Legacy and emerging airborne per- and polyfluoroalkyl substances (PFAS) collected on PM2.5 filters in close proximity to a fluoropolymer manufacturing facility.
Large fluoropolymer manufacturing facilities are major known sources of per- and polyfluoroalkyl substances (PFAS), many of which accumulate in groundwater, surface water, crops, wildlife, and people. Prior studies have measured high PFAS concentrations in groundwater, drinking water, soil, as well as dry and wet deposition near fluoropolymer facilities; however, much less is known about near-source PFAS air concentrations. We measured airborne PFAS on PM2.5 filters in close proximity to a major fluoropolymer manufacturing facility (Chemours' Fayetteville Works) located near Fayetteville, North Carolina, USA. Weekly PM2.5 filter samples collected over a six-month field campaign using high-volume air samplers at locations 3.7 km apart, north-northeast and south-southwest of the facility were analyzed for thirty-four targeted ionic PFAS species by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. Twelve emerging and ten legacy PFAS compounds were detected. Thirteen PFAS were found at higher concentrations in these nearfield samples than at regional background sites, suggesting a local source for these compounds. Five emerging and five legacy PFAS compounds had maximum concentrations exceeding 1 pg m-3. PFBA, PFHxA, PFHxDA, PFOS, PMPA, NVHOS, PFO5DoA, and Nafion BP1 contributed the most to the total (legacy + emerging) PFAS concentration (86%). Six PFAS, specifically PFBA, PFOS, PFO5DoA, Nafion BP1, Nafion BP2, and Nafion BP4, provide a consistent representative profile of elevated species across the two sites (with detection frequency >50%). To our knowledge, this is the first study to report both legacy and emerging ionic PFAS in air in close proximity to a U.S. fluoropolymer manufacturing facility.


Next-generation DNA damage sequencing.
Cellular DNA is constantly chemically altered by exogenous and endogenous agents. As all processes of life depend on the transmission of the genetic information, multiple biological processes exist to ensure genome integrity. Chemically damaged DNA has been linked to cancer and aging, therefore it is of great interest to map DNA damage formation and repair to elucidate the distribution of damage on a genome-wide scale. While the low abundance and inability to enzymatically amplify DNA damage are obstacles to genome-wide sequencing, new developments in the last few years have enabled high-resolution mapping of damaged bases. Recently, a number of DNA damage sequencing library construction strategies coupled to new data analysis pipelines allowed the mapping of specific DNA damage formation and repair at high and single nucleotide resolution. Strikingly, these advancements revealed that the distribution of DNA damage is heavily influenced by chromatin states and the binding of transcription factors. In the last seven years, these novel approaches have revealed new genomic maps of DNA damage distribution in a variety of organisms as generated by diverse chemical and physical DNA insults; oxidative stress, chemotherapeutic drugs, environmental pollutants, and sun exposure. Preferred sequences for damage formation and repair have been elucidated, thus making it possible to identify persistent weak spots in the genome as locations predicted to be vulnerable for mutation. As such, sequencing DNA damage will have an immense impact on our ability to elucidate mechanisms of disease initiation, and to evaluate and predict the efficacy of chemotherapeutic drugs.


Surgical left atrial appendage occlusion: evaluation of a novel device with magnetic resonance imaging.
Management of the left atrial appendage (LAA) is considered an important adjunct to ablation in cardiac surgical patients with atrial fibrillation (AF). However, current surgical techniques, both cut-and-sew and stapling, have been associated with incomplete LAA occlusion and complications. Using cardiac magnetic resonance imaging (MRI), we studied the safety and effectiveness of a new device for LAA occlusion in a primate model. Seven adult baboons underwent off-pump placement of an LAA clip (AtriCure Inc., Westchester, Ohio). LAA occlusion was confirmed intraoperatively by direct incision. All animals had MRI before and after clip placement to assess LAA perfusion, architecture, and overall cardiac function. Pathologic and histological studies were performed at 7, 30 and 180 days. Clip placement was successful in all (n=7) without any clip related complications. Complete LAA occlusion was demonstrated intraoperatively in all subjects. LAA occlusion was confirmed on pre-sacrifice MRI, and left and right ventricular function were unchanged from preoperative studies; however, clip placement caused small reductions in left ventricular end-diastolic, end-systolic, and stroke volumes. At sacrifice, direct inspection confirmed stable location, persistent LAA exclusion, tissue in-growth and homogenous epithelialization without damage to adjacent structures. Histological analysis revealed a regular in-growth pattern in all studied specimens. We demonstrated a safe, straightforward, persistent and effective method for LAA occlusion with this new LAA clip. MRI effectively demonstrated LAA occlusion and only minor changes in left ventricular volumes.


Chemical Composition and Antibacterial Activity of Essential Oils of Tagetes minuta (Asteraceae) against Selected Plant Pathogenic Bacteria.
The objective of this study was to determine the chemical composition and antibacterial activity of essential oils (EOs) of Tagetes minuta against three phytopathogenic bacteria Pseudomonas savastanoi pv. phaseolicola, Xanthomonas axonopodis pv. phaseoli, and Xanthomonas axonopodis pv. manihotis. The essential oils were extracted using steam distillation method in a modified Clevenger-type apparatus while antibacterial activity of the EOs was evaluated by disc diffusion method. Gas chromatography coupled to mass spectrometry (GC/MS) was used for analysis of the chemical profile of the EOs. Twenty compounds corresponding to 96% of the total essential oils were identified with 70% and 30% of the identified components being monoterpenes and sesquiterpenes, respectively. The essential oils of T. minuta revealed promising antibacterial activities against the test pathogens with Pseudomonas savastanoi pv. phaseolicola being the most susceptible with mean inhibition zone diameters of 41.83 and 44.83 mm after 24 and 48 hours, respectively. The minimum inhibitory concentrations and minimum bactericidal concentrations of the EOs on the test bacteria were in the ranges of 24-48 mg/mL and 95-190 mg/mL, respectively. These findings provide a scientific basis for the use of T. minuta essential oils as a botanical pesticide for management of phytopathogenic bacteria.


Matching of separatrix map and resonant dynamics, with application to global chaos onset between separatrices.
We have developed a general method for the description of separatrix chaos, based on the analysis of the separatrix map dynamics. Matching it with the resonant Hamiltonian analysis, we show that, for a given amplitude of perturbation, the maximum width of the chaotic layer in energy may be much larger than it was assumed before. We use the above method to explain the drastic facilitation of global chaos onset in time-periodically perturbed Hamiltonian systems possessing two or more separatrices, previously discovered [S. M. Soskin, O. M. Yevtushenko, and R. Mannella, Phys. Rev. Lett. 90, 174101 (2003)]. The theory well agrees with simulations. We also discuss generalizations and applications. The method may be generalized for single-separatrix cases. The facilitation of global chaos onset may be relevant to a variety of systems, e.g., optical lattices, magnetic and semiconductor superlattices, meandering flows in the ocean, and spinning pendulums. Apart from dynamical transport, it may facilitate noise-induced transitions and the stochastic web formation.


[A case of locally extended rectal carcinoma quickly responding to local intraarterial infusion therapy].
Chemotherapy combined with 5-FU and l-leucovorin has been reported to elicit a quick response in cases of lower rectal carcinoma. A 65-year-old woman developed pain in the right gluteal region due to locally extended rectal carcinoma, and was treated with intraarterial infusion therapy. The chemotherapy regimen was 5-FU (500 mg/body) and l-leucovorin (175 mg/body) administered over 3 hours once weekly to bilateral reservoirs through an infuser pump. After 2 sessions of the chemotherapy, the gluteal pain decreased, and after 3 sessions, CEA level was confirmed and the patient's QOL began to improve. Side effects of the intraarterial infusion chemotherapy were gluteal dermatitis, leg desensitization, and infection of the circumferential reservoir. Local intraarterial infusion chemotherapy can be safely performed on an outpatient basis, and appears to elicit quick response for locally extended advanced rectal carcinoma.


Effects of Very Low Nicotine Content Cigarettes on Smoking Behavior and Biomarkers of Exposure in Menthol and Non-menthol Smokers.
Because 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy. In a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence. At baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition. Although menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers. Results of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.


Severe refractory erythema nodosum leprosum successfully treated with the tumor necrosis factor inhibitor etanercept.
Erythema nodosum leprosum (ENL), or type II reaction, is a common complication of lepromatous leprosy that can cause significant patient debility. First-line therapy includes prednisone and thalidomide, with clofazimine reserved for patients who do not respond to first-line treatment. We present the case of a 33-year-old woman with ENL that failed to respond adequately to conventional therapy over a 6-year period. Because of the severe nature of her disease and the adverse effects of therapy that she experienced, a trial of etanercept was undertaken, which led to full resolution of her ENL. The rationale behind our choice of therapy and its future implications are discussed.


Elastin organization in pig and cardiovascular disease patients' pericardial resistance arteries.
Peripheral vascular resistance is increased in essential hypertension. This involves structural changes of resistance arteries and stiffening of the arterial wall, including remodeling of the extracellular matrix. We hypothesized that biopsies of the human parietal pericardium, obtained during coronary artery bypass grafting or cardiac valve replacement surgeries, can serve as a source of resistance arteries for structural research in cardiovascular disease patients. We applied two-photon excitation fluorescence microscopy to study the parietal pericardium and isolated pericardial resistance arteries with a focus on the collagen and elastin components of the extracellular matrix. Initial findings in pig tissue were confirmed in patient biopsies. The microarchitecture of the internal elastic lamina in both the pig and patient pericardial resistance arteries (studied at a transmural pressure of 100 mm Hg) is fiber like, and no prominent external elastic lamina could be observed. This microarchitecture is very different from that in rat mesenteric arteries frequently used for resistance artery research. In conclusion, we add three-dimensional information on the structure of the extracellular matrix in resistance arteries from cardiovascular disease patients and propose further use of patient pericardial resistance arteries for studies of the human microvasculature.


Prevention of the Post-Thrombotic Syndrome.
Post-thrombotic syndrome frequently affects patients following deep vein thrombosis. The clinical signs and symptoms of post-thrombotic syndrome reflect the underlying pathophysiology of venous obstruction, venous reflux as well as acute and chronic inflammation. Patients with post-thrombotic syndrome are at risk for long-term consequences including decreased quality of life, lost work productivity, and increased health expenditures. Unfortunately, despite recognition of pathophysiology and the clinical, physical, and economic impact of PTS, there have been few advances in prevention. PTS continues to be a frustrating condition to both prevent and manage. Preventing post-thrombotic syndrome begins with preventing deep vein thrombosis. In the setting of acute deep vein thrombosis-using available medical therapies to prevent the development of post-thrombotic syndrome is imperative. Patients should be provided optimal medical therapy with anticoagulation, maintaining therapeutic anticoagulation as much of the time as possible. Use of compression stockings, while contentious, are a low risk intervention which may provide benefit and are unlikely to be associated with harm. In the appropriate patient, considering endovenous procedures to decrease the thrombus burden and provide optimal preservation of venous valve function may be warranted.


Celastrol attenuates diabetic nephropathy by upregulating SIRT1-mediated inhibition of EZH2related wnt/β-catenin signaling.
Proteinuria is an independent risk factor for the progression of diabetic nephropathy (DN) and an imbalance in podocyte function aggravates proteinuria. Celastrol is the primary active ingredient of T. wilfordii, effective in treating DN renal injury; however, the mechanisms underlying its effect are unclear. We explored how celastrol prevents DN podocyte damage using in vivo and in vitro experiments. We randomly divided 24 male C57BLKS/J mice into three groups: db/m (n = 8), db/db (n = 8), and celastrol groups (db/db + celastrol, 1 mg/kg/d, gavage administration, n = 8). In vivo experiments lasted 12 weeks and intervention lasted ten weeks. Serum samples and kidney tissues were collected for biochemical tests, pathological staining, transmission electron microscopy, fluorescencequantitation polymerase chain reaction, and western blotting analysis. In vitro experiments to elaborate the mechanism of celastrol protection were performed on high glucose (HG)-induced podocyte injury. Celastrol reduced blood glucose levels and renal function index in db/db mice, attenuated renal histomorphological injury and glomerular podocyte foot injuries, and induced significant anti-inflammatory effects. Celastrol upregulated silent information regulator 2 related enzyme 1(SIRT1) expression and downregulated enhancer of zeste homolog (EZH2), inhibiting the wnt/β-catenin pathway-related molecules, such as wnt1, wnt7a, and β-catenin. SIRT1 repressed the promoter activity of EZH2, and was co-immunoprecipitated with EZH2 in mouse podocyte cells (MPC5). SIRT1 knockdown aggravated the protective effects of celastrol on MPC5 cells. Celastrol protected podocyte injury via SIRT1/EZH2, which participates in the wnt/β-catenin pathway. Overall, celastrol-mediated SIRT1 upregulation inhibited the EZH2-related wnt/β-catenin signaling pathway to attenuate DN and podocyte injury, providing a theoretical basis for celastrol clinical application.


A role for KH domain proteins (Sam68-like mammalian proteins and quaking proteins) in the post-transcriptional regulation of HIV replication.
Overexpression of Sam68 functionally substitutes for, as well as synergizes with, human immunodeficiency virus type 1 (HIV-1) Rev in RRE (Rev response element)-mediated gene expression and virus replication. In addition, COOH-terminal deletion and/or point mutants of Sam68 exhibit a transdominant negative phenotype for HIV replication. Sam68 is a member of KH domain family that includes SLM-1, SLM-2 (Sam68 like mammalian); and QKI-5, QKI-6, and QKI-7 (mouse quaking) proteins. The objective of this study was to examine the effects of these KH family proteins on RRE- and CTE (constitutive transport element of type-D retrovirus)-mediated transactivation. We now report that SLM-1 and SLM-2 proteins, which are the closest relatives of Sam68, marginally enhanced RRE-mediated transactivation, while QK isoforms that are distant relatives of Sam68 had no effect. Interestingly, these proteins still enhanced the effect of Rev in RRE-mediated gene expression. The increase in chloramphenicol acetyltransferase activity was also reflected at the levels of cytoplasmic RRE-chloramphenicol acetyltransferase mRNAs, indicating that Sam68 and KH proteins may have been involved in the stability or export of unspliced RNA. The increase in Rev activity was sensitive to leptomycin B, but not to olomoucine, indicating that the effect of SLM-1, SLM-2, QKI-5, QKI-6, and QKI-7 is exerted through a CRM-1-dependent mRNA export pathway. Thus, KH family proteins play an important role in the post-transcriptional regulation of HIV.


GPU Accelerated Drug Application on Signaling Pathways Containing Multiple Faults Using Boolean Networks.
Cell growth is governed by the flow of information from growth factors to transcription factors. This flow involves protein-protein interactions known as a signaling pathway, which triggers the cell division. The biological network in the presence of malfunctions leads to a rapid cell division without any necessary input conditions. The effect of these malfunctions or faults can be observed if it is simulated explicitly in the Boolean derivative of the biological networks. The consequences thus produced can be nullified to a large extent, with the application of a reduced combination of drugs. This paper provides an insight into the behavior of the signaling pathway in the presence of multiple concurrent malfunctions. First, we simulate the behavior of malfunctions in the Boolean networks. Next, we apply the drug therapy to reduce the effects of malfunctions. In our approach, we introduce a parameter called probabilistic_score, which identifies the reduced drug combinations without prior knowledge of the malfunctions, and it is more beneficial in realistic cancerous conditions. The combinations of different custom drug inhibition points are chosen to produce more efficient results than known drugs. Our approach is significantly faster as GPU acceleration has been carried out during modeling the multiple faults/malfunctions in the Boolean networks.


[Impact of cardiovascular illness on hospitalization costs in patients with rheumatoid arthritis].
The causes of admission and the distribution of direct medical costs were examined to establish the clinical predictors of high hospitalization costs in patients with rheumatoid arthritis. This retrospective study included all rheumatoid arthritis patients who were hospitalized in the Clínica Universitaria Bolivariana in Medellín, Colombia, between January 1999 and June 2003. Data were obtained from the medical records and from the hospital statistical section using a cost-analysis spreadsheet. A total of 41 patients were hospitalized 62 times (0.34 hospitalization per patient per year). Disease activity was the most important cause of admission (60%), followed by surgery (18%), and infection (10%). In 30 (48%) hospitalizations, at least one comorbidity was recorded, with cardiovascular disease being the most frequent (32%). The mean length of stay per patient was 5+/-6 days. The mean total cost was 1,277 US dollars, and the mean cost per day of hospitalization was 235 US dollars. Medications represented 54% of the total cost, whereas that representing medical care was only 3%. Variance analysis disclosed cardiovascular disease as the most important determinant of high costs (p<0.01). In conclusion, the direct costs for inpatients with rheumatoid arthritis were considerable, and arose mainly from organic complications. Prevention and treatment of cardiovascular disease are indispensable not only to reduce the economic burden of rheumatoid arthitis, but also to diminish the risk of mortality. These data assist in the estimation of health care resources and in the selection of public health policies for the improvement of patient outcomes.


Advanced glycation end-products and their receptor-mediated roles: inflammation and oxidative stress.
Glycation is a protein modification, which results in a change in a protein structure. Glycation is believed to be the etiology of various age-related diseases such as diabetes mellitus and Alzheimer's disease (AD). Activation of microglia and resident macrophages in the brain by glycated proteins with subsequent oxidative stress and cytokine release may be an important factor in the progression of AD. It is also suggested that interaction between an advanced glycation end product (AGE) and its receptor (RAGE) results in glial activation as well as cytokine release and reactive oxygen species release. The use of antioxidants, receptor mediated compounds and reactive oxygen species scavenging enzyme produce an opportunity to intervene with AGE-RAGE signaling pathway, and thereby to slow down the progression of aging-related diseases.


A randomized, multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1% sodium hyaluronate in the treatment of dry eye.
To investigate the efficacy of 2% rebamipide ophthalmic suspension compared with 0.1% sodium hyaluronate ophthalmic solution for the treatment of patients with dry eye. Randomized, multicenter, active-controlled parallel-group study. One hundred eighty-eight patients with dry eye. Following a 2-week screening period, patients were allocated randomly to receive 2% rebamipide or 0.1% sodium hyaluronate, administered as 1 drop in each eye 4 or 6 times daily, respectively, for 4 weeks. There were 2 primary end points: changes in the fluorescein corneal staining (FCS) score to determine noninferiority of 2% rebamipide and changes in the lissamine green conjunctival staining (LGCS) score to determine superiority. Secondary objective end points were Schirmer's test results and tear film breakup time (TBUT). Secondary subjective end points were dry eye-related ocular symptoms (foreign body sensation, dryness, photophobia, eye pain, and blurred vision) score and the patients' overall treatment impression score. In the primary analysis, the mean change from baseline in FCS scores verified noninferiority, indicated significant improvement, and, in LGCS scores, verified the superiority of 2% rebamipide to 0.1% sodium hyaluronate. Values for the Schirmer's test and TBUT were comparable between the 2 groups. For 2 dry eye-related ocular symptoms--foreign body sensation and eye pain--2% rebamipide showed significant improvements over 0.1% sodium hyaluronate. Patients had a significantly more favorable impression of 2% rebamipide than of 0.1% sodium hyaluronate; 64.5% rated treatment as improved or markedly improved versus 34.7%, respectively. No serious adverse events were observed. Administration of 2% rebamipide was effective in improving both the objective signs and subjective symptoms of dry eye. Those findings, in addition to the well-tolerated profile of 2% rebamipide, clearly show that it is an effective therapeutic method for dry eye. Proprietary or commercial disclosure may be found after the references.


Recent developments in biomarkers for the early detection of lung cancer: perspectives based on publications 2003 to present.
Given the poor prognosis associated with lung cancer, the ability to diagnose lung cancer in its early stages is considered crucial to achieving decreased lung cancer mortality. Herein, we discuss recent advances in biomarker discovery and evaluation of their potential application in the clinical setting. Novel potential biomarkers have been identified via new techniques including cDNA microarray analysis, comparative genomic hybridization, and proteomics. These factors have been evaluated in various validation studies including tissue microarrays, RT-PCR, and assays of bioactivity. The characterization of these potential biomarkers through analysis of pathways that have been associated with neo-plastic transformation may help to identify the precursor lesions that are associated with subsequent progression to invasive carcinoma. In addition, the past year has also produced intriguing results regarding the detection of biomarkers in easily accessible screening specimens such as sputa, serum, and exhaled breath. Recent advances in these aspects of biomarker identification for the early detection of lung cancer are reviewed. Identification of new candidate biomarkers and improved applications of previously detected biomarkers show great promise for the ultimate establishment of practical lung cancer screening. While recent studies engender optimism for the creation of clinically applicable screening tests, the biomarkers that have been identified need larger, follow-up validational studies and further characterization as to their biologic importance.


Crawling and walking infants elicit different verbal responses from mothers.
We examined mothers' verbal responses to their crawling or walking infants' object sharing (i.e. bids). Fifty mothers and their 13-month-olds were observed for 1 hour at home. Infants bid from a stationary position or they bid after carrying the object to their mothers. Mothers responded with affirmations (e.g. 'thank you'), descriptions ('red box'), or action directives ('open it'). Infants' locomotor status and the form of their bids predicted how mothers responded. Mothers of walkers responded with action directives more often than mothers of crawlers. Notably, differences in the responses of mothers of walkers versus those of crawlers were explained by differences in bid form between the two groups of infants. Walkers were more likely to engage in moving bids than crawlers, who typically shared objects from stationary positions. When crawlers displayed moving bids, their mothers offered action directives just as often as did mothers of walkers. Findings illustrate developmental cascades, wherein Infants' locomotor status affects how infants share objects with mothers, which in turn shapes mothers' verbal responses.


CRISPR/Cas9 Genome Editing of Epidermal Growth Factor Receptor Sufficiently Abolished Oncogenicity in Anaplastic Thyroid Cancer.
Anaplastic carcinoma of the thyroid (ATC), also called undifferentiated thyroid cancer, is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers. The aim of this study is to explore essential biomarker and use CRISPR/Cas9 with lentivirus delivery to establish a gene-target therapeutic platform in ATC cells. At the beginning, the gene expression datasets from 1036 cancers from CCLE and 8215 tumors from TCGA were collected and analyzed, showing EGFR is predominantly overexpressed in thyroid cancers than other type of cancers (P = 0.017 in CCLE and P = 0.001 in TCGA). Using CRISPR/Cas9 genomic edit system, ATC cells with EGFR sgRNA lentivirus transfection obtained great disruptions on gene and protein expression, resulting in cell cycle arrest, cell growth inhibition, and most importantly metastasis turn-off ability. In addition, the FDA-approved TKI of afatinib for EGFR targeting also illustrates great anticancer activity on cancer cell death occurrence, cell growth inhibition, and cell cycle arrest in SW579 cells, an EGFR expressing human ATC cell line. Furthermore, off-target effect of using EGFR sgRNAs was measured and found no genomic editing can be detected in off-target candidate gene. To conclude, this study provides potential ATC therapeutic strategies for current and future clinical needs, which may be possible in increasing the survival rate of ATC patients by translational medicine.


Electronic nicotine delivery system (electronic cigarette) awareness, use, reactions and beliefs: a systematic review.
We sought to systematically review the literature on electronic nicotine delivery systems (ENDS, also called electronic cigarettes) awareness, use, reactions and beliefs. We searched five databases for articles published between 2006 and 1 July 2013 that contained variations of the phrases 'electronic cigarette', 'e-cigarette' and 'electronic nicotine delivery'. Of the 244 abstracts identified, we excluded articles not published in English, articles unrelated to ENDS, dissertation abstracts and articles without original data on prespecified outcomes. Two reviewers coded each article for ENDS awareness, use, reactions and beliefs. 49 studies met inclusion criteria. ENDS awareness increased from 16% to 58% from 2009 to 2011, and use increased from 1% to 6%. The majority of users were current or former smokers. Many users found ENDS satisfying, and some engaged in dual use of ENDS and other tobacco. No longitudinal studies examined whether ENDS serve as 'gateways' to future tobacco use. Common reasons for using ENDS were quitting smoking and using a product that is healthier than cigarettes. Self-reported survey data and prospective trials suggest that ENDS might help cigarette smokers quit, but no randomised controlled trials with probability samples compared ENDS with other cessation tools. Some individuals used ENDS to avoid smoking restrictions. ENDS use is expanding rapidly despite experts' concerns about safety, dual use and possible 'gateway' effects. More research is needed on effective public health messages, perceived health risks, validity of self-reports of smoking cessation and the use of different kinds of ENDS.


Incidence of ProTaper Universal System Instrument Fractures - A Retrospective Clinical Study.
The aim of this retrospective clinical study was to evaluate the incidence of ProTaper Universal System instrument fractures, associated with observation of the arch, group of teeth, and root thirds in which these fractures occurred. From analysis of charts, clinical record cards and radiographs of endodontic treatments performed by postgraduate students using the ProTaper Universal System at a reference center, a total of 1031 teeth and 2355 canals were analyzed. The general incidence of instrument fractures and their frequency, considering the group of teeth, arch and root thirds, were cataloged and the data obtained were statistically analyzed (Exact Fischer test, with level of significance of 1%). The general percentage of fractures, considering the number of teeth and number of root canals evaluated was 4.4% and 1.9%, respectively. Instrument fractures occurred more frequently in the mandibular first (8.8%) and second (9.6%) molars, however, without statistically significant difference between them (P=0.81). In the first and second maxillary molars, the incidence of fracture was 4.7% and 5.1%, respectively, also without significant difference (P=0.81). Considering the dental arches (maxillary and mandibular), the fractures occurred with significantly higher frequency in the mandibular arch (66.7%), in comparison with the maxillary arch (33.3%) (P<0.01). A significantly higher percentage of fractures occurred in the apical third (84.4%) compared with the middle third (15.6%) (P<0.01). The general percentage of fractures, considering the number of teeth and number of root canals evaluated was 4.4% and 1.9%, respectively. However, the arch (mandibular) and root third (apical) had a significant effect on the incidence of instrument fractures.


Drug solubility in luminal fluids from different regions of the small and large intestine of humans.
The purpose of this work was to study the solubility of two drugs with different physicochemical properties in luminal fluids obtained from various regions of the human gastrointestinal (GI) tract and to determine the most important luminal parameters influencing their solubility. Jejunal fluids were aspirated from healthy volunteers via an oral intubation tube. Ileal and colonic fluids were obtained from patients undergoing GI surgery. Stoma fluids were also retrieved from patients. pH and buffer capacity of all fluids were determined. Saturation solubility of prednisolone (unionisable) and mesalamine (5-aminosalicylic acid) (zwitterionic) was measured. Mean solubility of prednisolone in the different luminal fluids was 0.50 mg/mL (±0.05) and did not vary significantly between the different regions of the GI tract (ANOVA, p > 0.05). No correlation between prednisolone solubility and jejunal bile salt content was found. Mesalamine solubility increased down the GI tract: 1.97 (±0.25), 3.26 (±0.08), 6.24 (±1.13) and 7.95 (±0.21) mg/mL in jejunal, ileal, ascending and transverse/descending colonic fluids respectively. Buffer capacity also increased and in one patient was observed to range from 6.4 to 28.6 reaching 44.4 mM/L/pH unit in ileal, ascending and transverse/descending colon fluids respectively. Mesalamine solubility was found to be dependent on both buffer capacity and pH, with buffer capacity being the most important (standardized coefficient β = 0.849, p < 0.0001) compared to pH (β = 0.219, p < 0.05). For drugs delivered as modified release formulations it is important to consider solubility in different regions of the GI tract as significant differences can arise which will ultimately influence drug bioavailability.


Use of long-acting reversible contraception in a cluster-random sample of female sex workers in Kenya.
To assess correlates of long-acting reversible contraceptive (LARC) use, and explore patterns of LARC use among female sex workers (FSWs) in Kenya. Baseline cross-sectional data were collected between September 2016 and May 2017 in a cluster-randomized controlled trial in Mombasa. Eligibility criteria included current sex work, age 16-34 years, not pregnant, and not planning pregnancy. Peer educators recruited FSWs from randomly selected sex-work venues. Multiple logistic regression identified correlates of LARC use. Prevalence estimates were weighted to adjust for variation in FSW numbers recruited across venues. Among 879 participants, the prevalence of contraceptive use was 22.6% for implants and 1.6% for intra-uterine devices (IUDs). LARC use was independently associated with previous pregnancy (adjusted odds ratio for one pregnancy, 11.4; 95% confidence interval, 4.25-30.8), positive attitude to and better knowledge of family planning, younger age, and lower education. High rates of adverse effects were reported for all methods. The findings suggest that implant use has increased among FSWs in Kenya. Unintended pregnancy risks remain high and IUD use is negligible. Although LARC rates are encouraging, further intervention is required to improve both uptake (particularly of IUDs) and greater access to family planning services.


Aspirin Induced Adverse Effects on the Small and Large Intestine.
Aspirin is in many ways a non- steroidal anti-inflammatory drug (NSAID) prototype. Similar to conventional NSAIDs the gastric side effects of aspirin are well studied. However its potential adverse effects on the small and large intestine are less well known and under- researched. Experimental studies support a pathogenic pathway leading to NSAID enteropathy involving the topical effects on the intestinal barrier (mucous layer, enterocytes) that lead to dysfunction and increased intestinal permeability followed by increased exposure to luminal triggers and acute inflammation. Although aspirin has a toxic effect in vitro, enteral or parenteral administration in vivo, in animal models, did not result to intestinal injury. In man, experimental studies have revealed changes in intestinal permeability similar to conventional NSAIDs but of lesser magnitude. The clinical implication of these changes though is not known. Population studies have associated aspirin use with occult gastrointestinal bleeding from the small or large bowel although the magnitude of this risk is difficult to estimate but certainly small. Associations to colitis flare-ups have been made in case reports and retrospective cohort studies but low dose aspirin appears safe. Complications of diverticular disease may also be more frequent with aspirin use.


Adsorption of large hydrocarbons on coinage metals: a van der Waals density functional study.
The adsorption of organic molecules onto the close-packed facets of coinage metals is studied, and how accurately adsorption heights can be described by using recent advances of the van der Waals density functional (vdWDF), with optPBE/vdWDF, optB86b/vdWDF, vdWDF2, and rev/vdWDF2 functionals is illustrated. The adsorption of two prototypical aromatic hydrocarbons is investigated, and the calculated adsorption heights are compared to experimental literature values from normal incident X-ray standing wave absorption and a state-of-the-art semi-empirical method. It is shown that both the optB86b/vdWDF and rev/vdWDF2 functionals describe adsorption heights with an accuracy of 0.1 Å, compared to experimental values, and are concluded as reliable methods of choice for related systems.


The coexistence of child undernutrition and maternal overweight: prevalence, hypotheses, and programme and policy implications.
The purpose of this paper is to document the prevalence of the phenomenon of the coexistence of a stunted child and an overweight mother (SCOWT) in the same household in low- and middle-income countries. We also explore whether this phenomenon is associated with a country's level of economic development and urbanization and highlight policy directions for public nutrition. Data from 36 Demographic and Health Surveys (DHS) were used (23 in Africa, 8 in Latin America, and 5 in Asia). Stunting was defined as height-for-age < -2 SD of the reference population and maternal overweight as a body mass index (BMI) of > 25 kg m(-2). World Bank and United Nations figures were used for gross national product per capita (an indicator of economic development) and for level of urbanization respectively. Descriptive statistics were derived, and multivariate linear regression analysis was used to model the association between economic development, urbanization and the prevalence of SCOWT. The prevalence of SCOWT is generally below 10%, except in four countries, of which three are in Latin America. Among our sample of countries, SCOWT is generally more prevalent in Latin America than in Africa, and is near or below 5% in all five countries of Asia. Contrary to our expectations, SCOWT is not necessarily more prevalent in urban than rural areas. We also find that when economic development is controlled for, SCOWT is associated with urbanization only in Latin America. In Africa and Asia, SCOWT is associated with economic development, but not urbanization. The concrete recognition of the SCOWT phenomenon is an important step to delineating more effective and integrated strategies to address problems of over- and undernutrition and dietary quality within countries, regions and households. This gives special importance to designing programmes and policies that will address the food and nutrition needs of each individual, rather than assuming that those needs are addressed by targeting programmes or policies to the household as a whole.


Qualitative and Quantitative Analysis of Smile Excursion in Facial Reanimation: A Systematic Review and Meta-analysis of 1- versus 2-stage Procedures.
Free functional muscle transfer has become a common treatment modality for smile restoration in long-lasting facial paralysis, but the selection of surgical strategy between a 1-stage and a 2-stage procedure has remained a matter of debate. The aim of this study was to compare the quantitative and qualitative outcomes of smile excursion between 1-stage and 2-stage free muscle transfers in the literature. A comprehensive review of the published literature between 1975 and end of January 2017 was conducted. The abstracts or titles of 2,743 articles were screened. A total of 24 articles met our inclusion criteria of performing a quantitative or qualitative evaluation of a free-functioning muscle transfer for smile restoration. For the purpose of meta-analysis, 7 articles providing quantitative data on a total of 254 patients were included. When comparing muscle excursion between 1-stage and 2-stage procedures, the average range of smile excursion was 11.5 mm versus 6.6 mm, respectively. For the purpose of systematic review, 17 articles were included. The result of the systematic review suggested a tendency toward superior functional results for the 1-stage procedure when comparing the quality of smile. The results of this review must be interpreted with great caution. Quantitative analysis suggests that 1-stage procedures produce better excursion than 2-stage procedures. Qualitative analysis suggests that 1-stage procedures might also produce superior results when based on excursion and symmetry alone, but these comparisons do not include one important variable dictating the quality of a smile-the spontaneity of the smile. The difficulty in comparing published results calls for a consensus classification system for facial palsy.


Matching into Integrated Plastic Surgery: The Value of Research Fellowships.
Integrated plastic surgery residency applicants sometimes complete research fellowships before residency. The average productivity and the impact of these fellowships on subsequent application to residency are unknown. The purpose of this study was to provide objective data to better understand the utility and productivity of a research fellowship. A national survey was conducted in which integrated plastic surgery residency applicants from 2013 to 2016 were surveyed regarding their experiences with research fellowships. American Council of Academic Plastic Surgeons members were also surveyed to elicit their perspectives on the value of these fellowships. Six hundred twenty-one integrated plastic surgery applicants from 2013 to 2016 were included in the study. Twenty-five percent of applicants participated in a research fellowship. Applicants who completed research fellowships were more likely to match into plastic surgery compared to those who did not (97 percent versus 81 percent, respectively; p < 0.05). Fellows were highly satisfied with their fellowship experience and produced an average of five publications and presentations per fellowship year. Sixty-three percent of research fellowships were performed to strengthen applications to categorical integrated plastic surgery residency. American Council of Academic Plastic Surgeons members considered three or four publications/presentations productive. Most do not recommend research fellowships to all medical students. Research fellowships can effectively prepare for categorical plastic surgery by improving publication and presentation experience. This is the first study to show that applicants who completed research fellowships were highly satisfied with their experience, accomplished higher than expected levels of productivity, and statistically significantly matched into an integrated plastic surgery residency more often than applicants without research fellowships.


Sunscreens in the United States: current status and future outlook.
Incidence rates of nonmelanoma skin cancer and melanoma has been on the rise in the United States for the past 20 years. UV radiation (UVR) exposure remains the most preventable environmental risk factor for these cancers. Aside from sun avoidance, sunscreens remain our best protection. UVR directly damages DNA and cause indirect cellular damage through the creation of reactive oxygen species, the sum of which leads to cutaneous immunosuppression and a tumorigenic milieu. The current generation of sunscreens protect from UVR through two main mechanisms: absorption and deflection. In the US, new Food and Drug Association rules require sunscreen manufacturers to evaluate their products not only on sun protection factor but also on broad spectrum UVA protection by the end of 2013. New labeling requirements will also be instituted. The American Academy of Dermatology and the American Academy of Pediatrics have provided specific recommendations for proper sun protection and sunscreen usage. Plant polyphenols such as those isolated from green tea, pomegranate, and grape seed remain an interesting avenue of research as additives to sunscreens or stand-alone products that appear to modulate the immunosuppressive effects of UVR on the skin. Additionally, although UVR induces endogenous cutaneous production of vitamin D, its damaging effects overshadow this positive benefit, especially in light of the ease of achieving recommended amounts of vitamin D through diet and supplementation.


Quantitative Multispectral Imaging Differentiates Melanoma from Seborrheic Keratosis.
Melanoma is a melanocytic tumor that is responsible for the most skin cancer-related deaths. By contrast, seborrheic keratosis (SK) is a very common benign lesion with a clinical picture that may resemble melanoma. We used a multispectral imaging device to distinguish these two entities, with the use of autofluorescence imaging with 405 nm and diffuse reflectance imaging with 525 and 660 narrow-band LED illumination. We analyzed intensity descriptors of the acquired images. These included ratios of intensity values of different channels, standard deviation and minimum/maximum values of intensity of the lesions. The pattern of the lesions was also assessed with the use of particle analysis. We found significantly higher intensity values in SKs compared with melanoma, especially with the use of the autofluorescence channel. Moreover, we found a significantly higher number of particles with high fluorescence in SKs. We created a parameter, the SK index, using these values to differentiate melanoma from SK with a sensitivity of 91.9% and specificity of 57.0%. In conclusion, this imaging technique is potentially applicable to distinguish melanoma from SK based on the analysis of various quantitative parameters. For this application, multispectral imaging could be used as a screening tool by general physicians and non-experts in the everyday practice.


Water and beverage consumption among children age 4-13y in the United States: analyses of 2005-2010 NHANES data.
Few studies have examined water consumption patterns among U.S. children. Additionally, recent data on total water consumption as it relates to the Dietary Reference Intakes (DRI) are lacking. This study evaluated the consumption of plain water (tap and bottled) and other beverages among US children by age group, gender, income-to-poverty ratio, and race/ethnicity. Comparisons were made to DRI values for water consumption from all sources. Data from two non-consecutive 24-hour recalls from 3 cycles of NHANES (2005-2006, 2007-2008 and 2009-2010) were used to assess water and beverage consumption among 4,766 children age 4-13y. Beverages were classified into 9 groups: water (tap and bottled), plain and flavored milk, 100% fruit juice, soda/soft drinks (regular and diet), fruit drinks, sports drinks, coffee, tea, and energy drinks. Total water intakes from plain water, beverages, and food were compared to DRIs for the U.S. Total water volume per 1,000 kcal was also examined. Water and other beverages contributed 70-75% of dietary water, with 25-30% provided by moisture in foods, depending on age. Plain water, tap and bottled, contributed 25-30% of total dietary water. In general, tap water represented 60% of drinking water volume whereas bottled water represented 40%. Non-Hispanic white children consumed the most tap water, whereas Mexican-American children consumed the most bottled water. Plain water consumption (bottled and tap) tended to be associated with higher incomes. No group of U.S. children came close to satisfying the DRIs for water. At least 75% of children 4-8y, 87% of girls 9-13y, and 85% of boys 9-13y did not meet DRIs for total water intake. Water volume per 1,000 kcal, another criterion of adequate hydration, was 0.85-0.95 L/1,000 kcal, short of the desirable levels of 1.0-1.5 L/1,000 kcal. Water intakes at below-recommended levels may be a cause for concern. Data on water and beverage intake for the population and by socio-demographic group provides useful information to target interventions for increasing water intake among children.


Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations.
Fluconazole (FLC) resistance is common in C. glabrata and echinocandins are often used as first-line therapy. Resistance to echinocandin therapy has been associated with FKS1 and FKS2 gene alterations. We reviewed records of all patients with C. glabrata bloodstream infection at Duke Hospital over the past decade (2001-2010) and correlated treatment outcome with minimum inhibitory concentration (MIC) results and the presence of FKS gene mutations. For each isolate, MICs to FLC and echinocandins (anidulafungin, caspofungin, and micafungin) and FKS1 and FKS2 gene sequences were determined. Two hundred ninety-three episodes (313 isolates) of C. glabrata bloodstream infection were analyzed. Resistance to echinocandins increased from 4.9% to 12.3% and to FLC from 18% to 30% between 2001 and 2010, respectively. Among the 78 FLC resistant isolates, 14.1% were resistant to 1 or more echinocandin. Twenty-five (7.9%) isolates harbored a FKS mutation. The predictor of a FKS mutant strain was prior echinocandin therapy (stepwise multivariable analysis, odds ratio, 19.647 [95% confidence interval, 7.19-58.1]). Eighty percent (8/10) of patients infected with FKS mutants demonstrating intermediate or resistant MICs to an echinocandin and treated with an echinocandin failed to respond or responded initially but experienced a recurrence. Echinocandin resistance is increasing, including among FLC-resistant isolates. The new Clinical and Laboratory Standards Institute clinical breakpoints differentiate wild-type from C. glabrata strains bearing clinically significant FKS1/FKS2 mutations. These observations underscore the importance of knowing the local epidemiology and resistance patterns for Candida within institutions and susceptibility testing of echinocandins for C. glabrata to guide therapeutic decision making.


Crime and COVID-19: effect of changes in routine activities in Mexico City.
This study aimed to determine whether crime patterns in Mexico City changed due to the COVID-19 pandemic, and to test whether any changes observed were associated with the disruption of routine activities, as measured by changes in public transport passenger numbers. The first objective was assessed by comparing the observed incidence of crime after the COVID-19 pandemic was detected in the country with that expected based on ARIMA forecasts based on the pre-pandemic trends. The second objective was assessed by examining the association between crime incidence and the number of passengers on public transport using regressions with ARIMA errors. Results indicated that most crime categories decreased significantly after the pandemic was detected in the country or after a national lockdown was instituted. Furthermore, the study found that some of the declines observed were associated with the reductions seen in public transport passenger numbers. However, the findings suggested that the changes in mobility explain part of the declines observed, with important variations per crime type. The findings contribute to the global evaluation of the effects of COVID-19 on crime and propose a robust method to explicitly test whether the changes observed are associated with changes in routine activities.


The RNA Complement of Outer Membrane Vesicles From Salmonella enterica Serovar Typhimurium Under Distinct Culture Conditions.
Bacterial outer membrane vesicles (OMVs), as well as OMV-associated small RNAs, have been demonstrated to play a role in host-pathogen interactions. The presence of larger RNA transcripts in OMVs has been less studied and their potential role in host-pathogen interactions remains largely unknown. Here we analyze RNA from OMVs secreted by Salmonella enterica serovar Typhimurium (S. Typhimurium) cultured under different conditions, which mimic host-pathogen interactions. S. Typhimurium was grown to exponential and stationary growth phases in minimal growth control medium (phosphate-carbon-nitrogen, PCN), as well as in acidic and phosphate-depleted PCN, comparable to the macrophage environment and inducing therefore the expression of Salmonella pathogenicity island 2 (SPI-2) genes. Moreover, Salmonella pathogenicity island 1 (SPI-1), which is required for virulence during the intestinal phase of infection, was induced by culturing S. Typhimurium to the stationary phase in Lysogeny Broth (LB). For each condition, we identified OMV-associated RNAs that are enriched in the extracellular environment relative to the intracellular space. All RNA classes could be observed, but a vast majority of rRNA was exported in all conditions in variable proportions with a notable decrease in LB SPI-1 inducing media. Several mRNAs and ncRNAs were specifically enriched in/on OMVs dependent on the growth conditions. Important to note is that some RNAs showed identical read coverage profiles intracellularly and extracellularly, whereas distinct coverage patterns were observed for other transcripts, suggesting a specific processing or degradation. Moreover, PCR experiments confirmed that distinct RNAs were present in or on OMVs as full-length transcripts (IsrB-1/2; IsrA; ffs; SsrS; CsrC; pSLT035; 10Sa; rnpB; STM0277; sseB; STM0972; STM2606), whereas others seemed to be rather present in a processed or degraded form. Finally, we show by a digestion protection assay that OMVs are able to prevent enzymatic degradation of given full-length transcripts (SsrS, CsrC, 10Sa, and rnpB). In summary, we show that OMV-associated RNA is clearly different in distinct culture conditions and that at least a fraction of the extracellular RNA is associated as a full-length transcripts with OMVs, indicating that some RNAs are protected by OMVs and thereby leaving open the possibility that those might be functionally active.


Differential diagnosis of breast lesions 5 mm or less: is there a role for magnetic resonance imaging?
According to magnetic resonance (MR) imaging Breast Imaging Reporting and Data System, foci are small enhanced lesions 5 mm or less in diameter. This study was conducted to (a) assess morphological and dynamic profiles in malignant versus benign foci in breast MR imaging (MRM) and to (b) identify overall diagnostic accuracy of MRM for differential diagnosis of foci. This study was approved by the local institutional review board; all patients gave written consent. All MRM (T1w-FLASH; 0.1 mmol/kg body weight gadolinium-diethylenetriamine penta-acetic acid; T2w-TSE; consecutive 12-year period; with histological verification after MRM were evaluated by 2 experienced (>500 MRM) radiologists in consensus using 16 predefined descriptors and were included into a database. A data set was created by extracting all lesions 5 mm or less (benign, 27; malignant, 61). Accuracy of individual descriptors was assessed (Crosstabs, chi2-test; positive/negative likelihood ratios (LR+/-); diagnostic odds ratio [DOR]). Binary logistic regression analysis was applied to identify overall diagnostic accuracy using all descriptors combined (area under the receiver operating characteristic curve,). Washout was typically associated with malignancy (P < 0.05; DOR, 3.5). Irregular shape was feasible for differential diagnosis of foci (DOR, 7.3), yet majority of malignancies demonstrated a round shape (55.6%). Additional descriptors such as blooming (DOR, 4.0, LR+, 2.8), adjacent vessel (DOR, 4.8; LR+, 4.5), and root sign (DOR, 5.6; LR+, 4.1) showed a high accuracy. Overall accuracy for differentiation of benign versus malignant foci showed an area under the curve of 0.887 (P = 0.0001). Assessment of dynamic and morphological profiles in foci 5 mm or less was feasible. Using all descriptors combined, a high potential for differential diagnosis of foci in magnetic resonance-mammography could be identified.


Population and Functional Genomics of Neisseria Revealed with Gene-by-Gene Approaches.
Rapid low-cost whole-genome sequencing (WGS) is revolutionizing microbiology; however, complementary advances in accessible, reproducible, and rapid analysis techniques are required to realize the potential of these data. Here, investigations of the genus Neisseria illustrated the gene-by-gene conceptual approach to the organization and analysis of WGS data. Using the gene and its link to phenotype as a starting point, the BIGSdb database, which powers the PubMLST databases, enables the assembly of large open-access collections of annotated genomes that provide insight into the evolution of the Neisseria, the epidemiology of meningococcal and gonococcal disease, and mechanisms of Neisseria pathogenicity.


Quantitative guidelines for force calibration through spectral analysis of magnetic tweezers data.
Single-molecule techniques are powerful tools that can be used to study the kinetics and mechanics of a variety of enzymes and their complexes. Force spectroscopy, for example, can be used to control the force applied to a single molecule and thereby facilitate the investigation of real-time nucleic acid-protein interactions. In magnetic tweezers, which offer straightforward control and compatibility with fluorescence measurements or parallel tracking modes, force-measurement typically relies on the analysis of positional fluctuations through video microscopy. Significant errors in force estimates, however, may arise from incorrect spectral analysis of the Brownian motion in the magnetic tweezers. Here we investigated physical and analytical optimization procedures that can be used to improve the range over which forces can be reliably measured. To systematically probe the limitations of magnetic tweezers spectral analysis, we have developed a magnetic tweezers simulator, whose outcome was validated with experimental data. Using this simulator, we evaluate methods to correctly perform force experiments and provide guidelines for correct force calibration under configurations that can be encountered in typical magnetic tweezers experiments.


The triggers or precipitants of the acute migraine attack.
The aim of this study was to evaluate and define the triggers of the acute migraine attack. Patients rated triggers on a 0-3 scale for the average headache. Demographics, prodrome, aura, headache characteristics, postdrome, medication responsiveness, acute and chronic disability, sleep characteristics and social and personal characteristics were also recorded. One thousand two hundred and seven International Classification of Headache Disorders-2 (1.1-1.2, and 1.5.1) patients were evaluated, of whom 75.9% reported triggers (40.4% infrequently, 26.7% frequently and 8.8% very frequently). The trigger frequencies were stress (79.7%), hormones in women (65.1%), not eating (57.3%), weather (53.2%), sleep disturbance (49.8%), perfume or odour (43.7%), neck pain (38.4%), light(s) (38.1%), alcohol (37.8%), smoke (35.7%), sleeping late (32.0%), heat (30.3%), food (26.9%), exercise (22.1%) and sexual activity (5.2%). Triggers were more likely to be associated with a more florid acute migraine attack. Differences were seen between women and men, aura and no aura, episodic and chronic migraine, and between migraine and probable migraine.


Parametric study of EEG sensitivity to phase noise during face processing.
The present paper examines the visual processing speed of complex objects, here faces, by mapping the relationship between object physical properties and single-trial brain responses. Measuring visual processing speed is challenging because uncontrolled physical differences that co-vary with object categories might affect brain measurements, thus biasing our speed estimates. Recently, we demonstrated that early event-related potential (ERP) differences between faces and objects are preserved even when images differ only in phase information, and amplitude spectra are equated across image categories. Here, we use a parametric design to study how early ERP to faces are shaped by phase information. Subjects performed a two-alternative force choice discrimination between two faces (Experiment 1) or textures (two control experiments). All stimuli had the same amplitude spectrum and were presented at 11 phase noise levels, varying from 0% to 100% in 10% increments, using a linear phase interpolation technique. Single-trial ERP data from each subject were analysed using a multiple linear regression model. Our results show that sensitivity to phase noise in faces emerges progressively in a short time window between the P1 and the N170 ERP visual components. The sensitivity to phase noise starts at about 120-130 ms after stimulus onset and continues for another 25-40 ms. This result was robust both within and across subjects. A control experiment using pink noise textures, which had the same second-order statistics as the faces used in Experiment 1, demonstrated that the sensitivity to phase noise observed for faces cannot be explained by the presence of global image structure alone. A second control experiment used wavelet textures that were matched to the face stimuli in terms of second- and higher-order image statistics. Results from this experiment suggest that higher-order statistics of faces are necessary but not sufficient to obtain the sensitivity to phase noise function observed in response to faces. Our results constitute the first quantitative assessment of the time course of phase information processing by the human visual brain. We interpret our results in a framework that focuses on image statistics and single-trial analyses.


Direct interaction of two polarity complexes implicated in epithelial tight junction assembly.
Tight junctions help establish polarity in mammalian epithelia by forming a physical barrier that separates apical and basolateral membranes. Two evolutionarily conserved multi-protein complexes, Crumbs (Crb)-PALS1 (Stardust)-PATJ (DiscsLost) and Cdc42-Par6-Par3-atypical protein kinase C (aPKC), have been implicated in the assembly of tight junctions and in polarization of Drosophila melanogaster epithelia. Here we identify a biochemical and functional link between these two complexes that is mediated by Par6 and PALS1 (proteins associated with Lin7). The interaction between Par6 and PALS1 is direct, requires the amino terminus of PALS1 and the PDZ domain of Par6, and is regulated by Cdc42-GTP. The transmembrane protein Crb can recruit wild-type Par6, but not Par6 with a mutated PDZ domain, to the cell surface. Expression of dominant-negative PALS1-associated tight junction protein (PATJ) in MDCK cells results in mis-localization of PALS1, members of the Par3-Par6-aPKC complex and the tight junction marker, ZO-1. Similarly, overexpression of Par6 in MDCK cells inhibits localization of PALS1 to the tight junction. Our data highlight a previously unrecognized link between protein complexes that are essential for epithelial polarity and formation of tight junctions.


NETosis in Cancer - Platelet-Neutrophil Crosstalk Promotes Tumor-Associated Pathology.
It has become increasingly clear that circulating immune cells in the body have a major impact on cancer development, progression, and outcome. The role of both platelets and neutrophils as independent regulators of various processes in cancer has been known for long, but it has quite recently emerged that the platelet-neutrophil interplay is yet a critical component to take into account during malignant disease. It was reported a few years ago that neutrophils in mice with cancer have increased propensity to form neutrophil extracellular traps (NETs) - web-like structures formed by externalized chromatin and secreted proteases. The initial finding describing this as a cell death-associated process has been followed by reports of additional mechanisms for NET formation (NETosis), and it has been shown that similar structures can be formed also without lysis and neutrophil cell death as a consequence. Furthermore, presence of NETs in humans with cancer has been verified in a few recent studies, indicating that tumor-induced NETosis is clinically relevant. Several reports have also described that NETs contribute to cancer-associated pathology, by promoting processes responsible for cancer-related death such as thrombosis, systemic inflammation, and relapse of the disease. This review summarizes current knowledge about NETosis in cancer, including the role of platelets as regulators of tumor-induced NETosis. It has been shown that platelets can serve as inducers of NETosis, and the platelet-neutrophil interface can therefore be an important issue to consider when designing therapies targeting cancer-associated pathology in the future.


Primary vitamin D target genes allow a categorization of possible benefits of vitamin D₃ supplementation.
Vitamin D deficiency has been associated with an increased risk of developing a number of diseases. Here we investigated samples from 71 pre-diabetic individuals of the VitDmet study, a 5-month high dose vitamin D3 intervention trial during Finnish winter, for their changes in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations and the expression of primary vitamin D target genes in peripheral blood mononuclear cells and adipose tissue. A negative correlation between serum concentrations of parathyroid hormone and 25(OH)D3 suggested an overall normal physiological vitamin D response among the participants. The genes CD14 and thrombomodulin (THBD) are up-regulated primary vitamin D targets and showed to be suitable gene expression markers for vitamin D signaling in both primary tissues. However, in a ranking of the samples concerning their expected response to vitamin D only the top half showed a positive correlation between the changes of CD14 or THBD mRNA and serum 25(OH)D3 concentrations. Interestingly, this categorization allows unmasking a negative correlation between changes in serum concentrations of 25(OH)D3 and the inflammation marker interleukin 6. We propose the genes CD14 and THBD as transcriptomic biomarkers, from which the effects of a vitamin D3 supplementation can be evaluated. These biomarkers allow the classification of subjects into those, who might benefit from a vitamin D3 supplementation, and others who do not.


Targeted delivery of pixantrone to neutrophils by poly(sialic acid)-p-octadecylamine conjugate modified liposomes with improved antitumor activity.
Based on the knowledge that poly(sialic acid) is a critical element for tumour development and that the receptors for its monomer are expressed on neutrophils, which play important roles in the progression and invasion of tumours, a poly(sialic acid)-p-octadecylamine conjugate (PSA-p-ODA) was synthesised and used to modify the surface of liposomal pixantrone (Pix-PSL) to improve the delivery of Pix to peripheral blood neutrophils (PBNs). The liposomes were fabricated using a remote loading technology via a pH gradient, and were then assessed for particle size, encapsulation efficiency, in vitro release, in vitro cytotoxicity, and pharmacokinetics. Simultaneously, in vitro and in vivo cellular uptake studies demonstrated that Pix-PSL provided an enhanced accumulation of Pix in PBNs. An in vivo study showed that the anti-tumour activity of Pix-PSL was superior to that of other formulations, probably owing to the efficient targeting of PBNs by Pix-PSL, after which PBNs containing Pix-PSL (Pix-PSL/PBNs) in the circulatory system are recruited by the tumour microenvironment. These findings suggest that PSA-p-ODA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumours, and thus represents a promising approach for the tumour targeting of chemotherapeutic treatments.


Differential diagnosis of hip disease versus spine disease.
Many clinicians find it difficult to differentiate between symptoms caused by a spine disorder or a hip disorder. If surgery is indicated, the order in which these operations take place is an important factor in the patient's long-term outcome. A prospective evaluation and retrospective chart review of patients with lower extremity pain was performed at the principal investigator's clinic to determine which signs and symptoms best predict the primary source of pain in patients with hip and spine disorders. Medical histories, physical examinations, and diagnostic tests were done on 97 patients with lower extremity pain to determine which signs and symptoms were the best predictors of a primary source of the pain (a hip or a spine disorder). The presence of a limp, groin pain, or limited internal rotation of the hip significantly predicted the diagnosis of a disorder as originating primarily from the hip, as opposed to originating from the spine. Patients with a limp were seven times more likely to have a hip disorder only or a hip and spine disorder than a spine only disorder. Similarly, patients with groin pain or limited internal rotation of the hips were seven and 14 times, respectively, more likely to have a hip disorder only or a hip and spine disorder than a spine only disorder. These variables are of primary importance to the clinician when making a differential diagnosis between hip disease and spine disease.


Expression of three forms of melanoma growth stimulating activity (MGSA)/gro in human retinal pigment epithelial cells.
To characterize mRNA expression and protein production of the cytokine MGSA/gro in human retinal pigment epithelial (RPE) cells and to determine whether expression of MGSA/gro is modulated by serum and the cytokines interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), or transforming growth factor beta (TGF beta) mediators implicated in proliferative vitreoretinopathy (PVR). Reverse-transcription polymerase chain reaction was used to determine the steady-state mRNA expression of three forms of MGSA/gro, alpha, beta, and gamma, by cultured human RPE cells in the presence or absence of recombinant IL-1 beta, TNF alpha, or TGF beta, or when serum-starved cells were re-fed with medium containing serum. Immunocytochemistry was used to characterize RPE cell-associated MGSA/gro protein, and immunoprecipitation of MGSA/gro from cell-conditioned medium was used to demonstrate MGSA/gro secretion. MGSA/gro mRNA was expressed minimally under basal conditions. Expression for all three forms of MGSA/gro mRNA was induced in a dose- and time-dependent manner after exposure to IL-1 beta, to a lesser extent after exposure to TNF alpha, but not after exposure to TGF beta. Serum induced MGSA/gro alpha and gamma transcripts, but not beta transcripts. Cell-associated MGSA/gro was identified on RPE cells grown in the absence of cytokines, but MGSA/gro was not secreted under these conditions. Exposure to IL-1 beta did not consistently cause increased cell-associated MGSA/gro; however, IL-1 beta induced secretion of MGSA/gro in a time-dependent manner. MGSA/gro is produced by human RPE in response to mediators implicated in PVR. Because MGSA/gro is a pleiotropic modulator of cell proliferation and inflammation, it may contribute to the intraocular wound healing response that characterizes PVR.


Epidemiological characteristics of HIV infected Korean: Korea HIV/AIDS Cohort Study.
To manage evidence-based diseases, it is important to identify the characteristics of patients in each country. The Korea HIV/AIDS Cohort Study seeks to identify the epidemiological characteristics of 1,442 Korean individuals with human immunodeficiency virus (HIV) infection (12% of Korean individuals with HIV infection in 2017) who visited 21 university hospitals nationwide. The descriptive statistics were presented using the Korea HIV/AIDS cohort data (2006-2016). Men accounted for 93.3% of the total number of respondents, and approximately 55.8% of respondents reported having an acute infection symptom. According to the transmission route, infection caused by sexual contact accounted for 94.4%, of which 60.4% were caused by sexual contact with the same sex or both males and females. Participants repeatedly answered the survey to decrease depression and anxiety scores. Of the total participants, 89.1% received antiretroviral therapy (ART). In the initial ART, 95.3% of patients were treated based on the recommendation. The median CD4 T-cell count at the time of diagnosis was 229.5 and improved to 331 after the initial ART. Of the patients, 16.6% and 9.4% had tuberculosis and syphilis, respectively, and 26.7% had pneumocystis pneumonia. In the medical history, sexually transmitted infectious diseases showed the highest prevalence, followed by endocrine diseases. The main reasons for termination were loss to follow-up (29.9%) and withdrawal of consent (18.7%). Early diagnosis and ART should be performed at an appropriate time to prevent the development of new infection.


The management of patients with uterine sarcoma: a debated clinical challenge.
Uterine sarcomas include a heterogeneous group of rare tumours that usually have an aggressive clinical behaviour and a poor prognosis. Total abdominal hysterectomy and bilateral salpingo-oophorectomy represents the standard surgical treatment. Pelvic and/or para-aortic lymphadenectomy is indicated for carcinosarcoma, but not for leiomyosarcoma and undifferentiated endometrial sarcoma. Some recent data on low numbers of patients with low-grade endometrial stromal sarcoma appear to show an incidence of nodal involvement higher than previously expected, thus suggesting a role for lymphadenectomy in this malignancy. Carcinosarcoma also requires a comprehensive surgical peritoneal staging. Postoperative treatment of uterine sarcomas has been long debated. Adjuvant pelvic radiotherapy appears to improve local control without any significant impact on overall survival. There is little evidence in the literature supporting the use of adjuvant chemotherapy in any gynaecological sarcomas except for carcinosarcomas. However, uterine sarcomas have a high tendency to develop distant recurrences, and recent data on adjuvant chemotherapy in soft tissue sarcomas are promising. As for the drugs to be used, it is worth noting that in a Swiss study, the combination of ifosfamide (IFO) and doxorubicin (DOX) obtained similar response rates in advanced gynaecological sarcomas and in advanced soft tissue sarcomas of other sites. In our decision-making scheme for early-stage disease, patients with leiomyosarcoma or undifferentiated endometrial sarcoma should receive adjuvant doxorubicin/epidoxorubicin (EPIDX)+ifosfamide, and those with carcinosarcoma should be treated with adjuvant cisplatin (CDDP)-based chemotherapy. The same drug regimens are used for the treatment of advanced disease. Sequential pelvic radiotherapy following chemotherapy could be delivered to selected cases. Recurrent disease often requires the integration of different therapeutic modalities, but no curative option is currently available with the possible exception of surgery for lung metastases and hormone therapy with or without debulking surgery for recurrent low-grade endometrial stromal sarcoma. Patients should be encouraged to enter clinical trials designed to identify new active drugs for these malignancies.


DEPRESSION STIGMA, RACE, AND TREATMENT SEEKING BEHAVIOR AND ATTITUDES.
This study examined the relationship between internalized and public stigma on treatment-related attitudes and behaviors in a community sample of 449 African American and white adults aged 18 years and older. Telephone surveys were administered to assess level of depressive symptoms, demographic characteristics, stigma, and treatment-related attitudes and behaviors. Multiple regression analysis indicated that internalized stigma mediated the relationship between public stigma and attitudes toward mental health treatment. Within group analyses indicated that the mediating effect of internalized stigma was significant for whites only. Among African Americans, internalized stigma did not mediate public stigma; it was directly related to attitudes toward mental health treatment. The internalization of stigma is key in the development of negative attitudes toward mental health treatment, and future research should focus on this aspect of stigma in both individual and community-based efforts to reduce stigma.


Fluoride-Induced Neuron Apoptosis and Expressions of Inflammatory Factors by Activating Microglia in Rat Brain.
Excessive exposure to fluoride results in structural and functional damages to the central nervous system (CNS), and neurotoxicity of fluoride may be associated with neurodegenerative changes. Chronic microglial activation appears to cause neuronal damage through producing proinflammatory cytokines and is involved in many neurodegenerative disorders. It is not known about effects on microglia of fluoride. In the present study, healthy adult Wistar rats were exposed to 60 and 120 ppm fluoride in drinking water for 10 weeks, and control rats received deionized water. After 10 weeks, rats were sacrificed under anesthesia then apoptosis in neuron and inflammatory factors secreted by microglia were determined. We found that apoptosis of neurons in fluoride-treated rat brain increased and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive immunofluorescence increased with increasing fluoride concentrations. Bax protein expression increased and Bcl-2 protein expression decreased in fluoride-treated rat brain compared with that of the control rat brain. The microglia in the hippocampus and cortex of fluoride-treated rats were activated by immunostaining with OX-42, a marker of activated microglia, and OX-42-positive microglia cells were more abundant in the hippocampus than in the cortex. The levels of IL-1β and IL-6 protein expression in OX-42-labeled microglial cells were significantly increased in the cortex and hippocampus of rats exposed to fluoride, and TNF-α immunoreactivity in microglial cells of the hippocampus was significantly higher in the 120 ppm fluoride-treated group than that in the control group. Our results indicate that fluoride induced neuron apoptosis and expressions of inflammatory factors by activating microglia in rat brain.


Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.
Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.


Insertional mutagenesis and recovery of interrupted genes of Streptococcus mutans by using transposon Tn917: preliminary characterization of mutants displaying acid sensitivity and nutritional requirements.
New vectors were constructed for efficient transposon Tn917-mediated mutagenesis of poorly transformable strains of Streptococcus mutans(pTV1-OK) and subsequent recovery of interrupted genes in Escherichia coli (pT21delta2TetM). In this report, we demonstrate the utility of Tn917 mutagenesis of a poorly transformable strain of S. mutans (JH1005) by showing (i) the conditional replication of pTV1-OK, a repA(Ts) derivative of the broad-host-range plasmid pWVO1 harboring Tn9l7, in JH1005 at the permissive temperature (30 degrees C) versus that at the nonpermissive temperature (45 degrees C); (ii) transposition frequencies similar to those reported for Bacillus subtilis (10(-5) to 10(-4)) with efficient plasmid curing in 90 to 97% of the erythromycin-resistant survivors following a temperature shift to 42 to 45 degrees C; and (iii) the apparent randomness of Tn917 insertion as determined by Southern hybridization analysis and the ability to isolate nutritional mutants, mutants in acid tolerance, and mutants in bacteriocin production, at frequencies ranging from 0.1 to 0.7%. Recovery of transposon-interrupted genes was achieved by two methods: (i) marker rescue in E. coli with the recovery vector pTV21delta2TetM, a tetracycline-resistant and ampicillin-sensitive Tn9l7-pBR322 hybrid, and (ii) "shotgun" cloning of genomic libraries of Tn917 mutants into pUC19. Sequence analyses revealed insertions at five different genetic loci in sequences displaying homologies to Clostridium spp.fhs (66% identity), E. coli dfp (43% identity), and B. subtilis ylxM-ffh (58% identity), icd (citC [69% identity]), and argD (61% identity). Insertions in icd and argD caused nutritional requirements; the one in ylxM-ffh caused acid sensitivity, while those in fhs and dfp caused both acid sensitivity and nutritional requirements. This paper describes the construction of pTV1-OK and demonstrates that it can be efficiently employed to deliver Tn917 into S. mutans for genetic analyses with some degree of randomness and that insertions in the chromosome can be easily recovered for subsequent characterization. This represents the first published report of successful Tn9l7 mutagenesis in the genus Streptococcus.


Protein-based multiplex assays: mock presubmissions to the US Food and Drug Administration.
As a part of ongoing efforts of the NCI-FDA Interagency Oncology Task Force subcommittee on molecular diagnostics, members of the Clinical Proteomic Technology Assessment for Cancer program of the National Cancer Institute have submitted 2 protein-based multiplex assay descriptions to the Office of In Vitro Diagnostic Device Evaluation and Safety, US Food and Drug Administration. The objective was to evaluate the analytical measurement criteria and studies needed to validate protein-based multiplex assays. Each submission described a different protein-based platform: a multiplex immunoaffinity mass spectrometry platform for protein quantification, and an immunological array platform quantifying glycoprotein isoforms. Submissions provided a mutually beneficial way for members of the proteomics and regulatory communities to identify the analytical issues that the field should address when developing protein-based multiplex clinical assays.


Cytomegalovirus infection enhances the immune response to influenza.
Cytomegalovirus (CMV) is a β-herpesvirus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli, and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV status. In contrast, CMV-seropositive young adults exhibited enhanced antibody responses to influenza vaccination, increased CD8(+) T cell sensitivity, and elevated levels of circulating interferon-γ compared to seronegative individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the ubiquity of CMV infection in humans and many other species.


Long-chain n-3 DHA reduces the extent of skeletal muscle fatigue in the rat in vivo hindlimb model.
Dietary fish oil modifies skeletal muscle membrane fatty acid composition and oxygen efficiency similar to changes in the myocardium. Oxygen efficiency is a key determinant of sustained force in mammalian skeletal muscle. Therefore, in the present study, we tested the effects of a fish-oil diet on skeletal muscle fatigue under the stress of contraction using the rat in vivo autologous perfused hindlimb model. For 8 weeks, male Wistar rats were fed a diet rich in saturated fat (SF), a diet rich in n-6 PUFA or a diet rich in long-chain (LC) n-3 PUFA DHA derived from fish oil. In anaesthetised, mechanically ventilated rats, with their hindlimbs perfused with arterial blood at a constant flow, the gastrocnemius-plantaris-soleus muscle bundle was stimulated via sciatic nerve (2 Hz, 6-12 V, 0·05 ms) to contract repetitively for 30 min. Rats fed the n-3 PUFA diet developed higher maximum twitch tension than those fed the SF and n-6 PUFA diets (P< 0·05) and sustained twitch tension through more repetitions before the tension declined to 50 % of the maximum twitch tension (P< 0·05). The n-3 PUFA group used less oxygen for tension developed and produced higher venous lactate concentrations with no difference in glycogen utilisation compared with the SF and n-6 PUFA groups. These results further support that incorporation of DHA into skeletal muscle membranes increases the efficiency of oxygen use over a range of contractile force and this is expressed as a higher sustained force and prolonged time to fatigue.


Cost estimate of platelet transfusion in the United States for patients with chronic liver disease and associated thrombocytopenia undergoing elective procedures.
This study aimed to estimate the cost of platelet transfusion in patients with chronic liver disease (CLD)-associated thrombocytopenia undergoing an elective procedure in the United States. The study was conducted in two parts: development of a conceptual framework identifying direct, indirect and intangible costs of platelet transfusion, followed by the estimation of the total cost of platelet transfusion in patients with CLD-associated thrombocytopenia before an elective procedure in the United States using the conceptual framework and cost data obtained from a literature search. The cost of the entire care required to raise a patient's platelet count before the procedure was considered. The final conceptual framework included the costs of generating the supply of platelets, the platelet transfusion itself, adverse events associated with platelet transfusion and refractoriness to platelet transfusion. When costs were accounted for in all the framework cost categories, the total direct cost of a platelet transfusion in a patient with CLD and associated thrombocytopenia was estimated to be in the range of $5258 to $13,117 (2017 US dollars) in the United States. The largest portion of costs was incurred by the transfusion event itself ($3723 to $4436) and the cost of refractoriness ($874 to $7578), which included the opportunity cost of a delayed procedure and subsequent platelet transfusions with human leukocyte antigen-matched platelets. Although we were unable to include all cost components identified in the conceptual framework in our total cost estimate, thus likely underestimating the true total cost, and despite the data gaps and challenges limiting our estimate of the full cost of a platelet transfusion in patients with CLD-associated thrombocytopenia undergoing an elective procedure in the United States, this study outlines a comprehensive conceptual framework for estimating the cost elements of a platelet transfusion in these patients.


Routine differential diagnosis of proteinurias by capillary electrophoresis.
Capillary electrophoresis is a relatively new analytical technique that begins to have an impact on both routine and research in clinical laboratories. Recently, a fully automated system has become commercially available (Paragon CZE 2000, Beckman, USA) for the analysis of human serum proteins. Urine protein analysis, on the other hand, is currently accomplished by electrophoresis of concentrated urine specimens. The method is used to distinguish the glomerular from the tubular proteinuria and for the identification of Bence-Jones proteins. The procedure is labor-intensive and technically demanding. We developed a technique for the serum capillary electrophoresis instrument that can also be applied routinely to the differential diagnosis of proteinurias. Overriding the programmed dilution step of the instrument, we were able to distinguish different types of proteinurias without concentration of specimens with a total protein content of 150-200 mg/l as determined by sulfosalicylic acid. The different electrophoretic patterns obtained by the capillary electrophoresis system for various specimens correlated well with established techniques (Hydragel Proteinurie Kit, Sebia, France). The method is applicable for routine analysis of urinary proteins. It is reliable, less expensive and faster than the conventional methods (electrophoretic or immunonephelometric) used today for the differentiation of proteinurias, and it can be used as a quick screening test.


Not just for stereotyping anymore: racial essentialism reduces domain-general creativity.
Individuals who believe that racial groups have fixed underlying essences use stereotypes more than do individuals who believe that racial categories are arbitrary and malleable social-political constructions. Would this essentialist mind-set also lead to less creativity? We suggest that the functional utility derived from essentialism induces a habitual closed-mindedness that transcends the social domain and hampers creativity. Across studies, using both individual difference measures (in a pilot test) and experimental manipulations (Experiments 1, 2a, and 2b), we found that an essentialist mind-set is indeed hazardous for creativity, with the relationship mediated by motivated closed-mindedness (Experiments 2a and 2b). These results held across samples of majority cultural-group members (Caucasian Americans, Israelis) and minority-group members (Asian Americans), as well as across different measures of creativity (flexibility, association, insight). Our findings have important implications for understanding the connection between racial intolerance and creativity.


Assessing fuel treatment effectiveness using satellite imagery and spatial statistics.
Understanding the influences of forest management practices on wildfire severity is critical in fire-prone ecosystems of the western United States. Newly available geospatial data sets characterizing vegetation, fuels, topography, and burn severity offer new opportunities for studying fuel treatment effectiveness at regional to national scales. In this study, we used ordinary least-squares (OLS) regression and sequential autoregression (SAR) to analyze fuel treatment effects on burn severity for three recent wildfires: the Camp 32 fire in western Montana, the School fire in southeastern Washington, and the Warm fire in northern Arizona. Burn severity was measured using differenced normalized burn ratio (dNBR) maps developed by the Monitoring Trends in Burn Severity project. Geospatial data sets from the LANDFIRE project were used to control for prefire variability in canopy cover, fuels, and topography. Across all three fires, treatments that incorporated prescribed burning were more effective than thinning alone. Treatment effect sizes were lower, and standard errors were higher in the SAR models than in the OLS models. Spatial error terms in the SAR models indirectly controlled for confounding variables not captured in the LANDFIRE data, including spatiotemporal variability in fire weather and landscape-level effects of reduced fire severity outside the treated areas. This research demonstrates the feasibility of carrying out assessments of fuel treatment effectiveness using geospatial data sets and highlights the potential for using spatial autoregression to control for unmeasured confounding factors.


Cartilage metabolism in the injured and uninjured knee of the same patient.
To examine if unilateral knee injury affects the synovial fluid concentrations of aggrecan fragments, cartilage oligomeric matrix protein (COMP) fragments, stromelysin-1, and tissue inhibitor of metalloproteinases-1 (TIMP-1) in the contralateral uninjured knee. Synovial fluids from the injured and uninjured knees were obtained at different times in a group of patients after unilateral knee trauma. Serum samples were obtained on the same occasion. Concentrations of aggrecan fragments were determined by precipitation with Alcian Blue; those of COMP fragments, stromelysin-1, and TIMP-1 were measured by immunoassay. Concentrations were compared with those in a reference group of 10 healthy volunteers. Immediately after knee injury, concentrations of aggrecan fragments, COMP fragments, stromelysin-1 and TIMP-1 were increased in the synovial fluid of the injured knee. However, concentrations of aggrecan and COMP fragments, and stromelysin-1 increased also in the contralateral uninjured knee immediately after injury, but less than in the injured knee. Subsequently, the concentrations of all markers decreased in the synovial fluid of the injured knee, but remained unchanged in the uninjured knee. The concentration of aggrecan fragments in the injured knee decreased to less than that in the uninjured knee in the chronic phase. Serum concentrations of COMP were much smaller than those in synovial fluid. The increased concentrations of aggrecan and COMP fragments and stromelysin-1 in the joint fluid of the contralateral, uninjured knee following unilateral knee injury, compared with concentrations in healthy reference knees, suggest changes in joint cartilage metabolism in both knees following unilateral knee injury. The mechanisms for these changes are unclear. The low serum concentration of COMP makes it less likely that there is any significant 'exchange' of molecular makers between the knees. A further consequence of these findings is that the contralateral knee cannot be recommended as the only control joint in studies of matrix metabolism in patients with unilateral knee injury.


A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: Results of 2 randomized, double-blind, phase 3 studies.
FMX101 4% is a topical minocycline foam for the treatment of moderate-to-severe acne. Evaluate the efficacy and safety of FMX101 4% in treating moderate-to-severe acne vulgaris. Two identical phase 3 studies were conducted. Subjects were randomized 2:1 to once-daily FMX101 4% or foam vehicle for 12 weeks. The coprimary end points were the change in inflammatory lesion count from baseline and the rate of treatment success according to the Investigator's Global Assessment (a score of 0 or 1 for clear or almost clear, with a ≥2-grade improvement) at week 12. A total of 961 subjects were enrolled (study 04, N = 466; study 05, N = 495). Compared with vehicle, FMX101 4% demonstrated a significantly greater reduction in inflammatory lesions in both studies (P < .05) and a greater rate of treatment success in study 05 according to the Investigator's Global Assessment (P < .05). Pooled analyses of the 2 studies demonstrated statistical significance for both coprimary end points (all P < .05). Noninflammatory lesion count was also significantly reduced with FMX101 4% versus with vehicle in both studies. FMX101 4% was generally safe and well tolerated. Skin-related adverse events were reported in less than 1% of subjects treated with FMX101 4%. Longer-term efficacy and safety outcomes are needed (ongoing). FMX101 4% topical minocycline foam significantly reduced both inflammatory and noninflammatory lesions and improved Investigator's Global Assessment scores in patients with moderate-to-severe acne.