Current State of Empyema Management.
Empyema affects up to 65,000 patients annually in the United States. Recent consensus guidelines demonstrate ambiguity about optimal treatment. We examined current treatment practices and outcomes for inpatient treatment of empyema using a comprehensive, longitudinal data set that encompasses an entire state cohort of hospitalized patients. We queried the Healthcare Cost and Utilization Project New York State Inpatient Database (2009 to 2014) for patients with primary empyema and subsequent readmissions. Patients were categorized into three groups by definitive treatment during their initial hospitalization: chest tube drainage, video-assisted thoracoscopic surgery (VATS) decortication and drainage, or open decortication and drainage. Treatment outcomes, including success rates, readmission, reintervention, and mortality, were compared between groups. The cohort included 4,095 patients undergoing intervention for primary empyema discharged during this period with chest tube, VATS, or open drainage and decortication. Most patients received definitive operative management (chest tube: 38.2%, VATS: 32.1%, open: 29.8%; p < 0.001). Patients had a high mortality rate during their initial hospitalization (chest tube: 15.4%, VATS: 4.7%, open: 6.0%; p < 0.001) and a substantial 30-day readmission rate for empyema (chest tube: 7.3%, VATS: 3.8%, open: 4.1%; p < 0.001), with reintervention at readmission significantly higher for chest tube (6.1%) vs surgical patients (VATS: 1.9%, open 2.1%; p < 0.001). This study characterizes recent treatment practices of patients with empyema. Higher readmission and reintervention rates were observed in patients managed with chest tubes, suggesting some of these patients may benefit from earlier definitive surgical intervention.


[Removal of oil in the lake water in Daqing area using subsurface constructed wetland].
Based on the water quality and climate of the oil contaminated lake in Daqing area, four simulated subsurface wetland systems were constructed in the field to study their removal effect of oil in lake water, including the gravel bed, the gravel-reed bed, the slag-reed bed and the slag bed. The research lasted about 360 d, including five periods: the start up period, the microorganism adding period, the slow-releasing carbon sources adding period, the low temperature period and the normal operation period. During the study, oil removal efficiency of the four units are 24.7%,28.4%, 45.9% and 42.9% respectirely, and the slag unit shows better than gravel unit. The adding of microorganism and slow-releasing carbon sources markedly improves the oil removal. The application of plant in the wetland system also promotes the oil removal. In all the four simulated subsurface wetland systems, 70% of the oil removal attributes to the adsorption effect.


The clinical significance of forkhead box protein A1 and its role in colorectal cancer.
Forkhead box protein A1 (FOXA1) is a transcription factor; recent studies have reported that FOXA1 has an oncogenic or tumor suppressive role in human malignancies, and its expression is associated with the prognosis of patients with cancer. However, further studies are required to determine the clinical significance of FOXA1 and its role in colorectal cancer (CRC). In the present study, FOXA1 expression was detected in 90 samples of CRC tissues and matched noncancerous tissues using immunohistochemistry. In these cases, FOXA1 expression was detected in 57.8% (52/90) of the CRC samples, whereas only 37.8% (34/90) of the noncancerous specimens exhibited a positive FOXA1 signal. In addition, the present study demonstrated that the mRNA expression levels of FOXA1 were significantly increased in CRC tissues compared with in matched tumor‑adjacent tissues. Furthermore, the positive expression of FOXA1 was associated with poor clinicopathological characteristics of CRC, including poor tumor differentiation, large tumor size, lymph node metastases and advanced tumor‑node‑metastasis tumor stage. Notably, patients with CRC with positive FOXA1 expression exhibited a significantly reduced 5-year survival rate compared with those with negative FOXA1 expression. Multivariate Cox regression analysis revealed that FOXA1 expression was an independent prognostic indicator for patients with CRC. In addition, FOXA1 knockdown evidently inhibited cell proliferation and induced apoptosis in SW480 and HCT116 CRC cells. Notably, FOXA1 knockdown also prominently reduced the expression of yes‑associated protein (YAP) in SW480 and HCT116 cells. In conclusion, the results of the present study indicated that FOXA1 may be considered a potential prognostic marker, and may promote tumor growth of CRC by upregulating YAP expression.


Exact, convergent periodic-orbit expansions of individual energy eigenvalues of regular quantum graphs.
We present exact, explicit, convergent periodic-orbit expansions for individual energy levels of regular quantum graphs in the paper. One simple application is the energy levels of a particle in a piecewise constant potential. Since the classical ray trajectories (including ray splitting) in such systems are strongly chaotic, this result provides an explicit quantization of a classically chaotic system.


Augmented passive transfer of contact sensitivity in severe combined immunodeficiency mice and its dependence of V beta 8+ cells in the picryl system.
The passive transfer of contact sensitivity using picryl chloride immune cells from H-2 syngenic BALB/c donors was analyzed in severe combined immunodeficiency (SCID) mice which lack functional T and B lymphocytes. H-2-restricted and antigen-specific contact sensitivity was transferred to SCID mice, and comparison between the level of contact sensitivity and the number of transferred cells showed a significantly more efficient transfer to SCID than to BALB/c mice. The cells passively transferring contact sensitivity were shown to carry the V beta 8 phenotype. Moreover, chromium-labeled cells from BALB/c PC1-primed donors localize normally in peripheral lymphoid organs and an increased percentage of cell arrival in the ears is clearly observed in SCID after challenge with picryl chloride.


Chemical Synthesis of Acyclic Nucleoside Phosphonate Analogs Linked with Cyclic Systems between the Phosphonate and the Base Moieties.
The syntheses of acyclic nucleoside phosphonate (ANP) analogs linked with cyclic systems are described in the present review. The purpose of the review is to report the methodology of ANP analogs and to give an idea on the synthesis of a therapeutic structural feature of such analogs. The cyclopropane systems were mainly prepared by diazomethane cyclopropanation catalyzed by Pd(OAc)2, intramolecular alkylation, Kulinkovich cyclopropanation, and use of difluorocyclopropane, and so forth. The preparation of methylenecyclopropane system was made by diazoacetate cyclopropanation catalyzed by Rhodium followed by addition-elimination reactions. For the preparation of a variety of tethered 1,2,3-triazole systems, 1,3-dipolar cycloaddition between azidealkylphosphonates and propargylated nucleobases was mainly applied. The formation of various phosphonate moieties was achieved via phosphonylation of alkoxide, cross-coupling between BrZnCF2P (O)(OEt)2 with iodoalkens catalyzed by CuBr, Michaelis-Arbuzov reaction with phosphite, and Rh(II)-catalyzed O-H insertion, and so forth.


Prediction of protein structure by evaluation of sequence-structure fitness. Aligning sequences to contact profiles derived from three-dimensional structures.
The problem of protein structure prediction is formulated here as that of evaluating how well an amino acid sequence fits a hypothetical structure. The simplest and most complicated approaches, secondary structure prediction and all-atom free energy calculations, can be viewed as sequence-structure fitness problems. Here, an approach of intermediate complexity is described, which involves; (1) description of a protein structure in terms of contact interface vectors, with both intra-protein and protein-solvent contacts counted, (2) derivation of sequence preferences for 2 up to 29 contact interface types, (3) generation of numerous hypothetical model structures by placing the input sequence into a large set of known three-dimensional structures in all possible alignments, (4) evaluation of these models by summing the sequence preferences over all structural positions and (5) choice of predicted three-dimensional structure as that with the best sequence-structure fitness. Evolutionary information is incorporated by using position-dependent core weights derived from multiple sequence alignments. A number of tests of the method are performed: (1) evaluation of cyclic shifts of a sequence in its native structure; (2) alignment of a sequence in its native structure, allowing gaps; (3) alignment search with a sequence or sequence fragment in a database of structures; and (4) alignment search with a structure in a database of sequences. The main results are: (1) a native sequence can very well find its native structure among a large number of alternatives, in correct alignment; (2) substructures, such as (beta alpha)n units, can be detected in spite of very low sequence similarity; (3) remote homologous can be detected, with some dependence on the set of parameters used; (4) contact interface parameters are clearly superior to classical secondary structure parameters; (5) a simple interface description in terms of just two states, protein-protein and protein-water contacts, performs surprisingly well; (6) the use of core weights considerably improves accuracy in detection of remote homologues; (7) based on a sequence database search with a myoglobin contact profile, the C-terminal domain of a viral origin of replication binding protein is predicted to have an all-helical fold. The sequence-structure fitness concept is sufficiently general to accommodate a large variety of protein structure prediction methods, including new models of intermediate complexity currently being developed.


Primary care nursing research and the Scottish School of Primary Care.
Research capability and research capacity are two fundamental requirements in the development of a research-active, evidence-based nursing profession. The Scottish School of Primary Care is developing programmes to address these issues across Scotland.


Scalable SoftGroup for 3D Instance Segmentation on Point Clouds.
This paper considers a network referred to as SoftGroup for accurate and scalable 3D instance segmentation. Existing state-of-the-art methods produce hard semantic predictions followed by grouping instance segmentation results. Unfortunately, errors stemming from hard decisions propagate into the grouping, resulting in poor overlap between predicted instances and ground truth and substantial false positives. To address the abovementioned problems, SoftGroup allows each point to be associated with multiple classes to mitigate the uncertainty stemming from semantic prediction. It also suppresses false positive instances by learning to categorize them as background. Regarding scalability, the existing fast methods require computational time on the order of tens of seconds on large-scale scenes, which is unsatisfactory and far from applicable for real-time. Our finding is that the k-Nearest Neighbor ( k-NN) module, which serves as the prerequisite of grouping, introduces a computational bottleneck. SoftGroup is extended to resolve this computational bottleneck, referred to as SoftGroup++. The proposed SoftGroup++ reduces time complexity with octree k-NN and reduces search space with class-aware pyramid scaling and late devoxelization. Experimental results on various indoor and outdoor datasets demonstrate the efficacy and generality of the proposed SoftGroup and SoftGroup++. Their performances surpass the best-performing baseline by a large margin (6% ∼ 16%) in terms of AP 50. On datasets with large-scale scenes, SoftGroup++ achieves a 6× speed boost on average compared to SoftGroup. Furthermore, SoftGroup can be extended to perform object detection and panoptic segmentation with nontrivial improvements over existing methods.


Vancomycin: an overview for the podiatric physician.
An increased reliance on vancomycin to treat bacterial infections has led to the emergence of vancomycin-resistant organisms. The podiatric physician must select and use vancomycin with due caution. This article presents a general review of vancomycin's pharmacology, pharmacokinetics, and dosing recommendations. Literature citations of clinically based evidence regarding the development and use of vancomycin nomograms are also presented. A vancomycin dosing nomogram is introduced as an effective tool for the prescribing podiatric physician. Appropriate use of the information presented may improve patient outcomes and enable the podiatric physician to treat patients with less effort and at a lower cost.


Infant nutrition and cognitive development in the first offspring of a national UK birth cohort.
Several studies show a modest beneficial effect of breastfeeding on cognitive development after controlling for sociodemographic confounders. It is still unclear, however, to what extent this is due to the nutritional advantage of breast milk or to environmental influences associated with breastfeeding. We compared verbal ability scores at age 8 years in 511 first-born offspring of the National Survey of Health and Development who were ever or never breastfed, adjusting for paternal occupation, maternal education, maternal cognitive performance, attendance at nursery school, and maternal age at birth of the participant. A positive association between breastfeeding and cognitive performance was found but this was no longer the case after adjusting for either paternal occupation, maternal education, or maternal cognitive performance in turn. In contrast, an association between breastfeeding and cognitive function was not found for mothers of these offspring. Breastfeeding was increasingly associated with a non-manual social class across the generations although it remains unclear how this might mediate the effect of breastfeeding on cognitive performance.


Guineensine, an Acyl-CoA: cholesterol acyltransferase inhibitor, from the fruits of Piper longum.
Bioactivity-guided fractionations for ACAT inhibitor led to the isolation of guineensine from the CHCl (3) extract of Piper longum. Its structure was identified by spectroscopic means (IR, UV, MS and NMR). Guineensine inhibited ACAT activity in a dose-dependent manner with an IC (50) value of 3.12 micro M.


How did women with breast cancer experience the first wave of the COVID-19 pandemic? A qualitative study.
The ongoing COVID-19 global pandemic is a stressful experience that is particularly likely to negatively affect cancer patients. The goal of this qualitative study was to explore how breast cancer patients experienced the first wave of the COVID-19 outbreak. As part of a larger study, 23 women accepted to take part in an individual phone interview investigating the psychosocial consequences of the COVID-19 pandemic. The hybrid inductive-deductive thematic analysis revealed the following themes: (1) increased general psychological distress; (2) concerns about the impact of treatment-related immunosuppression (i.e., increased risk of catching the SARS-CoV-2 and of developing more severe complications); (3) higher risk of catching the SARS-CoV-2 in the hospital; (4) possible impact of changes in cancer care trajectory on prognosis; (5) distress related to going to treatment alone; (6) social isolation and decreased family relationships; (7) increased responsibility at home; (8) variety of coping strategies used (i.e., adherence to public health measures, seeking professional help, avoidance); (9) difficulty receiving professional mental health services and social support; (10) anxiety related to return to work; and (11) uncertainty about the future. The COVID-19 outbreak is a major medical, psychological, social, and occupational stressor for women undergoing treatment for breast cancer. We offer recommendations to reduce the impact of subsequent waves of COVID-19 and other epidemics in this population.


Cookies enriched with anethole and secoisolariciresinol diglucoside from flaxseed and fennel seeds improve hypercholesterolemia, lipid profile, and liver functions: A pilot study.
Over millennia, flaxseeds and fennel seeds have captured greater attention owing to the broad spectrum of bioactive compounds and their respective therapeutic potential. They are well-known therapeutic plants, frequently used in home treatments for a variety of medical conditions. The novelty of this pilot study is to assess the beneficial health effects of secoisolariciresinol diglucoside (SDG) and anethole-based enriched cookies among hyperlipidemic patients. The result of sensory evaluation revealed that cookies with anethole and SDG (500 + 500 mg/day) were significantly acceptable in terms of color, texture, taste, and overall acceptability same as that of control. This study was performed among 34 patients with hyperlipidemia in a university-affiliated hospital, Lahore, Pakistan. In this study, patients received dietary supplementation with anethole and SDG (500 + 500 mg/day) administered in cookies for 8 weeks. Patients were assigned into two groups, intervention (receiving anethole + SDG-enriched cookies; n = 16) and placebo (n = 18), for 8 weeks. Both groups maintained the same diet and lifestyle. Pre- and postintervention weight, lipid profile, and liver enzyme levels were measured. Analysis of covariance and paired sample t-test were used for comparing the two groups. After 8 weeks, a significant mean weight loss was observed in the intervention group (4.26%) as compared to the placebo group (0.3%). A significant reduction of TC (177.02 ± 5.14 mg/dL; p = .024), TG (150.19 ± 7.94 mg/dL; p = .032), and LDL (87.38 ± 3.58 mg/dL; p = .001) were compared to the control group and HDL level (57.09 ± 3.90 mg/dL; p = .035) were increased in the intervention group as compared to the placebo. Meanwhile, it had a minor improvement in AST (30.97 ± 2.95 U/L; p = .01), ALT (33.05 ± 1.52 U/L; p = .025), and ALP (112.15 ± 4.03 U/L; p = .03) among the intervention group. Thus, based on the results from the study, it can be said that anethole + SDG-enriched bakery products could be developed as a functional dietary option for hyperlipidemia in developing countries like Pakistan.


Longitudinal Follow-Up of Children Born Preterm: Neurodevelopment From 2 to 10 Years of Age.
Objective: To investigate the rate and stability of impairments in children born preterm by assessing (1) early and school-age outcome in four developmental domains and (2) individual changes in outcome at both timepoints. Design: Prospective, longitudinal cohort study in children born in 2006-2007, <32 weeks' gestation. Follow-up at 2 and 10 years of age included standardized neurological, motor, cognitive and behavioral assessments. Children were categorized as having no, mild or moderate-severe impairment in these four domains. A composite impairment score was composed and the number of domains with impairments counted. For each child, individual outcomes at both timepoints were compared. Results: Follow-up at both time-points was available in 71/113(63%) children. At group level, there were no significant changes in the severity of impairments per domain. However, at individual level, there were less children with a mild abnormal composite score at 10 years of age (44 vs. 20%; p = 0.006), and more with a moderate-severe abnormal composite score (12 vs. 35%; p = 0.001). Especially children with normal/mild outcome at 2 years were likely to shift to other outcome categories over time. Conclusions: Children with early severe impairment are likely experiencing impairments later on, but early normal/mild abnormal outcomes should be interpreted with care, considering the large individual shifts over time. Long-term follow-up in all children born very preterm should therefore be continued to at least school-age.


Urethral Melanoma - Clinical, Pathological and Molecular Characteristics.
Mucosal melanoma involving the urethra is a rare disease with distinct clinical and molecular characteristics and poor outcomes. Our current knowledge is limited by the small number of reports regarding this disease. To describe the clinical, pathological, and molecular characteristics of urethral melanoma. We summarized the clinicopathologic data for 31 patients treated for urethral melanoma from 1986-2017 at our institution. Genomic data from our institutional sequencing platform MSK-IMPACT (n = 5) and gene-specific PCR data on BRAF, KIT, and/or NRAS (n = 8) were compared to genomic data of cutaneous melanomas (n = 143), vulvar/vaginal melanomas (n = 24), and primary non-melanoma urethral tumors (n = 5) from our institutional database. Twenty-three patients were diagnosed with localized disease, 7 had regional/nodal involvement and one had metastases. Initial treatment included surgery in 25 patients; seven had multimodal treatment. Median follow-up was 46 months (IQR 33-123). Estimated 5-year cancer-specific survival was 45%. No significant change in survival was observed based on a year of treatment.Primary urethral melanomas showed a higher frequency of TP53 mutations compared to cutaneous (80.0% vs. 18.2%, p = 0.006) and vulvar/vaginal melanomas (80.0 vs. 25.0%, p = 0.04). BRAF mutations were absent in urethral primaries (0% vs. 46% in cutaneous melanoma, p = 0.02). Tumor mutation burden was higher in cutaneous than urethral melanomas (p = 0.04). Urethral melanomas had a higher number of somatic alterations compared to non-melanoma urethral tumors (median 11 vs. 5, p = 0.03). Our findings support a unique mutational landscape of urethral melanoma compared to cutaneous melanoma. Survival remains poor and is unchanged over the time studied.


Incidence and Ocular Features of Pediatric Myasthenias.
To report the incidence, demographics, and ocular findings of children with myasthenia. Retrospective cohort study. The medical records of all children (<19 years) examined at Mayo Clinic with any form of myasthenia from January 1 1966, through December 31, 2015, were retrospectively reviewed. A total of 364 children were evaluated during the study period, of which 6 children were residents of the Olmsted County at the time of their diagnosis, yielding an annual age- and sex-adjusted incidence of 0.35 per 100 000 <19 years, or 1 in 285 714 <19 years. The incidence of juvenile myasthenia gravis (JMG) and congenital myasthenic syndrome (CMS) was 0.12 and 0.23 per 100 000, respectively. Of the 364 study children, 217 (59.6%) had JMG, 141 (38.7%) had CMS, and 6 (1.7%) had Lambert-Eaton syndrome, diagnosed at a median age of 13.5, 5.1, and 12.6 years, respectively. A majority of the JMG and CMS patients had ocular involvement (90.3% and 85.1%, respectively), including ptosis and ocular movement deficits. Among children with at least 1 year of follow-up (JMG; median, 7.1 years, CMS; median, 7.0 years), improvement was seen in 88.8% of JMG patients (complete remission in 31.3%) and in 58.3% of CMS patients. Although relatively rare, myasthenia gravis in children has 2 predominant forms, CMS and JMG, both of which commonly have ocular involvement. Improvement is more likely in children with the juvenile form.


Guanylate binding protein 5: Impairing virion infectivity by targeting retroviral envelope glycoproteins.
Guanylate binding proteins (GBPs) are interferon-inducible cellular factors that belong to the superfamily of guanosine triphosphatases (GTPases) and play important roles in the cell-intrinsic defense against bacteria, protozoa and viruses. In a recent report in Cell Host & Microbe, we identify GBP5 as novel restriction factor of HIV-1 that reduces the infectivity of progeny virions by interfering with processing and incorporation of the viral envelope (Env) glycoprotein. The inhibitory activity of GBP5 requires C-terminal isoprenylation, mediating Golgi-association, but not its GTPase function. Notably, GBP5 expression levels vary considerably in human macrophages and inversely correlate with infectious virus yield. We demonstrate that GBP5 can be evaded by an unusual tradeoff mechanism: Naturally occurring mutations in the start codon of the viral accessory gene vpu attenuate GBP5 inhibition by increasing Env expression at the cost of Vpu function. Whether direct counteraction mechanisms or more subtle changes balancing Vpu and Env expression also affect HIV-1 inhibition by GBP5 remains to be clarified. Other open questions are whether GBP5 restricts HIV-1 in CD4+ T cells and if other GBP family members also decrease infectivity of HIV and/or additional enveloped viruses.


Composite Flexible Sensor Based on Bionic Microstructure to Simultaneously Monitor Pressure and Strain.
To achieve the human sense of touch, a strain sensor needs to be coupled with a pressure sensor to identify the compliance of the contacted material. However, monitoring the pressure-strain signals simultaneously and ensuring no coupling effect between the two signals is the technical bottleneck for the flexible tactile sensor to. Herein, a composite flexible sensor based on microstructures of lotus leaf is designed and manufactured, which integrates the capacitive pressure sensor and the resistance strain sensor into one pixel to realize the simultaneous detection of pressure and strain. The electrode layer of the capacitance sensor also plays the role of the resistance strain sensor, which greatly simplifies the structure of the composite flexible sensor and obtains the compact size to integrate more easily. The device can simultaneously detect pressure and deformation, and more importantly, there is no coupling effect between the two kinds of signals. Here, the sensor has high pressure sensitivity (0.784 kPa-1 when pressure less than 100 kPa), high strain sensitivity (gauge factor = 4.03 for strain 0-40%), and can identify materials with different compliance, which indicates the tactile ability as the human skin performs.


[Zone therapy and asthma].
Many patients with asthma seek alternative or adjunctive therapies. One such modality is reflexology. Our aim was to examine the popular claim that reflexology treatment benefits bronchial asthma. Ten weeks of either active or simulated (placebo) reflexology were compared in an otherwise blind, controlled trial of 40 patients with asthma. Objective lung function tests did not change. Subjective scores and bronchial sensitivity to histamine improved on both regimens, but no differences were found in the groups receiving active or placebo reflexology. However, a trend in favour of reflexology became significant when a supplementary analysis of symptom diaries was carried out. At the same time a significant pattern compatible with subconscious un-blinding was found. We found no evidence that reflexology has a specific effect on asthma beyond a placebo influence.


Fish consumption and stroke: a community case-control study in Asturias, Spain.
The relationship between fish consumption and stroke is controversial. Actually, a low fish consumption may protect against ischemic stroke, while a fish diet is ecologically associated with an increased risk of hemorrhagic stroke. This study seeks to examine the relationship between fish consumption and stroke in a population with a high fish consumption and stroke incidence. A population-based case-control study was performed, lasting from September 1990 to December 1991. The study comprised 440 incident cases of stroke and 473 controls between the ages of 40 and 85. Cases were defined following WHO criteria, and controls were randomly selected from the study base population. Information on fish consumption was obtained with a food frequency questionnaire. After controlling for age, energy intake and several stroke risk factors, the risk of stroke increased with the consumption of fish, chi(2) 4.12, p = 0.04. Those in the highest quintile of consumption (46 g of fish/day) had a multivariate adjusted odds ratio (OR) of 1.95 (95% CI: 1.14-3.33) as compared to those in the lowest quintile of fish consumption (11 g/ day). The risk of cerebral infarction also increased with the consumption of fish, showing an OR of 1.98 (95% CI: 1.08-3.47). Those in the highest quintile of n-3 fatty acid consumption (660 mg/day) were at borderline higher risk of stroke, with an OR of 1.76 (95% CI: 0.95-3.26), and also of cerebral infarction (OR: 1.89, 95% CI: 0.95-3.75), as compared to those in the lower quintile of n-3 fatty acids consumption (115 mg/day). Although misclassification of exposure and residual confounding by unmeasured factors cannot be ruled out, a high fish consumption was associated with an increased risk of stroke and cerebral infarction in this study. More studies should be done to clarify the effect of fish consumption on stroke and stroke subtype in order to issue recommendations regarding the consumption of fish and the risk of stroke.


Fluids in porous media. I. A hard sponge model.
The morphology of many porous materials is spongelike. Despite the abundance of such materials, simple models which allow for a theoretical description of these materials are still lacking. Here, we propose a hard sponge model which is made by digging spherical cavities in a solid continuum. We found an analytical expression for describing the interaction potential between fluid particles and the spongelike porous matrix. The diagrammatic expansions of different correlation functions are derived as well as that of grand potential. We derived also the Ornstein-Zernike (OZ) equations for this model. In contrast to Madden-Glandt model of random porous media [W. G. Madden and E. D. Glandt, J. Stat. Phys. 51, 537 (1988)], the OZ equations for a fluid confined in our hard sponge model have some similarity to the OZ equations of a three-component fluid mixture. We show also how the replica method can be extended to study our sponge model and that the same OZ equations can be derived also from the extended replica method.


Automatic location of disruption times in JET.
The loss of stability and confinement in tokamak plasmas can induce critical events known as disruptions. Disruptions produce strong electromagnetic forces and thermal loads which can damage fundamental components of the devices. Determining the disruption time is extremely important for various disruption studies: theoretical models, physics-driven models, or disruption predictors. In JET, during the experimental campaigns with the JET-C (Carbon Fiber Composite) wall, a common criterion to determine the disruption time consisted of locating the time of the thermal quench. However, with the metallic ITER-like wall (JET-ILW), this criterion is usually not valid. Several thermal quenches may occur previous to the current quench but the temperature recovers. Therefore, a new criterion has to be defined. A possibility is to use the start of the current quench as disruption time. This work describes the implementation of an automatic data processing method to estimate the disruption time according to this new definition. This automatic determination allows both reducing human efforts to locate the disruption times and standardizing the estimates (with the benefit of being less vulnerable to human errors).


PCR-induced sequence alterations hamper the typing of prehistoric bone samples for diagnostic achondroplasia mutations.
Achondroplasia (ACH) is a skeletal disorder (MIM100800) with an autosomal dominant Mendelian inheritance and complete penetrance. Here we report the screening of ancient bone samples for diagnostic ACH mutations. The diagnostic G-->A transition in the FGFR3 gene at cDNA position 1138 was detected in cloned polymerase chain reaction (PCR) products obtained from the dry mummy of the Semerchet tomb, Egypt (first dynasty, approximately 4,890-5,050 BP [before present]), and from an individual from Kirchheim, Germany (Merovingian period, approximately 1,300-1,500 BP), both of which had short stature. However, these mutations were also reproducibly observed in four ancient control samples from phenotypically healthy individuals (false-positives), rendering the reliable molecular typing of ancient bones for ACH impossible. The treatment of a false-positive DNA extract with uracil N-glycosylase (UNG) to minimize type 2 transitions (G-->A/C-->T) did not reduce the frequency of the false-positive diagnostic ACH mutations. Recently, it was suggested that ancient DNA extracts may induce mutations under PCR. Contemporary human template DNA from a phenotypically healthy individual was therefore spiked with an ancient DNA extract from a cave bear. Again, sequences with the diagnostic G-->A transition in the FGFR3 gene were observed, and it is likely that the false-positive G-->A transitions result from errors introduced during the PCR reaction. Amplifications in the presence of MnCl(2) indicate that position 1138 of the FGFR3 gene is particularly sensitive for mutations. Our data are in line with previously published results on the occurrence of nonrandom mutations in PCR products of contemporary human mitochondrial HVRI template DNA spiked with ancient DNA extracts.


Comparison of two-dimensional vs three-dimensional camera systems in laparoscopic surgery.
The lack of depth perception and spatial orientation in video vision are the drawbacks of laparoscopic surgery. The advent of a three-dimensional camera system enables surgeons to regain binocular vision and may be advantageous in complex laparoscopic procedures. We prospectively studied two groups of surgeons (with and without experiences in laparoscopic surgery) who performed a designated standardized laparoscopic task using a two-dimensional camera system (Olympus OTV-S4) vs a three-dimensional camera system (Baxter-V. Mueller VS7700) and compared their time performances. The results suggested that only experience in laparoscopic surgery had significant effect on individual's performance. We could not demonstrate any superiority of the 3D system over the 2D system. However, two-thirds of the surgeons commented that the depth perception did improve. With further refinement of the technology, the 3D system may improve its potential in laparoscopic surgery.


Complete elucidation of the late steps of bafilomycin biosynthesis in Streptomyces lohii.
Bafilomycins are an important subgroup of polyketides with diverse biological activities and possible applications as specific inhibitors of vacuolar H+-ATPase. However, the general toxicity and structural complexity of bafilomycins present formidable challenges to drug design via chemical modification, prompting interests in improving bafilomycin activities via biosynthetic approaches. Two bafilomycin biosynthetic gene clusters have been identified, but their post-polyketide synthase (PKS) tailoring steps for structural diversification and bioactivity improvement remain largely unknown. In this study, the post-PKS tailoring pathway from bafilomycin A1 (1)→C1 (2)→B1 (3) in the marine microorganism Streptomyces lohii was elucidated for the first time by in vivo gene inactivation and in vitro biochemical characterization. We found that fumarate is first adenylated by a novel fumarate adenylyltransferase Orf3. Then, the fumaryl transferase Orf2 is responsible for transferring the fumarate moiety from fumaryl-AMP to the 21-hydroxyl group of 1 to generate 2. Last, the ATP-dependent amide synthetase BafY catalyzes the condensation of 2 and 2-amino-3-hydroxycyclopent-2-enone (C5N) produced by the 5-aminolevulinic acid synthase BafZ and the acyl-CoA ligase BafX, giving rise to the final product 3. The elucidation of fumarate incorporation mechanism represents the first paradigm for biosynthesis of natural products containing the fumarate moiety. Moreover, the bafilomycin post-PKS tailoring pathway features an interesting cross-talk between primary and secondary metabolisms for natural product biosynthesis. Taken together, this work provides significant insights into bafilomycin biosynthesis to inform future pharmacological development of these compounds.


Spatial rogue waves in the actively Q-switched Nd:YAG laser under low Kerr nonlinearity.
We report the generation of spatial rogue waves in an actively Q-switched Nd:YAG laser. We observed that spatial rogue waves can emerge when the laser operates in a low-power regime below the self-focusing limit, while the lasing takes place at a large number of high-order transverse modes. These results suggest that the main mechanism leading to rogue waves generation is the modal overlap while large Kerr nonlinearity in the cavity is not a necessary factor in the process of spatial rogue waves formation. We have also investigated the spatio-temporal and coherence properties of the observed rogue waves.


Dysphagia as a symptom of anterior cervical hyperostosis - Case report.
Degenerative lesions with hyperostosis on the anterior surface of cervical spine are common in clinical practice. In addition to pain being an effect of spinal dysfunction, they sometimes cause difficulties in swallowing or speaking as well as breathing disorders. A 52-year-old farmer with 4-year history of gradually intensifying dysphagia was admitted to hospital due to inability to intake a solid food, significant weight loss, and because of the appearance of a new symptom - dysphonia. Previous conservative treatment for swallow difficulties was ineffective. CT revealed a bone excrescence on the anterior surface of two cervical vertebrae which caused an oesophageal obstruction and compression of the vocal folds. Structural abnormalities of cervical spine should be considered in differential diagnosis of symptoms from the oesophagus and upper respiratory tract, especially when a first-line conservative treatment is not effective. In these cases, surgical removal of the osteophyte is an effective way of treatment.


Carbon Monoxide: A Mild and Efficient Reducing Agent towards Atomically Precise Gold Nanoclusters.
In recent years, thiolate-protected gold nanoclusters (or thiolated Au NCs) with a core size below 2 nm have emerged as a new class of multifunctional nanoparticles because of their unique molecular-like properties and the potential to use these properties in many practical applications. A general synthesis of Au NCs may involve the use of a strong reducing agent (e.g., sodium borohydride (NaBH4 )), which often leads to the formation of mix-sized Au NCs if no delicate control is applied. To obtain atomically precise Au NCs, additional physical or chemical selection processes (e.g., high-resolution separation or size-focusing) are required, which are difficult to be scaled up or are limited to only thermodynamically stable products. By introducing a milder reducing agent - carbon monoxide (CO) - both stable and metastable thiolated Au NCs, including Au10-12 , Au15 , Au18 , Au25 , and Au29 , can be synthesized in a one-pot manner. In addition, CO reduction also enables the synthesis of a highly luminescent Au22 (SG)18 NC. Furthermore, the intermediates of Au NC growth can be tracked in the CO-reduction system due to the mild and readily stoppable nature of CO reduction. Therefore, the use of CO reduction may bring new flexibilities in designing synthetic strategies and understanding the growth mechanism of atomically precise Au NCs, which could contribute to a better design of functional Au NCs, further paving their way towards practical applications in various fields.


Characterization of a novel metagenome-derived 6-phospho-β-glucosidase from black liquor sediment.
The enzyme 6-phospho-β-glucosidase is an important member of the glycoside hydrolase family 1 (GH1). However, its catalytic mechanisms, especially the key residues determining substrate specificity and affinity, are poorly understood. A metagenome-derived gene sequence, encoding a novel 6-phospho-β-glucosidase designated Pbgl25-217, was isolated and characterized. The optimal conditions for enzymatic activity were 37°C and pH 7; Ca(2+), Mg(2+), and Mn(2+) stabilized the activity of Pbgl25-217, whereas Ni(2+), Fe(2+), Zn(2+), Cu(2+), and Fe(3+) inhibited its activity. The Km and Vmax of Pbgl25-217 were 4.8 mM and 1,987.0 U mg(-1), respectively. Seven conserved residues were recognized by multiple alignments and were tested by site-directed mutagenesis for their functions in substrate recognition and catalytic reaction. The results suggest that residues S427, Lys435, and Tyr437 act as "gatekeepers" in a phosphate-binding loop and play important roles in phosphate recognition. This functional identification may provide insights into the specificity of 6-phospho-β-glycosidases in GH1 and be useful for designing further directed evolution.


Tunneling spectroscopy of Andreev energy levels in a quantum dot coupled to a superconductor.
The coupling of a quantum dot with a BCS-type superconducting reservoir results in an intriguing system where low energy physics is governed by the interplay of two distinct phases, singlet and doublet. In this Letter we show that the spectrum of Andreev energy levels, which capture the properties of the two phases, can be detected in transport measurements with a quantum dot strongly coupled to a superconducting lead and weakly coupled to a normal metal lead. We observe phase transitions between BCS singlet and degenerate magnetic doublet states when the quantum dot chemical potential is tuned with an electrostatic gate, in good qualitative agreement with numerical renormalization group calculations.


Efficacy of low-density lipoprotein apheresis in patients with peripheral arterial occlusive disease undergoing hemodialysis treatment.
Low-density lipoprotein (LDL) apheresis is effective in the treatment of peripheral arterial occlusive disease (PAOD). In the present study, we attempted to determine whether LDL apheresis is effective even for PAOD patients undergoing hemodialysis, who tend to be refractory to any treatment, and if so, to determine the mechanism of its efficacy. Serum levels of lipids and vascular growth factors, leg symptom, and endothelium-dependent vasodilation were investigated before and after 10 sessions of LDL apheresis in 11 PAOD patients undergoing hemodialysis. Serum levels of total cholesterol, LDL cholesterol, and triglyceride exhibited drastic reduction, which completely disappeared 4 weeks after the final apheresis. Resting leg pain was improved in 6 cases even 4 weeks after final apheresis. Endothelium-dependent vasodilation was significantly increased 4 weeks after final apheresis (1.6 +/- 0.6 to 4.7 +/- 1.0%, p < 0.05). Levels of vascular growth factors, hepatocyte growth factor and vascular endothelial growth factor were not changed during treatment. These findings suggested that LDL apheresis is effective even in PAOD patients undergoing hemodialysis. Our findings suggest that its mechanisms of efficacy include improvement of vascular endothelial dysfunction, in addition to drastic but acute reduction of lipid levels. Since PAOD patients undergoing hemodialysis tend to be resistant to any treatment and are at high risk for lower-extremity amputation, LDL apheresis could be a useful strategy for treatment of them.


The effect of sucralfate on serum lipids and lipoproteins in normal volunteers [corrected].
Sucralfate is used in the treatment and prophylaxis of peptic ulcer disease. One possible mechanism of action is the binding of bile acids. Because the absorption of dietary fat and cholesterol is dependent on the presence of bile acids in the small intestines, sucralfate therapy may produce changes in serum lipoprotein composition qualitatively similar to bile acid sequestrants, such as cholestyramine, which reduce serum cholesterol levels. Although changes in total serum cholesterol have not been reported in sucralfate efficacy studies, the effect of sucralfate on serum lipoprotein composition has not been specifically addressed. The purpose of this study was to prospectively examine the effect of sucralfate on serum lipids and lipoproteins in normal volunteers. Eight healthy volunteers (six men, two women) were recruited for this 10-week study. Drugs known to affect cholesterol levels were not permitted before or during the study. Diet composition during the study period was unaltered from before the study. Subjects took 1 g sucralfate orally 1 hour before meals and at bedtime (four times a day) for 8 weeks, followed by a 2-week washout period. Fasting blood samples were obtained at baseline and weekly, and were analyzed for serum total and HDL cholesterol and for triglycerides. Levels of LDL cholesterol were estimated. After eight weeks of sucralfate, HDL cholesterol increased from baseline by 2.5 mg/dL (6.6%, from 37.6 +/- 9.5 to 40.1 +/- 8.69 mg/dL), and LDL cholesterol decreased by 7.6 mg/dL (6.4%, from 134 +/- 28.1 to 125.4 +/- 34.1). Total cholesterol decreased by 3.5 mg/dL (1.8%, from 192.9 +/- 34.3 to 189.4 +/- 37.2 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)


Cost-effectiveness analysis of a lung cancer screening programme in Spain.
To evaluate the cost-effectiveness of the implementation of national lung cancer (LC) screening programme (SP) in a high-risk population from the perspective of the Spanish National Health System (NHS). A cost-effectiveness analysis for a LC SP was carried out on a lifetime horizon. A Markov model was designed that assumed two scenarios, one with the implementation of the SP and another one without it. Effectiveness and cost of LC management, diagnosis and screening were included in the different health states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate its robustness. A discount rate was set at 3% both for effectiveness and cost. In the base-case, an increase of 4.80 quality-adjusted life years (QALY) per patient was obtained, resulting in an incremental cost-effectiveness ratio of €2345/QALY. Probabilistic sensitivity analysis showed the national LC SP to be cost-effective in 80% of cases (probability=0.8) for a willingness-to-pay threshold equivalent to the gross domestic product per capita in Spain, which was set at €25 854/QALY in 2018 based on the per capita income of Spain. The sensitivity analysis indicates that the obtained results are robust in terms of changes in the presentation rates and costs, and the cost-effectiveness thresholds. This analysis suggests that the implementation of a LC SP in the high-risk Spanish population would be a cost-effective strategy for the Spanish NHS.


How to link organizational resilience to transformational entrepreneurship behavior as theoretical framework gap - A systematic literature review.
Background: Numerous enterprises face great challenges during uncertain economic conditions. This is particularly true for micro, small, and medium-scale companies, which are slumped against disruption from the COVID-19 pandemic-owing to lockdowns, decreased demand, and a disrupted supply chain. This has impacted the economy worldwide but also the social community and the environment that forms its ecosystem. Organizational resilience allows for socio-economic growth and enterprises to build environmental sustainability and balanced community development. Therefore, the behavior of companies must be transformed in building entrepreneurship to encourage socio-economic growth. Methods: We conducted an advanced search on Business Source Premier, ABI/INFORM (ProQuest), Emerald Insight, and Web of Science database between March and June 2022. We screened the bibliographies of the articles from the database search using a set of inclusion criteria such as studies with quantitative design with unit analysis population sample based microfinance institutions and cooperative-based microfinance institutions, MSEs, and MSMEs as well as other industries such as travel agents, property, restaurants, food and beverages, manufacturing and plantations; exploration of transformational entrepreneurship behavior and organizational resilience determinant factors and conceptual manuscripts written in English; and published between 2005 till 2019 for transformational entrepreneurship and 1997 till 2000 for organizational resilience. Results: This study reviewed 22 articles focusing on the role and influence of organizational resilience on transformational entrepreneurship behavior from a lens that posits the importance of organizational resilience in the face of uncertain economic turbulence. The orientation of entrepreneurship behavior has been neglected in research so far. This systematic literature review study reveals important research gaps, such as the influence of organizational resilience in promoting the development of transformational entrepreneurship behavior and the determinants that build organizational resilience. Conclusions: Research related to a company's transformational entrepreneurship behavior offers a broad area of scientific research; hence, encouraging further investigation is necessary.


Fecal Microbiota Transplantation as a Novel Therapy for Ulcerative Colitis: A Systematic Review and Meta-Analysis.
Variation in clinical evidence has prevented the adoption of fecal microbiota transplantation (FMT) in patients with ulcerative colitis (UC). We aimed to conduct a systematic review and meta-analysis to determine the efficacy and safety of FMT in UC.A systematic literature search was performed in 5 electronic databases from inception through September 2015. Inclusion criteria were reports of FMT in patients with UC. Studies were excluded if they did not report clinical outcomes or included patients with infections. Clinical remission (CR) was defined as the primary outcome.Eleven studies (2 randomized controlled trials (RCTs), 1 open-label case-control study, and 8 cohort studies) with a total of 133 UC patients were included in the analysis. In 11 studies (including 8 noncontrol cohort studies and the treatment arms of 3 clinical control trials), the pooled proportion of patients who achieved CR was 30.4% (95% CI 22.6-39.4%), with a low risk of heterogeneity (Cochran Q test, P = 0.139; I = 33%). A subgroup analysis suggested that no difference in CR was detected between upper gastrointestinal delivery versus lower gastrointestinal delivery. Furthermore, subgroup analysis revealed that there was no difference in CR between single infusion versus multiple infusions (>1) of FMT. All studies reported mild adverse events.FMT is potentially useful in UC disease management but better-designed RCTs are still required to confirm our findings before wide adoption of FMT is suggested. Additionally, basic guidelines are needed imminently to identify the right patient population and to standardize the process of FMT.


A uniform strain criterion for trabecular bone adaptation: do continuum-level strain gradients drive adaptation?
In this paper, it is postulated that the apparent density of trabecular bone adapts so that continuum-level strains within the bone are uniform and, as a consequence, spatial strain gradients within the bone/marrow continuum are minimized. The feasibility of a uniform strain criterion was tested using computational finite-element analysis of the proximal femur. We demonstrated that (1) this criterion produced a realistic apparent density distribution in the proximal femur, (2) the solutions for apparent density were convergent and unique, (3) predicted apparent densities compared well to experimental measurements, and (4) strain gradients within the bone/marrow continuum were reduced substantially. Thus, a possible goal of trabecular bone adaptation may be the reduction of strain gradients within the bone/marrow continuum. Osteocytes within the bone tissue and bone cells on the surface of a trabeculum are mechanosensitive and play a role in bone adaptation. In addition, the bone marrow is rich in osteoprogenitor cells near the bone surface that are mechanosensitive. Strain gradients within bone/marrow continuum cause pressure gradients in the marrow, causing extracellular fluid flow which could stimulate osteoprogenitor cells and contribute to bone adaptation.


Antibiotic resistance of prevalent Salmonella and Shigella strains in northwest Ethiopia.
Salmonella and Shigella strains were isolated prospectively from in- and outpatient specimens of the Gondar College teaching hospital over a two year period, from June 1994 to May 1996. Of 7993 miscellaneous specimens cultured, 80 yielded Salmonella and 147 Shigella. Serogroup B dominated among the salmonella, accounting for 61% of isolates, followed by S. typhi (21%). S. flexneri (58.5%) and S. dysenteriae (36.7%) were the most frequently isolated species among the Shigella. Results of sensitivity testing to five commonly used antibiotics in the area: ampicillin, chloramphenicol, gentamicin, tetracycline and cotrimoxazole, showed multiple drug resistance among the isolates of both salmonella and shigella. Only 4% of shigella were sensitive to all five antibiotics screened for in the study. Overall sensitive of shigella isolates to individual antibiotics was 8.8% to tetracycline, 10% to ampicillin, 28% to co-trimoxazole and 98% to gentamicin. No resistance was observed to nalidixic acid among 108 shigella strains tested for this antibiotic. The continued sensitivity of S. typhi to chloramphenicol, cotrimoxazole, ampicillin and the other commonly used antibiotics is noted. It is recommended that nalidixic acid be introduced into the area under strict regulation for treatment of severe cases of shigella dysentery, an illness which is highly endemic in the region and the cause of occasional epidemics with high mortality.


Phosphorylation of Capsaicinoid Derivatives Provides Highly Potent and Selective Inhibitors of the Transcription Factor STAT5b.
Design approaches for inhibitors of protein-protein interactions are rare, but highly sought after. Here, we report that O-phosphorylation of simple derivatives of the natural products dihydrocapsaicin and N-vanillylnonanamide leads to inhibitors of the SH2 domain of the transcription factor STAT5b. The most potent molecule is obtained from dihydrocapsaicin in only three synthetic steps. It has submicromolar affinity for the SH2 domain of STAT5b (Ki = 0.34 μM), while displaying 35-fold selectivity over the highly homologous STAT5a (Ki = 13.0 μM). The corresponding pivaloyloxymethyl ester inhibits STAT5b with selectivity over STAT5a in human tumor cells. Importantly, it inhibits cell viability and induces apoptosis in human tumor cells in a STAT5-dependent manner. Our data validate O-phosphorylation of appropriately preselected natural products or natural product derivatives as a semirational design approach for small molecules that selectively inhibit phosphorylation-dependent protein-protein interaction domains in cultured human tumor cells.


An optical measurement method for the simultaneous assessment of respiration and heart rates in preterm infants.
Many conventional medical monitoring devices, while not technically invasive, are nevertheless obtrusive insofar as they require contact with the patient. This obtrusiveness sometimes poses problems in daily clinical practice. The need for contact with electrodes or transducers is particularly relevant in the case of patients recovering in intensive care units where continuous monitoring is required, in turn requiring continuous direct transducer contact for prolonged periods. Among the many physiological parameters commonly acquired, the respiratory and the cardiac rates of the patients are of primary importance. Typically these two parameters are measured respectively using spirometry and electrocardiography (ECG), both involving obtrusive measurement systems requiring contact with the patient with an air conduit and electrodes. This paper presents an optical measurement method for the simultaneous assessment of respiration and heart rates based on the measurement of the chest wall movements, associated with inspiratory/expiratory activities of the lungs and by the mechanical pumping action of the heart. The measurement method has been adapted for use with preterm infants and it has been applied to 55 patients recovering in a Neonatal Intensive Care Unit. The method is based on the use of a laser Doppler vibrometer (LDVi) pointed at the left, ventral thoracic surface of the patient. LDVi-based measures of respiration and heart rate have been simultaneously acquired for each patient, in parallel with the same quantities acquired using conventional reference instrumentation (flow-meter and ECG) for comparison purposes. Results show that for respiration rate, differences with respect to the spirometer data are <3%, while for the cardiac rate they are <6% with respect to ECG data. The method proposed in this paper has the advantage of requiring no contact with the patient. Moreover, it supports, by means of a single instrument, the simultaneous measurement of respiration and heart rates, thus reducing the burden of the number of electrodes, transducers, and other instrumentation that must be applied to the patient--a consideration that is particularly important in the Neonatal Intensive Care Unit. In addition to the measurement of respiration rate, we also describe the sensitivity of the LDVi method in detecting key respiration events (irregular inspiration/expiration cycles, apneas, and hiccups) which are relevant to clinical monitoring.


Estrogen receptor-related receptor γ uppresses hypoxia-induced angiogenesis by regulating VEGFA in endometrial cancer.
Estrogen receptor-related receptor γ (ERRγ), is implicated in cancer cell proliferation and metastasis. The function of ERRγ in tumor angiogenesis, however, is to be revealed. This study was designed to elaborate the regulatory effect of ERRγ on angiogenesis in endometrial cancer (EC). Immunohistochemistry (IHC) was adopted to determine the protein expression of ERRγ, VEGFA, CD31 and hypoxia-inducible factor-1 (HIF-1) in tumor tissues. HEC-1A cells stably expressing ERRγ were established bytransfection, and then an endothelial cell tube formation assay was performed. CCK-8 assay was employed for cell viability, and wound healing assay for cell migration ability. Besides, western blot, ELISA and qRT-PCR were used to examine the VEGFA expression. After hypoxia treatment of ERRγ overexpressing HEC-1A cells, the ERRγ expression and VEGFA expression were determined by western blot. Finally, EC xenografts in nude mice were constructed by subcutaneous injection of ERRγ stably expressing HEC-1A cells and control HEC-1A cells. IHC results revealed a negative correlation between the expression of ERRγ and VEGFA in EC tissues. ERRγ overexpression significantly decreased the level of HIF-1 in tumor tissue of nude mice. ERRγ overexpression down-regulated inhibited angiogenesis capability and inhibited the proliferation and migration of HEC-1A cells. Furthermore, ERRγ expression was suppressed under the condition of hypoxia while restoration of ERRγ partially inhibited hypoxia-induced VEGFA expression in HEC-1A cells. ERRγ is an angiogenesis suppressor and involved in hypoxia-induced VEGFA expression in EC. Hence, ERRγ might be a promising antiangiogenic target for human EC.


Familial hypercholesterolemia in children.
This review provides an update on recent advances in the diagnosis and management of children with familial hypercholesterolemia. A large cross-sectional cohort study of paediatric familial hypercholesterolemia demonstrated that affected children had a 5-fold more rapid increase of carotid arterial wall intima-media thickness during childhood years than their affected siblings. This faster progression led to a significant deviation in terms of intima-media thickness from the age of 12 years and onwards. Low-density lipoprotein cholesterol was a strong and independent predictor of carotid artery intima-media thickness in these children, which confirms the pivotal role of low-density lipoprotein cholesterol for the development of atherosclerosis. In this condition lipid lowering by statin therapy is accompanied by carotid intima-media thickness regression in familial-hypercholesterolemic children, which suggests that initiation of low-density lipoprotein cholesterol-reducing medication in childhood already can inhibit or possibly reduce the faster progression of atherosclerosis. Furthermore, these trials demonstrated that statins are safe and do not impair growth or sexual development in these children. Conversely, products containing plant sterols reduced low-density lipoprotein cholesterol levels by 14%, but did not improve endothelial dysfunction as assessed by flow-mediated dilatation. Children with familial hypercholesterolemia clearly benefit from lipid-lowering strategies. Statins are safe agents and have been proven to reduce elevated low-density lipoprotein cholesterol levels significantly. In addition, statins improve surrogate markers for atherosclerosis. Therefore these agents should become the pivotal therapy in children with familial hypercholesterolemia.


Non-Covalent Functionalization of Carbon Nanotubes for Electrochemical Biosensor Development.
Carbon nanotubes (CNTs) have been widely studied and used for the construction of electrochemical biosensors owing to their small size, cylindrical shape, large surface-to-volume ratio, high conductivity and good biocompatibility. In electrochemical biosensors, CNTs serve a dual purpose: they act as immobilization support for biomolecules as well as provide the necessary electrical conductivity for electrochemical transduction. The ability of a recognition molecule to detect the analyte is highly dependent on the type of immobilization used for the attachment of the biomolecule to the CNT surface, a process also known as biofunctionalization. A variety of biofunctionalization methods have been studied and reported including physical adsorption, covalent cross-linking, polymer encapsulation etc. Each method carries its own advantages and limitations. In this review we provide a comprehensive review of non-covalent functionalization of carbon nanotubes with a variety of biomolecules for the development of electrochemical biosensors. This method of immobilization is increasingly being used in bioelectrode development using enzymes for biosensor and biofuel cell applications.


[Giant cell tumor of the C2 colonized by an aneurismal bone cyst. Report of case].
Giant cell tumor is colonized by aneurismal bone cyst in only 15% of cases and cervical localisation accounts for less than 1% of giant cell tumors. We are reporting a rare case of a C2 hypervascularized giant cell tumor colonized by an aneurismal bone cyst treated with an effective preoperative Onyx embolization followed by a full tumor resection. The patient experienced a moderate cervical spine injury 2 months prior admission followed by a progressive stiff neck and cervicalgia. CT and MRI identified a lytic lesion of the body and lateral masses of the C2 with encasement of both vertebral arteries. The angiography showed a hypervascularization of the lesion from the vertebral and external carotid arteries as well as a thrombosis of the V3 segment of the right vertebral artery at the C1 level. A posterior occipito-C3/C4 fixation and a tumor biopsy were performed. Histopathological examination concluded to a giant cell tumor colonized by an aneurismal bone cyst. Three weeks later, the patient developed a right upper extremity deficit. The MRI showed an increased C1-C2 stenosis and an increase of the hypervascularization. Three sessions of embolization by the onyx were performed. During surgery a near total tumor devascularisation was observed and a complete resection of the tumor was achieved through an anterolateral approach. Reconstruction consisted of a cementoplasty of the C2 body and odontoïd process with an anterior C3-prosthesis plate. The postoperative course was uneventful.


Incentives and opportunism: from the carrot to the stick.
Cooperation in public good games is greatly promoted by positive and negative incentives. In this paper, we use evolutionary game dynamics to study the evolution of opportunism (the readiness to be swayed by incentives) and the evolution of trust (the propensity to cooperate in the absence of information on the co-players). If both positive and negative incentives are available, evolution leads to a population where defectors are punished and players cooperate, except when they can get away with defection. Rewarding behaviour does not become fixed, but can play an essential role in catalysing the emergence of cooperation, especially if the information level is low.


Towards culturally appropriate assessment of Aboriginal and Torres Strait Islander social and emotional well-being.
Identification of need for specialist assessment and the use of relevant cultural information to inform mental health assessment and care are two key factors in improving Aboriginal and Torres Strait Islander access to and experience of mental health care. This paper describes the Here and Now Aboriginal Assessment tool (HANAA) and the Cultural Information Gathering Tool (CIGT), two instruments developed to be used respectively by non-mental health clinicians and Aboriginal and Torres Strait Islander mental health workers. Following widespread consultations and feedback, two independent groups of mental health clinicians based in Western Australia and Queensland were involved in developing the HANAA and CIGT. Both the HANAA and CIGT fill unmet needs in terms of instruments that can be used by non-specialists working with Aboriginal and Torres Strait Islander people. Preliminary use of the HANAA and CIGT suggests that they are well received, easy to deploy and effective instruments that promote cultural security and communication with Aboriginal and Torres Strait Islander people.


Gaze patterns during presentation of fixed and random phase radial frequency patterns.
Radial frequency (RF) patterns, circles which have had their radius modulated as a function of their polar angle, have been used in the examination of the integration of contour information around closed contour patterns. Typically, these patterns have been presented in a random orientation from trial-to-trial in order to maintain spatial uncertainty as to the location of the deformation on the pattern, as it may affect observer strategy and performance. However, the effect of fixed and random orientation (phase) on observer gaze strategies used to discriminate RF patterns has not been directly tested. This study compared fixation patterns across four conditions: fixed phase single cycle; random phase single cycle; fixed phase three cycle; and random phase three cycle RF3 patterns. The results showed that observers fixated on the known location of deformation for the fixed phase single cycle condition but used a more central fixation for the other three conditions. This strategy had a significant effect on observer thresholds for the fixed phase single cycle condition, with greater adherence to the strategy resulting in lower thresholds. It was also found that for the single cycle patterns observers tended to fixate on different locations on the pattern: on the maximum orientation difference from circular for the fixed phase pattern; and on the point of maximum curvature for the random phase pattern. These differences in gaze patterns are likely driven by the underlying local or global processing of the fixed or random phase single cycle patterns, respectively.


Impact of the New Glomerular Filtration Rate Formulas on Kidney Function Assessment in Living Kidney Donors and Candidates.
New estimated glomerular filtration rate (GFR) equations that do not include a race coefficient have been created to better estimate kidney function, reduce inequities in kidney disease care, and improve the historically limited access to transplantation in African Americans. The impact of these new equations on estimated GFR (eGFR) in living donors pre- and postdonation is not known. To address this, we conducted a single-center retrospective cohort study of 150 kidney donors and donor candidates. We calculated pre- and postdonation eGFR using the old and new equations and compared them with measured GFR by 2.8 mCi Tc-99m diethylene triamine penta-acetic acid clearance (mGFRDTPA) and 24-h creatinine clearance (mGFRCrCl). We evaluated the impact of the new equations on donation eligibility and postdonation eGFR. We found that using the new eGFR equations resulted in higher predonation eGFR compared with the old equations but remained significantly lower than mGFRDTPA and mGFRCrCl. We also found that using the new eGFR equations would not exclude any potential donors based on our center's GFR criteria for donation. At 6 mo postdonation, the new equations resulted in higher eGFR values compared with the old equations. The new eGFR equations continue to underestimate GFR in healthy donor candidates but would not exclude any potential donors from donation and resulted in higher eGFR predonation and postdonation in a predominantly White population. eGFR equations designed specifically for potential kidney donors are still needed for better kidney function assessment.


Trained-user opinion about Welfare Quality measures and integrated scoring of dairy cattle welfare.
The Welfare Quality (WQ) protocol for on-farm dairy cattle welfare assessment describes 27 measures and a stepwise method for integrating values for these measures into 11 criteria scores, grouped further into 4 principle scores and finally into an overall welfare categorization with 4 levels. We conducted an online survey to examine whether trained users' opinions of the WQ protocol for dairy cattle correspond with the integrated scores (criteria, principles, and overall categorization) calculated according to the WQ protocol. First, the trained users' scores (n = 8-15) for reliability and validity and their ranking of the importance of all measures for herd welfare were compared with the degree of actual effect of these measures on the WQ integrated scores. Logistic regression was applied to identify the measures that affected the WQ overall welfare categorization into the "not classified" or "enhanced" categories for a database of 491 European herds. The smallest multivariate model maintaining the highest percentage of both sensitivity and specificity for the "enhanced" category contained 6 measures, whereas the model for "not classified" contained 4 measures. Some of the measures that were ranked as least important by trained users (e.g., measures relating to drinkers) had the highest influence on the WQ overall welfare categorization. Conversely, measures rated as most important by the trained users (e.g., lameness and mortality) had a lower effect on the WQ overall category. In addition, trained users were asked to allocate criterion and overall welfare scores to 7 focal herds selected from the database (n = 491 herds). Data on all WQ measures for these focal herds relative to all other herds in the database were provided. The degree to which expert scores corresponded to each other, the systematic difference, and the correspondence between median trained-user opinion and the WQ criterion scores were then tested. The level of correspondence between expert scoring and WQ scoring for 6 of the 12 criteria and for the overall welfare score was low. The WQ scores of the protocol for dairy cattle thus lacked correspondence with trained users on the importance of several welfare measures.


[Intertypic antigenic determinants of intracellular proteins of different poliovirus serotypes].
Antibody against intracellular virus-specific proteins was produced by immunization of monkeys with extracts of cells infected with poliovirus of one of the three serotypes. Interactions of homotypic and heterotypic antibodies with labeled intracellular virus-specific proteins were studied. Immune complexes formed at this interaction were adsorbed on the surface of Staphylococcus aureus (strain Cowan I) cells, and the virus-specific proteins contained in these complexes were then analysed by polyacrylamide gel electrophoresis. The experimental results indicate the occurrence of identical (or close) antigenic determinants at least in the majority of similar intracellular proteins of polioviruses of the three serotypes.


Rate-dependent class III antiarrhythmic action, negative chronotropy, and positive inotropy of a novel Ik blocking drug, UK-68,798: potent in guinea pig but no effect in rat myocardium.
The electromechanical effects of UK-68,798 (UK), a novel class III antiarrhythmic drug, were studied in guinea pig and rat papillary muscles (PMs) and atria in vitro using conventional microelectrode technique. UK (10(-8)-10(-6) M) prolonged the action potential duration (APD) by 21-58% and effective refractory period in parallel, without affecting the resting potential or maximum rate of depolarization in guinea pig PM stimulated at 1 Hz. UK increased the contractile force without prolonging the time to peak force or relaxation. In comparison, 5 x 10(-5) M d-sotalol was needed to induce the same electrophysiological effects as 10(-8) M UK. UK prolonged the APD significantly less at 2 Hz than at 1 and 0.5 Hz. Early afterdepolarizations (EADs) developed in 2 of 11 preparations after 10(-6) M at 0.5 Hz. No reversal of drug effect was seen after up to 2 h washout. UK (10(-9)-10(-5) M) reduced the spontaneous heart rate and prolonged the sinus node recovery time of guinea pig right atria. No effects on rat PM or atria, even after 10(-5) M, indicate a selective action of UK on the delayed rectifying outward potassium current, Ik. These results indicate a potent and selective, rate-dependent class III antiarrhythmic action of UK-68,798 linked with positive inotropy. Increased APD, bradycardia, and induction of EADs, however, represent a potential arrhythmogenic combination.


Applications of a blood-brain barrier technology platform to predict CNS penetration of various chemotherapeutic agents. 1. Anti-infective drugs.
Except for a few well-documented CNS therapeutics, quantitative data on blood-brain barrier (BBB) permeation is incomplete, unreliable or nonexistent and this is a major impediment in BBB modeling. Furthermore, only the passive diffusion component is generally taken into account. Three techniques of modeling (in vivo, in vitro and in silico) were set up and compared. The in silico predicted permeation of 287 anti-infective drugs has been faced to clinical observations. Good correlations were observed between in vitro permeability coefficients, influx transfer coefficients from in vivo studies and Pe scores from the computational model. High Pe score values are associated with an increase of reported CNS side effects.


Living apart together-bacterial volatiles influence methanotrophic growth and activity.
Volatile organic compounds play an important role in microbial interactions. However, little is known about how volatile-mediated interactions modulate biogeochemical processes. In this study, we show the effect of volatile-mediated interaction on growth and functioning of aerobic methane-oxidizing bacteria, grown in co-culture with five different heterotrophs. Both growth and methane oxidation of Methylobacter luteus were stimulated by interaction with specific heterotrophs. In Methylocystis parvus, we observed significant growth promotion, while methane oxidation was inhibited. Volatolomics of the interaction of each of the methanotrophs with Pseudomonas mandelii, revealed presence of a complex blend of volatiles, including dimethylsulfide, dimethyldisulfide, and bicyclic sesquiterpenes. Although the ecological role of the detected compounds remains to be elucidated, our results provide unprecedented insights into interspecific relations and associated volatiles for stimulating methanotroph functioning, which is of substantial environmental and biotechnological significance.


Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity.
Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N-methylnicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme's active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic nicotinamide binding pocket via π-π stacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell proliferation of the HSC-2 human oral cancer cell line.


Peripartum metabolic profiles in a Holstein dairy herd with alarm level prevalence of subclinical ketosis detected in early lactation.
The aim of this study was to characterize peripartum metabolic profiles, including the insulin sensitivity index, in cows diagnosed with subclinical ketosis (SCK) in the early stage of lactation. Cows that calved from January 2011 through December 2014 on a dairy farm with alarm level prevalence of SCK in Hokkaido, Japan (n = 175) were used. Blood and body condition scores (BCS) were obtained at regular health examinations in 2 consecutive periods, the first between 14 and 2 d before parturition, and the second between 3 and 14 d after parturition. Animals were divided into 3 groups at postpartum sampling: an SCK group with 35 multiparous and 15 primiparous cows having β-hydroxybutyrate (BHBA) concentrations ≥ 1.2 mM without clinical signs, a disease group of 36 multiparous and 9 primiparous cows that received treatment between parturition and postpartum sampling, and a control group consisting of 49 multiparous and 31 primiparous cows with BHBA concentrations < 1.2 mM. The prepartum revised quantitative insulin sensitivity check index was significantly lower in the multiparous SCK and disease groups than in the control group, demonstrating decreased insulin sensitivity in these cows, but not in primiparous cows. The prepartum BCS was significantly higher only in the multiparous SCK and disease groups. The prepartum apolipoprotein B-100 (ApoB-100) concentration was significantly decreased in the multiparous disease group, suggesting hepatic lipidosis. Conversely, primiparous cows had a higher prepartum ApoB-100 concentration. Prepartum decreased insulin sensitivity in the multiparous SCK and disease groups was considered to facilitate progression to SCK after calving.


Enzootic occurrence of chloramphenicol-resistant Salmonella typhimurium var copenhagen in calf population.
Chloramphenicol (CP)-resistant Salmonella typhimurium var copenhagen was frequently isolated (44.1 to 76.7%) from dead, diseased, and healthy calves on 3 farms in 1973 in northern Japan. On 2 of the farms, CP-resistant salmonella appeared suddenly during an epizootic of salmonella infection, and persisted. Of 87 CP-resistant to tetracycline (TC), streptomycin (SM), and sulfonamides (SA), and the remaining 13 isolates from dead calves on a farm were resistant to TC, SM, SA, and kanamycin (KM). Resistance patterns of all CP-resistant isolates were transferred completely.


Recombinant vaccine-induced protection against the highly pathogenic simian immunodeficiency virus SIV(mac251): dependence on route of challenge exposure.
Vaccine protection from infection and/or disease induced by highly pathogenic simian immunodeficiency virus (SIV) strain SIV(mac251) in the rhesus macaque model is a challenging task. Thus far, the only approach that has been reported to protect a fraction of macaques from infection following intravenous challenge with SIV(mac251) was the use of a live attenuated SIV vaccine. In the present study, the gag, pol, and env genes of SIV(K6W) were expressed in the NYVAC vector, a genetically engineered derivative of the vaccinia virus Copenhagen strain that displays a highly attenuated phenotype in humans. In addition, the genes for the alpha and beta chains of interleukin-12 (IL-12), as well as the IL-2 gene, were expressed in separate NYVAC vectors and inoculated intramuscularly, in conjunction with or separate from the NYVAC-SIV vaccine, in 40 macaques. The overall cytotoxic T-lymphocyte (CTL) response was greater, at the expense of proliferative and humoral responses, in animals immunized with NYVAC-SIV and NYVAC-IL-12 than in animals immunized with the NYVAC-SIV vaccine alone. At the end of the immunization regimen, half of the animals were challenged with SIV(mac251) by the intravenous route and the other half were exposed to SIV(mac251) intrarectally. Significantly, five of the eleven vaccinees exposed mucosally to SIV(mac251) showed a transient peak of viremia 1 week after viral challenge and subsequently appeared to clear viral infection. In contrast, all 12 animals inoculated intravenously became infected, but 5 to 6 months after viral challenge, 4 animals were able to control viral expression and appeared to progress to disease more slowly than control animals. Protection did not appear to be associated with any of the measured immunological parameters. Further modulation of immune responses by coadministration of NYVAC-cytokine recombinants did not appear to influence the outcome of viral challenge. The fact that the NYVAC-SIV recombinant vaccine appears to be effective per se in the animal model that best mirrors human AIDS supports the idea that the development of a highly attenuated poxvirus-based vaccine candidate can be a valuable approach to significantly decrease the spread of human immunodeficiency virus (HIV) infection by the mucosal route.


Dose-response meta-analysis of differences in means.
Meta-analytical methods are frequently used to combine dose-response findings expressed in terms of relative risks. However, no methodology has been established when results are summarized in terms of differences in means of quantitative outcomes. We proposed a two-stage approach. A flexible dose-response model is estimated within each study (first stage) taking into account the covariance of the data points (mean differences, standardized mean differences). Parameters describing the study-specific curves are then combined using a multivariate random-effects model (second stage) to address heterogeneity across studies. The method is fairly general and can accommodate a variety of parametric functions. Compared to traditional non-linear models (e.g. E max, logistic), spline models do not assume any pre-specified dose-response curve. Spline models allow inclusion of studies with a small number of dose levels, and almost any shape, even non monotonic ones, can be estimated using only two parameters. We illustrated the method using dose-response data arising from five clinical trials on an antipsychotic drug, aripiprazole, and improvement in symptoms in shizoaffective patients. Using the Positive and Negative Syndrome Scale (PANSS), pooled results indicated a non-linear association with the maximum change in mean PANSS score equal to 10.40 (95 % confidence interval 7.48, 13.30) observed for 19.32 mg/day of aripiprazole. No substantial change in PANSS score was observed above this value. An estimated dose of 10.43 mg/day was found to produce 80 % of the maximum predicted response. The described approach should be adopted to combine correlated differences in means of quantitative outcomes arising from multiple studies. Sensitivity analysis can be a useful tool to assess the robustness of the overall dose-response curve to different modelling strategies. A user-friendly R package has been developed to facilitate applications by practitioners.


Immunosuppression in Solid-Organ Transplantation: Essentials and Practical Tips.
A multidisciplinary team approach is essential for successful management of patients with solid-organ transplant. Transplant nursing encompasses care and support of transplant recipients as well as caregivers and organ donors through all phases of transplantation, from pretransplant evaluation to posttransplant recovery and maintenance. The field of solid-organ transplantation has advanced rapidly, and new treatments continue to emerge. Nurses who are responsible for the care of transplant recipients should have a knowledge base in transplant immunology and pharmacology. This review discusses mechanism of action, indication, side effects, and drug interactions of commonly used immunosuppressive medications in solid-organ transplantation. Nonoral routes of drug administration, therapeutic drug monitoring, and patient monitoring strategies are also included as practical tips for bedside nurses who are responsible for delivery of direct patient care and education of patients and their caregivers. This review focuses on the following medications: antithymocyte globulins, basiliximab, alemtuzumab, corticosteroids, tacrolimus, cyclosporine, azathioprine, mycophenolate mofetil/mycophenolate sodium, sirolimus, everolimus, belatacept, intravenous immunoglobulin, and rituximab.


Assessment of Knowledge, Attitude, and Disposal Practice of Unused and Expired Pharmaceuticals in Community of Adigrat City, Northern Ethiopia.
Medicines have become part of our day-to-day life. Due to different reasons, patients may not use all the medications dispensed to them. The storage of drugs at home promotes self-medication, which results in variety of adverse consequences. Global growth in health-seeking awareness and behavior among people has resulted in increment of medicine consumption over years. However, Ethiopians have little awareness about proper disposal of unused and expired pharmaceuticals. Besides, large quantities remain unused or expired since not all medications given to the consumers are consumed. Hence, this study could serve as an indicator for the country policy makers concerning pharmaceutical waste management. To assess knowledge, attitude, and disposal practice of unused and expired pharmaceuticals in the community of Adigrat city, Tigray, Ethiopia, 2019. Methodology. A cross-sectional study was conducted among 359 respondents from the residents of Adigrat city. Semistructured questionnaires, which focused on knowledge, attitudes, and disposal practices for unused and expired medications, were used to collect data from respondents. Epi-data 3.0 suite and the statistical package for social sciences (SPSS) version 20 were used in data entry and analysis. All of the 359 returned questionnaires were valid for data entry and analysis. Of the 359 respondents, 57.7% were men and the majority (93%) were Orthodox Christians. Almost half of the respondents (50.14%) have good knowledge concerning the disposal of unused and expired pharmaceuticals. Most (82.2%) of the respondents have a positive attitude towards the disposal of unused and expired pharmaceuticals. Around fifty-two (52.4) of the respondents had unused medicines stored at home, with analgesics being the most common (41.5%). Around three-quarters (75.2%) and 63% of the respondents discarded unused and expired medicines in the garbage bins, respectively. Although the majority of the respondents had a positive attitude towards the disposal of unused and expired medications, almost half of the sample population were unaware of proper disposal practices. Furthermore, less were inclined to practice proper disposal of unused and expired medications in the city. Therefore, we recommend further studies that focus on how the disposal attitude of the population can influence their knowledge and practice of the disposal of unused and expired medications.


Role of right atrial receptors in the control of drinking in the rat.
Balloons were implanted at the junction of the superior vena cava and right atrium of the rat. Inflation of the balloon stretched the vein-atrial junction but did not cause a change in either arterial or central venous blood pressure. Inflating the balloon attenuated spontaneous night-time water intake and the drinking responses to 24 h water deprivation and subcutaneous (s.c.) isoprenaline (10 micrograms/kg body wt.). Water intake after I.P. hyperoncotic colloid (polyethylene glycol 20 M) was virtually abolished when the balloon was inflated immediately before giving access to water (4 h after injection). Inflating the balloon had no effect on drinking following I.V. hypertonic saline (5 ml 2M-NaCl/kg body wt.). These results support the hypothesis that volume receptors on the right side of the heart are involved in controlling water intake.


Non-aqueous enzymology approach for improvement of reagentless mediator-based glucose biosensor.
The formation of Nafion membranes containing glucose oxidase and dimethylferrocene as a mediator was optimized using a previously reported non-aqueous enzymology approach for biosensor development. Enzyme immobilization in Nafion membranes was carried out from water-organic mixtures with a high content of organic solvent. The mediator based reagentless glucose electrode was tested in a flow injection system. The response towards glucose addition was stable: the reproducibility during 50 assays exceeded 95%. The response was linear over the glucose concentration range 0.5-50 mM.


Effect of adrenergic stimulation on clearance from small ciliated airways in healthy subjects.
Mucociliary transport is an important clearance mechanism of larger airways, but in the smallest ciliated airways (bronchioles) it may be less effective. The present study aimed at investigating whether clearance from the bronchioles in subjects with healthy airways was stimulated by an adrenergic agonist (terbutaline sulphate). Tracheobronchial clearance was studied twice in 10 healthy subjects after inhalation of 6-micron (aerodynamic diameter) monodisperse Teflon particles labeled with 111In. At one exposure, oral treatment with terbutaline sulphate, known to stimulate clearance in large airways, began immediately after inhalation of the particles. The other exposure was a control measurement. The particles were inhaled at an extremely slow flow, 0.05 L/s, which gave deposition mainly in the small ciliated airways (bronchioles). Lung retention was measured at 0, 24, 48, and 72 h. Clearance was significant every 24 h for both exposures (p < .05, two-tailed paired t-test), with similar fractions of retained particles at all time points. During treatment with terbutaline sulphate, the subjects' pulse rates tended to be higher, but clearance rates did not increase. We found, as expected, no significant correlation between lung retention and lung function in either exposure. This study shows that an adrenergic agonist does not significantly influence overall clearance from the bronchiolar region in healthy subjects. This suggests that mucociliary transport does not significantly contribute to clearance from the smallest ciliated airways. Other mechanisms may be more important for the transportation of mucus from these airways.


A diagnostic pitfall: pancreatic tuberculosis, not pancreatic cancer.
Abdominal tuberculosis (TB) is one of the most common forms of extra-pulmonary tuberculosis and is responsible for considerable morbidity and mortality globally. Tuberculosis can involve any part of the gastrointestinal tract from mouth to anus, the peritoneum, liver, spleen and the pancreatobiliary system. The occurrence of abdominal TB is independent of pulmonary disease in most patients, with a reported incidence of co-existing pulmonary disease varying from 6 to 38% worldwide. We report a case of pancreatic tuberculosis also involving the vertebrae, which was initially treated as a case of pancreatic cancer.


The chemistry of mycophenolic acid--synthesis and modifications towards desired biological activity.
Mycophenolic acid (MPA) is a basis for the immunosuppressive drugs used in clinic against rejection in solid organs transplantations. Since its physiological activity is very promising, numerous studies have been performed to establish mechanism of action, structure - activity relationship (SAR), synthesis of MPA derivatives to improve or extent its clinical use to anticancer one, especially. The reported methods for preparation of MPA analogues have been achieved by semi-synthetic approaches or total synthesis and accomplished by in vitro or / and in vivo evaluations. In this review we would like to bring together chemical aspects of these compounds and their implementations within biological activity, their synthesis and structural modifications referred to the structure-activity relationship (SAR).


Seasonal influenza vaccination among Mexican migrants traveling through the Mexico-US border region.
Mobile populations are at high risk for communicable diseases and can serve as a bridge between sending and receiving communities. The objective of this study is to determine the rates of, and factors associated with, seasonal influenza vaccination among Mexican migrants traveling through the US-Mexico border. We used a 2013 cross-sectional population-based survey of adult mobile Mexican migrants traveling through the Mexico-US border region (N=2313; weighted N=652,500). We performed a multivariable logistic regression analysis to model the odds of receiving an influenza vaccination in the past year by sociodemographics, migration history, health status, and access to health care. The seasonal influenza vaccination rate in this population was 18.6%. Gender, health status, and health insurance were associated with the likelihood to receive an influenza vaccination. Overall, the rates of seasonal influenza vaccination in circular Mexican migrants are low compared to adults in Mexico and the US Efforts are needed to increase influenza vaccination among this highly mobile population, particularly in adults with chronic conditions.


Feasibility of a Real-Time Clinical Augmented Reality and Artificial Intelligence Framework for Pain Detection and Localization From the Brain.
For many years, clinicians have been seeking for objective pain assessment solutions via neuroimaging techniques, focusing on the brain to detect human pain. Unfortunately, most of those techniques are not applicable in the clinical environment or lack accuracy. This study aimed to test the feasibility of a mobile neuroimaging-based clinical augmented reality (AR) and artificial intelligence (AI) framework, CLARAi, for objective pain detection and also localization direct from the patient's brain in real time. Clinical dental pain was triggered in 21 patients by hypersensitive tooth stimulation with 20 consecutive descending cold stimulations (32°C-0°C). We used a portable optical neuroimaging technology, functional near-infrared spectroscopy, to gauge their cortical activity during evoked acute clinical pain. The data were decoded using a neural network (NN)-based AI algorithm to classify hemodynamic response data into pain and no-pain brain states in real time. We tested the performance of several networks (NN with 7 layers, 6 layers, 5 layers, 3 layers, recurrent NN, and long short-term memory network) upon reorganized data features on pain diction and localization in a simulated real-time environment. In addition, we also tested the feasibility of transmitting the neuroimaging data to an AR device, HoloLens, in the same simulated environment, allowing visualization of the ongoing cortical activity on a 3-dimensional brain template virtually plotted on the patients' head during clinical consult. The artificial neutral network (3-layer NN) achieved an optimal classification accuracy at 80.37% (126,000/156,680) for pain and no pain discrimination, with positive likelihood ratio (PLR) at 2.35. We further explored a 3-class localization task of left/right side pain and no-pain states, and convolutional NN-6 (6-layer NN) achieved highest classification accuracy at 74.23% (1040/1401) with PLR at 2.02. Additional studies are needed to optimize and validate our prototype CLARAi framework for other pains and neurologic disorders. However, we presented an innovative and feasible neuroimaging-based AR/AI concept that can potentially transform the human brain into an objective target to visualize and precisely measure and localize pain in real time where it is most needed: in the doctor's office. RR1-10.2196/13594.


Association of tooth count with cognitive decline and dementia in the Finnish adult population.
To evaluate whether tooth loss is associated with cognitive decline and incident dementia. We analysed data from the Finnish population-based Health 2000 and follow-up Health 2011 surveys (participants aged ≥30 years and without dementia at baseline; N = 5506 at baseline and 3426 at 11-year follow-up). Dementia diagnoses until 2015 were ascertained from national registers (N = 5542). Tooth count was dichotomized as adequate (≥20) versus tooth loss (<20). Tooth loss was further stratified into 10-19 teeth, 1-9 teeth and edentulism. Upper and lower jaws were also considered separately. Baseline cognitive test scores were dichotomized by median as high versus low, and 11-year change as decline versus no decline. Tooth loss (<20) was associated with lower baseline overall cognition (odds ratio [OR] = 1.21, 95% confidence interval [CI] = 1.03-1.43), 11-year cognitive decline (OR = 1.30, 95% CI = 1.05-1.70) and higher 15-year dementia risk (hazard ratio = 1.52, 95% CI = 1.15-2.02) after adjusting for multiple confounders. After adjustment for dentures, associations became non-significant, except for 10-19 teeth remaining and dementia. Results were similar after considering reverse causality bias; however, 10-19 teeth remaining was significantly associated with 11-year cognitive decline even after adjustment for dentures. No jaw-specific differences were observed. Tooth loss adversely impacts the risk of cognitive decline and dementia. The role of dentures should be further explored.