with two different constructs: one introduces a single nucleotide change in the PCNA gene and the other allows for a conditional inactivation of the wild-type PCNA allele. By using MLPA probes consisting of three oligonucleotides we were able to simultaneously detect and quantify both wild-type and mutant alleles.


The role of memory reactivation during wakefulness and sleep in determining which memories endure.
Consolidation makes it possible for memories of our daily experiences to be stored in an enduring way. We propose that memory consolidation depends on the covert reactivation of previously learned material both during sleep and wakefulness. Here we tested whether the operation of covert memory reactivation influences the fundamental selectivity of memory storage--of all the events we experience each day, which will be retained and which forgotten? We systematically manipulated the value of information learned by 60 young subjects; they learned 72 object-location associations while hearing characteristic object sounds, and a number on each object indicated the reward value that could potentially be earned during a future memory test. Recall accuracy declined to a greater extent for low-value than for high-value associations after either a 90 min nap or a 90 min wake interval. Yet, via targeted memory reactivation of half of the low-value associations using the corresponding sounds, these memories were rescued from forgetting. Only cued associations were rescued when sounds were applied during wakefulness, whereas the entire set of low-value associations was rescued from forgetting when the manipulation occurred during sleep. The benefits accrued from presenting corresponding sounds show that covert reactivation is a major factor determining the selectivity of memory consolidation in these circumstances. By extension, covert reactivation may determine the ultimate fate of our memories, though wake and sleep reactivation might play distinct roles in this process, the former helping to strengthen individual, salient memories, and the latter strengthening, while also linking, categorically related memories together.


Medication Review with Follow-Up for End-Stage Renal Disease: Drug-Related Problems and Negative Outcomes Associated with Medication-A Systematic Review.
This article reviews the available scientific literature on drug-related problems and negative outcomes associated with medications identified by medication review with follow-up for end-stage renal disease and discussed with the physicians. A systematic review was conducted of the scientific literature retrieved from the following databases: MEDLINE (via PubMed), Web of Science, SCOPUS, Cochrane Library: The Cochrane Central Register and Control Trials (CENTRAL) and Literatura Latinoamericana y del Caribe (LILACS), Medicina en Español (MEDES), and the SciELO bibliographic database (a collection of scientific journals). The following terms were used as descriptors and searched in free text: "end-stage renal disease", "medication review", "drug-related problems", and "negative outcomes associated with medication". The following limits were applied: "humans" and "adults (more than 18 years)". A total of 59 references were recovered and, after applying inclusion/exclusion criteria, 16 articles were selected. Of these selected articles, 15 provided information on drug-related problems and only 1 on negative outcomes associated with medications. It can be concluded that drug-related problems and negative outcomes associated with medications affect patients with end-stage renal disease, mainly those receiving renal replacement therapy. More evidence is needed, especially on negative outcomes associated with medication.


Combined technique for the correction of lower-limb deformities resulting from metabolic bone disease.
We present the results of the surgical correction of lower-limb deformities caused by metabolic bone disease. Our series consisted of 17 patients with a diagnosis of hypophosphataemic rickets and two with renal osteodystrophy; their mean age was 25.6 years (14 to 57). In all, 43 lower-limb segments (27 femora and 16 tibiae) were osteotomised and the deformity corrected using a monolateral external fixator. The segment was then stabilised with locked intramedullary nailing. In addition, six femora in three patients were subsequently lengthened by distraction osteogenesis. The mean follow-up was 60 months (18 to 120). The frontal alignment parameters (the mechanical axis deviation, the lateral distal femoral angle and the medial proximal tibial angle) and the sagittal alignment parameters (the posterior distal femoral angle and the posterior proximal tibial angle) improved post-operatively. The external fixator was removed either at the end of surgery or at the end of the lengthening period, allowing for early mobilisation and weight-bearing. We encountered five problems and four obstacles in the programme of treatment. The use of intramedullary nails prevented recurrence of deformity and refracture.


Effect of bupropion treatment on brain activation induced by cigarette-related cues in smokers.
Nicotine-dependent smokers exhibit craving and brain activation in the prefrontal and limbic regions when presented with cigarette-related cues. Bupropion hydrochloride treatment reduces cue-induced craving in cigarette smokers; however, the mechanism by which bupropion exerts this effect has not yet been described. To assess changes in regional brain activation in response to cigarette-related cues from before to after treatment with bupropion (vs placebo). Randomized, double-blind, before-after controlled trial. Academic brain imaging center. Thirty nicotine-dependent smokers (paid volunteers). Participants were randomly assigned to receive 8 weeks of treatment with either bupropion or a matching placebo pill (double-blind). Subjective cigarette craving ratings and regional brain activations (blood oxygen level-dependent response) in response to viewing cue videos. Bupropion-treated participants reported less craving and exhibited reduced activation in the left ventral striatum, right medial orbitofrontal cortex, and bilateral anterior cingulate cortex from before to after treatment when actively resisting craving compared with placebo-treated participants. When resisting craving, reduction in self-reported craving correlated with reduced regional brain activation in the bilateral medial orbitofrontal and left anterior cingulate cortices in all participants. Treatment with bupropion is associated with improved ability to resist cue-induced craving and a reduction in cue-induced activation of limbic and prefrontal brain regions, while a reduction in craving, regardless of treatment type, is associated with reduced activation in prefrontal brain regions.


Two models of managed long-term care: comparing PACE with a Medicaid-only plan.
In this study an attempt is made to understand how a Medicaid-only managed long-term-care (MMLTC) plan for elders differs from the Program of All-Inclusive Care for the Elderly (PACE), a fully integrated model, in terms of structure, operations, patient population, and service utilization. With the use of information from the Outcome and Assessment Information Set and administrative data from a MMLTC plan in New York City, enrollees were compared at the start of care and their first-year service utilization with PACE, using the PACE national data set. The plans differ in the range of services covered and in the larger number of members served by the MMLTC plan. The served populations differ in their sociodemographic profiles and have levels of functional need that are high, but they also differ in their relative severity of dependency in activities of daily living and instrumental activities of daily living. During the first year of enrollment, the utilization of traditional home- and community-based services was higher in PACE than in the MMLTC plan, although MMLTC plan members received much more care in the home. Total hospital utilization was lower in PACE, but nursing home utilization was higher. MMLTC is a feasible option for serving a population whose level of impairment is similar to that of PACE. Whereas PACE's reliance on adult day centers is seemingly associated with a stronger medical focus and lower hospital use, the MMLTC plan's emphasis on home-based personal care seems to be linked with lower nursing home use.


Perinatal risk factors for developmental dysplasia of the hip.
To identify perinatal risk factors for developmental dysplasia of the hip (DDH) and define the risk for each factor. In this case control study, using logistic regression analysis, all 1127 cases of isolated DDH live born in South Australia in 1986-93 and notified to the South Australian Birth Defects Register were included; controls comprised 150130 live births in South Australia during the same period without any notified congenital abnormalities. Breech presentation, oligohydramnios, female sex and primiparity were confirmed as risk factors for DDH. Significant findings were an increased risk for vaginal delivery over caesarean section for breech presentation (as well as an increased risk for emergency section over elective section), high birthweight (> or = 4000 g), postmaturity and older maternal age; multiple births and preterm births had a reduced risk. There was no increased risk for caesarean section in the absence of breech presentation. For breech presentation, the risk of DDH was estimated to be at least 2.7% for girls and 0.8% for boys; a combination of factors increased the risk. It is suggested that the risk factors identified be used as indications for repeat screening at 6 weeks of age and whenever possible in infancy. Other indications are family history and associated abnormalities.


Practical and operational considerations related to paediatric oral drug formulation: An industry survey.
For over 15 years, US and EU regulations ensure that medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations, implying dedicated research. To shed light on how these regulations have been adopted by pharmaceutical companies and how various aspects of paediatric oral drug formulation development are currently handled, an exploratory survey was conducted. Topics included: general company policy, regulatory aspects, dosage form selection, in-vitro, in-silico and (non-)clinical in-vivo methods, and food effects assessment. The survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharmaceutical industry. Even though significant improvements have been made in paediatric product development, major challenges remain. In this respect, dosage form selection faces a discrepancy between the youngest age groups (liquid products preference) and older subpopulations (adult formulation preference). Additionally, concerted research is needed in the development and validation of in-vitro tools and physiology based pharmacokinetic models tailored to the paediatric population, and in estimating the effect of non-standard and paediatric relevant foods. The current momentum in paediatric drug development and research should allow for an evolution in standardised methodology and guidance to develop paediatric formulations, which would benefit pharmaceutical industry and regulators.


Glutamine-Elicited Secretion of Glucagon-Like Peptide 1 Is Governed by an Activated Glutamate Dehydrogenase.
Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo in mice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.


Medicolegal aspects of paternity testing.
Blood group testing has achieved wide acceptance by the courts as a major scientific determinant in paternity proceedings. Other tests, including H-LA types and hemoglobin determinations, are also being used with increasing frequency; however, there are legal safeguards which must be met to satisfy the court's need to ensure the validity of the tests and their interpretation. In order for the results of paternity testing to be admitted into testimony (evidence) the following should be established: 1) proof that proper persons provided the blood samples; 2) consent to the tests and permission for release of information regarding test results; 3) proof that the speciment was correctly labeled and transported; 4) documented accuracy of the testing procedures; 5) fact testimony regarding the test results; and 6) expert testimony explaining the exclusion principle. In the future, laboratory personnel can expect wider application of these and other laboratory results to legal proceedings. For determinations derived from any laboratory testing to be admissable as evidence, the courts will apply the above safeguards.


The genome of the leaf-cutting ant Acromyrmex echinatior suggests key adaptations to advanced social life and fungus farming.
We present a high-quality (>100× depth) Illumina genome sequence of the leaf-cutting ant Acromyrmex echinatior, a model species for symbiosis and reproductive conflict studies. We compare this genome with three previously sequenced genomes of ants from different subfamilies and focus our analyses on aspects of the genome likely to be associated with known evolutionary changes. The first is the specialized fungal diet of A. echinatior, where we find gene loss in the ant's arginine synthesis pathway, loss of detoxification genes, and expansion of a group of peptidase proteins. One of these is a unique ant-derived contribution to the fecal fluid, which otherwise consists of "garden manuring" fungal enzymes that are unaffected by ant digestion. The second is multiple mating of queens and ejaculate competition, which may be associated with a greatly expanded nardilysin-like peptidase gene family. The third is sex determination, where we could identify only a single homolog of the feminizer gene. As other ants and the honeybee have duplications of this gene, we hypothesize that this may partly explain the frequent production of diploid male larvae in A. echinatior. The fourth is the evolution of eusociality, where we find a highly conserved ant-specific profile of neuropeptide genes that may be related to caste determination. These first analyses of the A. echinatior genome indicate that considerable genetic changes are likely to have accompanied the transition from hunter-gathering to agricultural food production 50 million years ago, and the transition from single to multiple queen mating 10 million years ago.


Causal Support: Modeling Causal Inferences with Visualizations.
Analysts often make visual causal inferences about possible data-generating models. However, visual analytics (VA) software tends to leave these models implicit in the mind of the analyst, which casts doubt on the statistical validity of informal visual "insights". We formally evaluate the quality of causal inferences from visualizations by adopting causal support-a Bayesian cognition model that learns the probability of alternative causal explanations given some data-as a normative benchmark for causal inferences. We contribute two experiments assessing how well crowdworkers can detect (1) a treatment effect and (2) a confounding relationship. We find that chart users' causal inferences tend to be insensitive to sample size such that they deviate from our normative benchmark. While interactively cross-filtering data in visualizations can improve sensitivity, on average users do not perform reliably better with common visualizations than they do with textual contingency tables. These experiments demonstrate the utility of causal support as an evaluation framework for inferences in VA and point to opportunities to make analysts' mental models more explicit in VA software.


A Neurobiological Model of Borderline Personality Disorder: Systematic and Integrative Review.
Borderline personality disorder (BPD) is a severe mental disorder with a multifactorial etiology. The development and maintenance of BPD is sustained by diverse neurobiological factors that contribute to the disorder's complex clinical phenotype. These factors may be identified using a range of techniques to probe alterations in brain systems that underlie BPD. We systematically searched the scientific literature for empirical studies on the neurobiology of BPD, identifying 146 articles in three broad research areas: neuroendocrinology and biological specimens; structural neuroimaging; and functional neuroimaging. We consolidate the results of these studies and provide an integrative model that attempts to incorporate the heterogeneous findings. The model specifies interactions among endogenous stress hormones, neurometabolism, and brain structures and circuits involved in emotion and cognition. The role of the amygdala in BPD is expanded to consider its functions in coordinating the brain's dynamic evaluation of the relevance of emotional stimuli in the context of an individual's goals and motivations. Future directions for neurobiological research on BPD are discussed, including implications for the Research Domain Criteria framework, accelerating genetics research by incorporating endophenotypes and gene × environment interactions, and exploring novel applications of neuroscience findings to treatment research.


[Choice of optimal surgical reconstruction at patients with critical limb ischemia due to infrainguinal atherosclerotic arterial occlusive disease].
One hundred and four patients with atherosclerotic lesion of femoro-popliteal segment and III-IV stage of ischemia underwent vascular surgical procedures. Results of these operations were analyzed depending on state of distal arterial bed. Autovenous femoro-popliteal bypass (FPB) with reversed autovein was performed at 49 (47.1%) patients, femoro-tibial bypass (FTB) with autovein in situ - at 55 (52.9%). Clinical and angiographic variants of favorable and unfavorable prognosis of FBP and FTB are described. It is demonstrated that severe lesion of outflow distal arteries is the main cause of bypasses thrombosis. Protective arteriovenous fistula in the region of FTB distal anastomosis improves significantly short-term results of operation.


Genomic fingerprinting of epidemic and endemic strains of Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia) by arbitrarily primed PCR.
Arbitrarily primed PCR (AP-PCR) was used to type 64 clinical isolates of Stenotrophomonas maltophilia from 60 patients and the hands of one nurse. Forty-seven different patterns were observed, most patients having isolates with unique genomic fingerprints. A single pattern, however, was obtained from six of eight patients involved in an intensive care nursery outbreak, confirming the suspected nosocomial transmission of this microorganism. This strain was also found in four other patients hospitalized at the same time but in different units. AP-PCR typing results had a good correlation with the 49 patterns obtained when the isolates were typed by contour-clamped homogeneous electric field gel electrophoresis. Although AP-PCR is slightly less discriminatory than contour-clamped homogeneous electric field gel electrophoresis, it offers several advantages and should be considered as a practical option for molecular typing during investigations of outbreaks.


Pemphigus is associated with KIR3DL2 expression levels and provides evidence that KIR3DL2 may bind HLA-A3 and A11 in vivo.
Although HLA-A3 and A11 have been reported to be ligands for KIR3DL2, evidence for any in vivo relevance of this interaction is still missing. To explore the functional importance of KIR3DL2 allelic variation, we analyzed the autoimmune disease pemphigus foliaceus, previously associated (lower risk) with activating KIR genes. KIR3DL2*001 was increased in patients (odds ratio (OR) = 2.04; p = 0.007). The risk was higher for the presence of both KIR3DL2*001 and HLA-A3 or A11 (OR = 3.76, p = 0.013), providing the first evidence that HLA-A3 and A11 may interact with KIR3DL2 in vivo. The nonsynonymous single nucleotide polymorphism 1190T (rs3745902) was associated with protection (OR = 0.52, p = 0.018). This SNP results in a threonine-to-methionine substitution. Individuals who have methionine in this position exhibit a lower percentage of KIR3DL2-positive natural killer (NK) cells and also lower intensity of KIR3DL2 on expressing natural killer cells; additionally, we show that the expression of KIR3DL2 is independent of other killer cell immunoglobulin-like receptors. Pemphigus foliaceus is a very unique complex disease strongly associated with immune-related genes. It is the only autoimmune disease known to be endemic, showing a strong correlation with environmental factors. Our data demonstrate that this relatively unknown autoimmune disease may facilitate understanding of the molecular mechanisms of KIR3DL2 ligand recognition.


Meditation can reduce habitual responding.
Although cognitive aspects of meditation underlie much of its clinical application, very little research has examined meditation's cognitive consequences. This investigation provides experimental support for the idea that meditation leads to a reduction in habitual responding using randomly selected subjects, a secular form of meditation, and a full experimental design. To test the hypothesis that meditation leads to a reduction in habitual responding. Studies 1 and 2 each incorporated pre-test and post-test designs with a 20-minute intervening attention task (meditation, rest, or a cognitive control). Yale University in New Haven, Conn, and the University of California, Berkeley. One hundred and twenty and 90 undergraduates participated in Studies 1 and 2, respectively. Stroop and Word Production (category generation and stem-completion) tasks assessed habitual responding in Study 1. Galvanic Skin response measured arousal in Study 1. The category generation task assessed habitual responding in Study 2. Tellegen's Absorption Scale (TAS) measured attention ability. In Study 1, meditation participants showed a reduction in habitual responding on the Stroop task as compared to controls. Study 1 revealed no statistically significant effects in the word production task. Stroop task performance was not mediated by arousal reduction. In Study 2, meditation participants showed a reduction in habitual responding on the category production task. Specifically, when participants generated either typical or atypical items, on average, meditation participants produced more atypical items than controls. Category production performance was not mediated by Tellegen's Absorption Scale (TAS) scores. Overall, high TAS scores were related to atypical responding. Across cognitive tasks, when participants understood that the goal was to respond non-habitually, meditation reduced habitual responding.


[Cryosurgical treatment of malignant tumors in the cerebral hemispheres].
In 35 patients with deep-lying and medial gliomas (25 cases of glioblastoma multiforma, 10 cases of dedifferentiated astrocytoma), stereotactic cryodestructions were performed after preceding biopsies. Diagnosis was made in the usual manner, mainly by means of angiography. Sites of action were the tumour mass proper and the blood supply zones. In some cases, partial removal of the tumour was carried out in the usual way before or after cryodestruction. There are 3 kinds of further development after cryodestruction: regression, slow progression and rapid progression. Progression was found in 14 patients; 9 patients died within 2 weeks after the operation. In their cases, cryodestruction was by far insufficient. Dedifferentiated astrocytomas showed more a regressive behaviour than multiform glioblastomas. The possibility of local chemotherapy was also utilised.


Bone Marrow-Derived Cells Participate in Composition of the Satellite Cell Niche in Intact and Regenerating Mouse Skeletal Muscle.
The cellular components of the satellite cell niche participate in the regulation of skeletal muscle regeneration. Beside myogenic cells at different developmental stages, this niche is formed by cells of the immune system, the interstitial connective tissue and the vascular system. Unambiguous determination of the origin of these cell types could contribute to optimization of the cell-based therapy of skeletal muscle disorders. In our work, we intravenously transplanted mouse GFP+ unseparated bone marrow cells into whole-body lethally irradiated immunocompetent mice four weeks before cardiotoxin-induced injury of the recipients' skeletal muscles. Seven and 28 days after the toxin injection, the injured regenerating and contralateral intact muscles were examined for identification of GFP+ bone marrow-derived cells by direct fluorescence, protein immunohistochemistry and immunogold transmission electron microscopy. In both the intact and injured muscles, GFP positivity was determined in immune cells, mainly in macrophages, and in interstitial spindleshaped cells. Moreover, in the injured muscles, rare GFP+ endothelial cells of the blood vessels and newly formed myotubes and muscle fibres were present. Our results confirmed the ability of bone marrowderived cells to contribute to the cellular component of the satellite cell niche in the intact and regenerating skeletal muscle. These cells originated not only from haematopoietic stem cells, but obviously also from other stem or progenitor cells residing in the bone marrow, such as multipotent mesenchymal stromal cells and endothelial progenitors.


Platelet-activating factor receptor mRNA is localized in eosinophils and epithelial cells in rat small intestine: regulation by dexamethasone and gut flora.
Platelet-activating factor (PAF) is a potent mediator involved in bowel injury. We investigated PAF receptor transcription and its mRNA localization in the small intestine of normal (conventionally fed) and germ-free rats, by competitive polymerase chain reaction (PCR) and in situ hybridization. A dose of PAF (1.5 microg/kg, i.v.) insufficient to cause gross bowel injury was injected into rats. Some rats were pretreated with dexamethasone (1 mg/kg). We found: (1) PAF receptor (PAF-R) mRNA localized predominantly in lamina propria eosinophils and in epithelial cells; (2) PAF increased PAF-receptor signals in the epithelial cells; (3) Dexamethasone depleted eosinophils in the intestine and markedly decreased PAF-receptor transcripts; the response to PAF was also weaker than control rats; (4) Germ-free rats had less PAF-R mRNA than normal rats, and showed a weaker response to PAF than conventionally fed rats. Thus, we conclude: (1) PAF receptor mRNA is constitutively expressed in the epithelium and in lamina propria eosinophils in the intestine. (2) PAF-R transcription is up-regulated by PAF and gut flora, mostly in the epithelium. (3) PAF-R transcription is down-regulated by glucocorticoids, mainly as a result of eosinophil depletion. These results suggest a functional role for PAF receptors both in host defence and the inflammatory response in the small intestine.


Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19: A Randomized Clinical Trial.
The effect of high-flow oxygen therapy vs conventional oxygen therapy has not been established in the setting of severe COVID-19. To determine the effect of high-flow oxygen therapy through a nasal cannula compared with conventional oxygen therapy on need for endotracheal intubation and clinical recovery in severe COVID-19. Randomized, open-label clinical trial conducted in emergency and intensive care units in 3 hospitals in Colombia. A total of 220 adults with respiratory distress and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 200 due to COVID-19 were randomized from August 2020 to January 2021, with last follow-up on February 10, 2021. Patients were randomly assigned to receive high-flow oxygen through a nasal cannula (n = 109) or conventional oxygen therapy (n = 111). The co-primary outcomes were need for intubation and time to clinical recovery until day 28 as assessed by a 7-category ordinal scale (range, 1-7, with higher scores indicating a worse condition). Effects of treatments were calculated with a Cox proportional hazards model adjusted for hypoxemia severity, age, and comorbidities. Among 220 randomized patients, 199 were included in the analysis (median age, 60 years; n = 65 women [32.7%]). Intubation occurred in 34 (34.3%) randomized to high-flow oxygen therapy and in 51 (51.0%) randomized to conventional oxygen therapy (hazard ratio, 0.62; 95% CI, 0.39-0.96; P = .03). The median time to clinical recovery within 28 days was 11 (IQR, 9-14) days in patients randomized to high-flow oxygen therapy vs 14 (IQR, 11-19) days in those randomized to conventional oxygen therapy (hazard ratio, 1.39; 95% CI, 1.00-1.92; P = .047). Suspected bacterial pneumonia occurred in 13 patients (13.1%) randomized to high-flow oxygen and in 17 (17.0%) of those randomized to conventional oxygen therapy, while bacteremia was detected in 7 (7.1%) vs 11 (11.0%), respectively. Among patients with severe COVID-19, use of high-flow oxygen through a nasal cannula significantly decreased need for mechanical ventilation support and time to clinical recovery compared with conventional low-flow oxygen therapy. ClinicalTrials.gov Identifier: NCT04609462.


A Multicenter Phase II Study of AMG 337 in Patients with MET-Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma and Other MET-Amplified Solid Tumors.
MET gene amplification is associated with poor prognosis in gastric/gastroesophageal junction/esophageal (G/GEJ/E) cancers. We determined antitumor activity, safety, and pharmacokinetics of the small-molecule MET inhibitor AMG 337 in MET-amplified G/GEJ/E adenocarcinoma or other solid tumors.Patients and Methods: In this phase II, single-arm study, adults with MET-amplified G/GEJ/E adenocarcinoma (cohort 1) or other MET-amplified solid tumors (cohort 2) received AMG 337 300 mg/day orally in 28-day cycles. The primary endpoint was objective response rate (ORR; cohort 1). Secondary endpoints included ORR (cohort 2), progression-free survival (PFS), overall survival (OS), and safety. Of 2101 patients screened for MET amplification, 132 were MET-amplified and 60 were enrolled: 45 in cohort 1, and 15 in cohort 2. Fifty-six patients (97%) had metastatic disease; 57 had prior lines of therapy (1 prior line, 29%; ≥2 prior lines, 69%). A protocol-permitted review showed efficacy that was lower-than-expected based on preliminary data from a first-in-human study, and enrollment was stopped. Fifty-eight patients received ≥1 AMG 337 dose. ORR in cohort 1 was 18% (8 partial responses). No responses were observed in cohort 2. Of 54 evaluable patients, median (95% CI) PFS and OS were 3.4 (2.2-5.0) and 7.9 (4.8-10.9) months, respectively. The most frequent adverse events (AEs) were headache (60%), nausea (38%), vomiting (38%), and abdominal pain, decreased appetite, and peripheral edema (33% each); 71% had grade ≥3 AEs and 59% had serious AEs. AMG 337 showed antitumor activity in MET-amplified G/GEJ/E adenocarcinoma but not in MET-amplified non-small-cell lung cancer.See related commentary by Ma, p. 2375.


MIL-100(Fe) Sub-Micrometric Capsules as a Dual Drug Delivery System.
Nanoparticles of metal-organic frameworks (MOF NPs) are crystalline hybrid micro- or mesoporous nanomaterials that show great promise in biomedicine due to their significant drug loading ability and controlled release. Herein, we develop porous capsules from aggregate of nanoparticles of the iron carboxylate MIL-100(Fe) through a low-temperature spray-drying route. This enables the concomitant one-pot encapsulation of high loading of an antitumor drug, methotrexate, within the pores of the MOF NPs, and the collagenase enzyme (COL), inside the inter-particular mesoporous cavities, upon the formation of the capsule, enhancing tumor treatment. This association provides better control of the release of the active moieties, MTX and collagenase, in simulated body fluid conditions in comparison with the bare MOF NPs. In addition, the loaded MIL-100 capsules present, against the A-375 cancer cell line, selective toxicity nine times higher than for the normal HaCaT cells, suggesting that MTX@COL@MIL-100 capsules may have potential application in the selective treatment of cancer cells. We highlight that an appropriate level of collagenase activity remained after encapsulation using the spray dryer equipment. Therefore, this work describes a novel application of MOF-based capsules as a dual drug delivery system for cancer treatment.


[5 years of monoclonal antibodies at the Central Veterinary Institute].
The use of monoclonal antibodies in veterinary research during recent years opened up several new possibilities for the study of fundamental problems and the improvement or development of diagnostic techniques. At the Central Veterinary Institute (CVI), Lelystad, the Netherlands, a large number of monoclonal antibodies to various animal pathogens were prepared and used. Our recently acquired knowledge and extensive diagnostic potential in cases of infectious disease offer adequate possibilities for the improvement or development of methods to control particular forms of disease in animals. The progress made in this fields and the use of monoclonal antibodies of the CVI are briefly reviewed.


[Thoracoscopic esophagectomy].
In recent years, the number of facilities performing thoracoscopic surgery of the esophagus has increased. Thoracoscopic surgery has many advantages, such as a magnification effect, good lighting, and a wide field of view. Esophagectomy requires fine manipulation within a deep and narrow space. Thus, thoracoscopic surgery is suitable for the performance of esophagectomy. The body position during this procedure may be either prone or left lateral decubitus. Because there are advantages in both cases, the relative merits are controversial. The operation time is longer than that of open thoracotomy, but the amount of bleeding is small in most cases of thoracoscopic esophagectomy. There are also some reports that thoracoscopic esophagectomy is comparable with open esophagectomy in terms of radicality and quality of lymph node dissection, and the intensive care unit and hospital stay durations are shortened. Robot-assisted esophagectomy is a promising technology for the fine manipulations and high quality 3-dimensional visualization required in the performance of esophageal thoracoscopic surgery. Thoracoscopic esophagectomy will become more widespread and undergo further development in the future with the spread of robotic surgery and 3-dimensional endoscopic surgery.


Effects of localised cerebral lesions and dysphasia on verbal memory.
Twenty-nine patients with unilateral left hemisphere lesions, 22 patients with unilateral right hemisphere lesions, and 19 neurological control patients with extracerebral lesions were assessed on verbal memory recall and recognition tests and on a battery of language tests. The left hemisphere group was significantly impaired in memory and language skills. Significant verbal memory impairment was found both in the subgroup of left hemisphere lesion patients whose lesions involved the temporal lobe and in the subgroup whose lesions did not. However, no significant differences between these left hemisphere subgroups' levels of performance on memory tasks emerged, even when dysphasia was taken into account. This study, therefore, fails to support the notion of a specific anatomical correlate of verbal memory impairment within the left hemisphere. Dysphasic subjects were significantly impaired on verbal memory tasks but displayed the same pattern of sensitivity to the effects of word frequency and word concreteness on verbal memory as control subjects, suggesting that the verbal memory of the dysphasic subjects was quantitatively rather than qualitatively impaired. This impairment could not be attributed to deficits in the comprehension or expression of the memory test items, and it is, therefore, proposed that language disturbances may hinder the efficient use of such language based procedures as may subserve verbal memory.


Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention.
Recent studies have suggested that proton pump inhibitors (PPIs) might reduce the inhibitory effect of clopidogrel on platelet aggregation, possibly through inhibition of the hepatic cytochrome P450 2C19 (CYP2C19) isoenzyme. The prevalence of CYP2C19 loss-of-function alleles is much greater among East Asians than among other populations. Thus, potential drug interactions might be more apparent. Therefore, we conducted a nationwide, population-based study using the Taiwan National Health Insurance database. We identified 3,278 patients (mean age 65.9 +/- 11.9 years, 71.9% men) with coronary artery disease who had taken clopidogrel after percutaneous coronary intervention from the 1 million sampling cohort data set since January 1, 2002. Of the 3,278 patients, 572 had received concomitant PPIs for underlying gastrointestinal disease and 2,706 had not used PPIs. To the end of 2007, 1,410 patients had been rehospitalized, 970 patients had undergone revascularization, and 499 patients had died. According to the Kaplan-Meier analysis, the incidence of rehospitalization (p = 0.001) and mortality (p <0.001) was significantly greater for the patients with concomitant PPI use than for those without concomitant PPI use. However, the incidence of revascularization was similar in the 2 groups. Multivariate analyses showed that concomitant PPI use was associated with an increased risk of rehospitalization (hazard ratio 1.23, 95% confidence interval 1.07 to 1.41, p = 0.003) and mortality (hazard ratio 1.65, 95% confidence interval 1.35 to 2.01, p <0.001). In conclusion, the concomitant use of clopidogrel and PPIs should be done with care to avoid adverse outcome in East Asians patients who have undergone percutaneous coronary intervention.


Three-dimensional spinal coupling mechanics: Part II. Implications for chiropractic theories and practice.
To compare the current knowledge of 3-D spinal mechanics and abnormal equilibrium states with chiropractic motion theories, chiropractic vertebral letter listing theories, and chiropractic technique theories. A manual search of available reference texts and a computer search of literature from Index Medicus were collected with an emphasis on 3-D studies of human spinal movements, segmental instability, Euler buckling of the spine, and chiropractic theories concerning vertebral movements. Previous spinal coupling results based upon two-dimensional radiographic studies are inadequate and inaccurate. Therefore, the validity of any chiropractic technique procedure, listing, motion analysis or adjusting style based on the two-dimensional radiograph and coupling studies must be questioned. We have identified four types of spinal subluxations (displacements) in the biomechanical literature: (a) posture main motion and associated segmental coupling, (b) Euler buckling viewed in the anteroposterior view, (c) snap through viewed in the lateral view and (d) segmental instability. Full three-dimensional investigations of spinal coupling patterns have shown that the vertebrae rotate and translate in all three axes and that previous theories of spinal coupling based upon two-dimensional studies are inaccurate and invalid. Previous chiropractic letter listings (e.g., PRI, PLS, etc.) of spinal displacements are inadequate and invalid. Only one of the four types of biomechanical displacements, segmental instability, is consistent with the traditional chiropractic theory of segmental spinal displacements; in general, this does not respond well to care. In general, vertebrae displacement must be viewed in the context of equilibrium configurations and one vertebra can not be displaced as an individual misalignment. Validity questions arise for any technique methods that use letter listings of displacement taken from motion palpation or two-dimensional radiographic analysis.


Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells.
Adult stem cells reside in different tissues and organs of the adult organism. Among these cells are MSCs that are located in the adult bone marrow and NSCs that exist in the adult central nervous system (CNS). In transplantation experiments, MSCs demonstrated neuroprotective and neuroregenerative effects that were associated with functional improvements. The underlying mechanisms are largely unidentified. Here, we reveal that the interactions between adult MSCs and NSCs, mediated by soluble factors, induce oligodendrogenic fate decision in NSCs at the expense of astrogenesis. This was demonstrated (a) by an increase in the percentage of cells expressing the oligodendrocyte markers GalC and myelin basic protein, (b) by a reduction in the percentage of glial fibrillary acidic protein (GFAP)-expressing cells, and (c) by the expression pattern of cell fate determinants specific for oligodendrogenic differentiation. Thus, it involved enhanced expression of the oligodendrogenic transcription factors Olig1, Olig2, and Nkx2.2 and diminished expression of Id2, an inhibitor of oligodendrogenic differentiation. Results of (a) 5-bromo-2'-deoxyuridine pulse-labeling of cells, (b) cell fate analysis, and (c) cell death/survival analysis suggested an inductive mechanism and excluded a selection process. A candidate factor screen excluded a number of growth factors, cytokines, and neurotrophins that have previously been shown to influence neurogenesis and neural differentiation from the oligodendrogenic activity derived from the MSCs. This work might have major implications for the development of future transplantation strategies for the treatment of degenerative diseases in the CNS.


The product of the yvoC (gerF) gene of Bacillus subtilis is required for spore germination.
All known gerF mutations affecting Bacillus subtilis spore germination have been mapped, by a combination of recombination and complementation analysis, to yvoC (Igt), a gene belonging to the yvoB (ptsK) yvoC (Igt) yvoDEF operon. Examination of the properties of null mutants confirmed that the only gene in the operon that affects germination is yvoC, which encodes a homologue of known prelipoprotein diacylglyceryl transferases. As several germination proteins (GerAC, GerBC, GerKC, GerD) are predicted lipoproteins, it is not unreasonable to assume that a defect in prelipoprotein processing will affect spore germination. Two other null mutants in this chromosomal region showed a clear phenotype: the nagA gene is required for growth on N-acetylglucosamine, whereas a null mutation in yvoB (ptsK) affects colony formation from single cells.


Legacy and alternative per- and polyfluoroalkyl substances in the U.S. general population: Paired serum-urine data from the 2013-2014 National Health and Nutrition Examination Survey.
Concerns are heightened from detecting environmentally persistent man-made per- and polyfluoroalkyl substances (PFAS) in drinking water systems around the world. Many PFAS, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), remain in the human body for years. Since 1999-2000, assessment of exposure to PFOS, PFOA, and other select PFAS in the U.S. general population has relied on measuring PFAS serum concentrations in participants of the National Health and Nutrition Examination Survey (NHANES). Manufacturers have replaced select chemistries ("legacy" PFAS) with PFAS with shorter biological half-lives (e.g., GenX, perfluorobutanoate [PFBA]) which may efficiently eliminate in urine. However, knowledge regarding exposure to these compounds is limited. We analyzed 2682 urine samples for 17 legacy and alternative PFAS in 2013-2014 NHANES participants ≥6 years of age. Concentrations of some of these PFAS, measured previously in paired serum samples from the same NHANES participants, suggested universal exposure to PFOS and PFOA, and infrequent or no exposure to two short-chain PFAS, perfluorobutane sulfonate and perfluoroheptanoate. Yet, in urine, PFAS were seldom detected; the frequency of not having detectable concentrations of any of the 17 PFAS was 67.5%. Only two were detected in >1.5% of the population: PFBA (13.3%) and perfluorohexanoate (PFHxA, 22.6%); the 90th percentile urine concentrations were 0.1 μg/L (PFBA), and 0.3 μg/L (PFHxA). These results suggest that exposures to short-chain PFAS are infrequent or at levels below those that would result in detectable concentrations in urine. As such, these findings do not support biomonitoring of short-chain PFAS or fluorinated alternatives in the general population using urine, and highlight the importance of selecting the adequate biomonitoring matrix.


Program conditions that foster quality physical activity participation experiences for people with a physical disability: a systematic review.
Background: Due to the numerous barriers people with a physical disability face to being physically active, emphasis in practice and research is often placed on creating opportunities for participation. As such, the quality of the experience is often ignored once an individual is participating.Purpose: An understanding of how to create quality physical activity experiences is critical to foster enjoyable and sustained participation. The aim of this systematic review was to identify intervention and/or program conditions that may foster key elements that shape quality participation (QP) experiences.Methods: In all, 24 qualitative and 6 quantitative studies met inclusion criteria. The results of the qualitative studies were synthesized using thematic analysis.Results: The synthesis identified two program conditions as important for fostering QP elements: (1) group-based programing: participating with peers can be linked to belongingness and mastery and (2) leadership: knowledgeable instructors may foster mastery and autonomy. The quantitative studies lacked variability in program conditions and QP elements, which precluded associating specific conditions with elements of a quality experience.Conclusions: Although the qualitative findings highlight two program conditions which may foster QP elements, overall, evaluations of physical activity interventions involving people with disabilities rarely include experiential aspects of participation.Implications for rehabilitationGroup-based programming and leadership are two program conditions that may foster elements of quality participation.Physical activity organizers need to consider group composition. Physical activity programs should consist of peers with a disability, as appropriate, in order to promote belongingness.Physical activity programs should provide disability-specific training to leaders or seek leaders with disability-specific knowledge, in addition to physical activity knowledge and skills.


In vitro actions on human cancer cells and the liquid chromatography-mass spectrometry/mass spectrometry fingerprint of phytochemicals in rice protein isolate.
Rice protein isolate (RPI) has been reported to reduce the incidence of 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats. To determine the potential role of phytochemicals associated with the RPI, we studied in vitro antitumor activities of an ether fraction from RPI using human tumor cell lines, including two human breast carcinoma cell lines (MDA-MB-453 and MCF-7) and two myeloma cell lines (RPMI-8226 and IM-9). Concentration-dependent antiproliferative effects of the ether fraction were observed in all cell lines using the standard 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Fraction-induced apoptosis (P < 0.05) was detected in all cell lines, and this was associated with the induction of proapoptotic bax protein and cdk inhibitors (p21) and the suppression of cdk4 and cyclin D1 activity. Liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) with both positive and negative modes was used to analyze the phytochemicals in the ether fraction from RPI. Fifty-seven phytochemicals were identified or characterized by their diagnostic fragmentation patterns and direct comparison with the authentic standards on the basis of electrospray ionization-MS/MS data. The major components bound to RPI were lysoglycerophospholipids, fatty acids, and fatty acid 3-[2-(2,3-dihydroxy-propoxycarbonyl)-2-hydroxy-ethoxy]-2-hydroxy-propyl esters.


A Cost Effectiveness Analysis of Rivaroxaban Compared to Warfarin for Deep Vein Thrombosis (DVT) Treatment in Ethiopia.
Deep vein thrombosis and pulmonary embolism are known by the collective name venous thromboembolism. Deep vein thrombosis is the third most common cardiovascular disorder in the world. The disease is also prevalent in Africa including Ethiopia, besides lack of studies that show epidemiology of the disease. To assess cost effectiveness of rivaroxaban compared to warfarin-based therapy for deep vein thrombosis patients in Ethiopia. A Markov model was built to compare cost and effectiveness of rivaroxaban 15mg bid for three weeks and 20mg per day for the rest to adjusted dose of warfarin for one year using a restricted societal perspective. The population in this analysis was a hypothetical cohort of deep vein thrombosis patients 40 years old with no contraindication, comorbidity and concomitant therapy. The patients were followed yearly for 24 years up to their average life expectancy. Rivaroxaban therapy resulted in higher quality adjusted life years with a value of 16.78, while warfarin-based treatment resulted in 16.34 quality adjusted life years. Total lifetime costs were $988.58 for rivaroxaban and $932.92 for unfractionated heparin/warfarin. Therefore, rivaroxaban resulted in a gain of 0.443 quality adjusted life years at an additional cost of $55.661. The incremental cost effectiveness ratios for rivaroxaban compared with warfarin was $125.683 per quality adjusted life year saved which is less than willingness to pay threshold of $783 per quality adjusted life year saved. Warfarin resulted in a net monetary benefit of $11,859.72, while that of rivaroxaban is $12,150.82, meaning rivaroxaban is cost-effective. Sensitivity analyses found that the model was sensitive to utility of no deep vein thrombosis, effectiveness of rivaroxaban and cost of rivaroxaban respectively. This study showed that rivaroxaban is a cost effective alternative and substituting rivaroxaban for warfarin is acceptable to willingness to pay threshold.


Clinical differences among angiotensin II receptor antagonists.
The six major classes of antihypertensive agents prescribed worldwide are similar in efficacy but dissimilar in tolerability. Recently, the World Health Organization-International Society of Hypertension (WHO-ISH) concluded that agents from all six classes are suitable for the initiation and maintenance of antihypertensive therapy, including the newest class of agents, the angiotensin II receptor antagonists (AIIRAs). The ideal antihypertensive agent should be effective and well tolerated, as well as synergistic in blood pressure-lowering effects when combined with other agents. As monotherapy, AIIRAs have demonstrated efficacy similar to other classes of antihypertensive agents in numerous clinical trials. Several AIIRAs have also demonstrated enhanced efficacy when combined with a low dose of the diuretic hydrochlorothiazide (HCTZ). A well-known feature of this new class of agents is placebo-level tolerability; however, less is known about intra-class differences. Losartan, the first approved AIIRA, has become an important benchmark for within-class comparisons with respect to antihypertensive efficacy. Head-to-head comparisons between losartan and newer AIIRAs have been conducted; their cumulative results indicate that the antihypertensive effect and antagonistic activity of losartan may be the weakest among AIIRAs. In a recent clinical trial, we demonstrated that irbesartan produces statistically superior blood pressure reduction when compared to valsartan. This may have clinical implications for agent selection among the AIIRAs.