1D "Spikelet" Projections from Heteronuclear 2D NMR Data-Permitting 1D Chemometrics While Preserving 2D Dispersion.
Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for the non-targeted metabolomics of intact biofluids and even living organisms. However, spectral overlap can limit the information that can be obtained from 1D 1H NMR. For example, magnetic susceptibility broadening in living organisms prevents any metabolic information being extracted from solution-state 1D 1H NMR. Conversely, the additional spectral dispersion afforded by 2D 1H-13C NMR allows a wide range of metabolites to be assigned in-vivo in 13C enriched organisms, as well as a greater depth of information for biofluids in general. As such, 2D 1H-13C NMR is becoming more and more popular for routine metabolic screening of very complex samples. Despite this, there are only a very limited number of statistical software packages that can handle 2D NMR datasets for chemometric analysis. In comparison, a wide range of commercial and free tools are available for analysis of 1D NMR datasets. Overtime, it is likely more software solutions will evolve that can handle 2D NMR directly. In the meantime, this application note offers a simple alternative solution that converts 2D 1H-13C Heteronuclear Single Quantum Correlation (HSQC) data into a 1D "spikelet" format that preserves not only the 2D spectral information, but also the 2D dispersion. The approach allows 2D NMR data to be converted into a standard 1D Bruker format that can be read by software packages that can only handle 1D NMR data. This application note uses data from Daphnia magna (water fleas) in-vivo to demonstrate how to generate and interpret the converted 1D spikelet data from 2D datasets, including the code to perform the conversion on Bruker spectrometers.


Twelve tips for medical students to establish a collaborative flashcard project.
Medical students employ various study strategies to master large amounts of information during their medical education. Digital flashcards are an interactive, self-directed study stool that may improve knowledge retention by combining the principles of active recall and spaced-repetition. They may be studied during and beyond undergraduate medical education. However, making flashcards can be an onerous task. In this article, we describe twelve tips on how to establish and maintain a collaborative digital flashcard project based on the undergraduate medical curriculum.


Metastatic prostatic carcinoma mimicking a unilateral sacroiliitis.
We describe a 65-year-old male who presented with unilateral sacroiliitis as the first manifestation of metastatic prostatic carcinoma. When progressive symptoms are unresponsive to conventional therapy, a reconsideration of the diagnosis is necessary with appropriate further imaging studies. We discuss the differential diagnosis of sacroiliitis including, mechanisms of joint involvement in malignancy, and present a review of the literature.


Predictive Model for Site-Selective Aryl and Heteroaryl C-H Functionalization via Organic Photoredox Catalysis.
Direct C-H functionalization of aromatic compounds is a useful synthetic strategy that has garnered much attention because of its application to pharmaceuticals, agrochemicals, and late-stage functionalization reactions on complex molecules. On the basis of previous methods disclosed by our lab, we sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems commonly used in the pharmaceutical industry. Using electron density calculations, we were able to predict the site selectivity of direct C-H functionalization in a number of heterocycles and identify general trends observed across heterocycle classes.


A qualitative assessment of dental care access and utilization among the older adult population in the United States.
This article presents an in-depth, qualitative assessment of the needs, issues, opportunities, and barriers concerning dental access and availability of oral care among older Americans. For the rapidly aging U.S. population, access and barriers to the provision of dental services were evaluated. The nature and types of services utilized by various segments of this population were examined and the attitudes, opinions, and perceptions of dental professionals regarding the delivery of services were analyzed. From this research, potential opportunities for strategic partnerships between organized dentistry and industry were developed. These collaborative partnerships will seek to improve access to oral health care for the fastest growing segment of the U.S. population.


Risk of hospitalization associated with anticholinergic medication for patients with dementia.
With the ageing of the general population, demand has grown for measures to prevent hospitalization for dementia, which can exacerbate problems associated with activities of daily living in elderly individuals. Anticholinergic medication has been shown to cause falls, delirium, and cognitive impairment in aged patients. However, the risk of hospitalization associated with the administration of anticholinergics is unclear. We analyzed the records of 61 outpatients (26 men, 35 women; mean age: 78 ± 7 years; mean follow-up period: 420 days) diagnosed with dementia (Alzheimer's disease: n = 45; dementia with Lewy bodies: n = 3; undifferentiated n = 13) and prescribed anti-dementia drugs between May 2013 and December 2014. Medication history was noted, and the patients were divided into two groups according to the Anticholinergic Risk Scale: with risk (n = 13) and without risk (n = 48). Outcome was judged based on an end-point of hospitalization or death. Kaplan-Meier survival and Cox proportional hazard analyses were performed. Eight patients with anticholinergic risk and 12 without anticholinergic risk reached the end-point (P < 0.005). Analysis with a proportional hazard model showed that anticholinergic medication administration was related to a higher risk for reaching the end-point (crude hazard ratio: 3.62, 95% confidence interval: 1.45-9.04, P < 0.01; adjusted hazard ratio: 4.54, 95% confidence interval: 1.03-20.0, P < 0.05). In contrast, Mini-Mental State Examination score, Charlson Comorbidity Index, and the number of drugs were not major risk factors for hospitalization in patients with dementia. The Anticholinergic Risk Scale findings were shown to be a strong predictor of hospitalization for patients with dementia. We should evaluate the anticholinergic burden before initiating anti-dementia therapy.


Comments on eurytrematosis in Brazil and the possibility of human infection.
The manuscript "Eurytrematosis: An emerging and neglected disease in South Brazil" discusses some aspects of Eurytrema sp. fluke as an animal pathogen and based in some aspects of the parasitism in cattle and the life cycle of Eurytrema sp. Authors suggest the possibility of human infection, once there is no research on this subject in Brazil. In human cases reported, the mechanism of infection was not disclosed, so it keeps the discussion opened. Although we focused on animal eurytrematosis, we speculated the possibility of human infection by Eurytrema sp. in Brazil, but after all, the only way to determine it, would be a study searching for people infected through coprological or serological tests.


ADMM ⊇ Projective Dynamics: Fast Simulation of Hyperelastic Models with Dynamic Constraints.
We apply the alternating direction method of multipliers (ADMM) optimization algorithm to implicit time integration of elastic bodies, and show that the resulting method closely relates to the recently proposed projective dynamics algorithm. However, as ADMM is a general purpose optimization algorithm applicable to a broad range of objective functions, it permits the use of nonlinear constitutive models and hard constraints while retaining the speed, parallelizability, and robustness of projective dynamics. We further extend the algorithm to improve the handling of dynamically changing constraints such as sliding and contact, while maintaining the benefits of a constant, prefactored system matrix. We demonstrate the benefits of our algorithm on several examples that include cloth, collisions, and volumetric deformable bodies with nonlinear elasticity and skin sliding effects.


Artificial Intelligence in The Management of Neurodegenerative Disorders.
Neurodegenerative disorders are characterized by a gradual but irreversible loss of neurological function. The ability to detect and treat these conditions successfully is crucial for ensuring the best possible quality of life for people who suffer from them. The development of effective new methods for managing and treating neurodegenerative illnesses has been made possible by recent developments in computer technology. In this overview, we take a look at the prospects for applying computational approaches, such as drug design, AI, ML, and DL, to the treatment of neurodegenerative diseases. To review the current state of the field, this article discusses the potential of computational methods for early disease detection, quantifying disease progression, and understanding the underlying biological mechanisms of neurodegenerative diseases, as well as the challenges associated with these approaches and potential future directions. Moreover, it delves into the creation of computational models for the individualization of care for neurodegenerative diseases. The article concludes with suggestions for future studies and clinical applications, highlighting the advantages and disadvantages of using computational techniques in the treatment of neurodegenerative diseases.


Cost minimisation analysis: kilovoltage imaging with automated repositioning versus electronic portal imaging in image-guided radiotherapy for prostate cancer.
To compare the treatment time and cost of prostate cancer fiducial marker image-guided radiotherapy (IGRT) using orthogonal kilovoltage imaging (KVI) and automated couch shifts and orthogonal electronic portal imaging (EPI) and manual couch shifts. IGRT treatment delivery times were recorded automatically on either unit. Costing was calculated from real costs derived from the implementation of a new radiotherapy centre. To derive cost per minute for EPI and KVI units the total annual setting up and running costs were divided by the total annual working time. The cost per IGRT fraction was calculated by multiplying the cost per minute by the duration of treatment. A sensitivity analysis was conducted to test the robustness of our analysis. Treatment times without couch shift were compared. Time data were analysed for 8648 fractions, 6057 from KVI treatment and 2591 from EPI treatment from a total of 294 patients. The median time for KVI treatment was 6.0 min (interquartile range 5.1-7.4 min) and for EPI treatment it was 10.0 min (interquartile range 8.3-11.8 min) (P value < 0.0001). The cost per fraction for KVI was A$258.79 and for EPI was A$345.50. The cost saving per fraction for KVI varied between A$66.09 and A$101.64 by sensitivity analysis. In patients where no couch shift was made, the median treatment delivery time for EPI was 8.8 min and for KVI was 5.1 min. Treatment time is less on KVI units compared with EPI units. This is probably due to automation of couch shift and faster evaluation of imaging on KVI units. Annual running costs greatly outweigh initial setting up costs and therefore the cost per fraction was less with KVI, despite higher initial costs. The selection of appropriate IGRT equipment can make IGRT practical within radiotherapy departments.


The Complete Digital Workflow in Implant Dentistry.
Current diagnostic and treatment planning tools support a complete digital workflow that takes the guesswork out of implant dentistry and facilitates asynchronous collaboration between all involved specialties, from the restorative dentist to the surgeon to the dental laboratory. Long gone are the days of freehanded implant placement as guided as well as navigated surgery and now even robots provide unprecedented precision and predictability in implant placement based on the individual medical, morphologic, and anatomic situation of each patient.


Lipidated Calcitonin Gene-Related Peptide (CGRP) Peptide Antagonists Retain CGRP Receptor Activity and Attenuate CGRP Action In Vivo.
Signaling through calcitonin gene-related peptide (CGRP) receptors is associated with pain, migraine, and energy expenditure. Small molecule and monoclonal antibody CGRP receptor antagonists that block endogenous CGRP action are in clinical use as anti-migraine therapies. By comparison, the potential utility of peptide antagonists has received less attention due to suboptimal pharmacokinetic properties. Lipidation is an established strategy to increase peptide half-life in vivo. This study aimed to explore the feasibility of developing lipidated CGRP peptide antagonists that retain receptor antagonist activity in vitro and attenuate endogenous CGRP action in vivo. CGRP peptide analogues based on the archetypal CGRP receptor antagonist, CGRP8-37, were palmitoylated at the N-terminus, position 24, and near the C-terminus at position 35. The antagonist activities of the lipidated peptide analogues were tested in vitro using transfected Cos-7 cells expressing either the human or mouse CGRP receptor, amylin subtype 1 (AMY1) receptor, adrenomedullin (AM) receptors, or calcitonin receptor. Antagonist activities were also evaluated in SK-N-MC cells that endogenously express the human CGRP receptor. Lipidated peptides were then tested for their ability to antagonize endogenous CGRP action in vivo using a capsaicin-induced dermal vasodilation (CIDV) model in C57/BL6J mice. All lipidated peptides except for the C-terminally modified analogue retained potent antagonist activity compared to CGRP8-37 towards the CGRP receptor. The lipidated peptides also retained, and sometimes gained, antagonist activities at AMY1, AM1 and AM2 receptors. Several lipidated peptides produced robust inhibition of CIDV in mice. This study demonstrates that selected lipidated peptide antagonists based on αCGRP8-37 retain potent antagonist activity at the CGRP receptor and are capable of inhibition of endogenous CGRP action in vivo. These findings suggest that lipidation can be applied to peptide antagonists, such as αCGRP8-37 and are a potential strategy for antagonizing CGRP action.


Gradient Projection with Approximate L₀ Norm Minimization for Sparse Reconstruction in Compressed Sensing.
In the reconstruction of sparse signals in compressed sensing, the reconstruction algorithm is required to reconstruct the sparsest form of signal. In order to minimize the objective function, minimal norm algorithm and greedy pursuit algorithm are most commonly used. The minimum L₁ norm algorithm has very high reconstruction accuracy, but this convex optimization algorithm cannot get the sparsest signal like the minimum L₀ norm algorithm. However, because the L₀ norm method is a non-convex problem, it is difficult to get the global optimal solution and the amount of calculation required is huge. In this paper, a new algorithm is proposed to approximate the smooth L₀ norm from the approximate L₂ norm. First we set up an approximation function model of the sparse term, then the minimum value of the objective function is solved by the gradient projection, and the weight of the function model of the sparse term in the objective function is adjusted adaptively by the reconstruction error value to reconstruct the sparse signal more accurately. Compared with the pseudo inverse of L₂ norm and the L₁ norm algorithm, this new algorithm has a lower reconstruction error in one-dimensional sparse signal reconstruction. In simulation experiments of two-dimensional image signal reconstruction, the new algorithm has shorter image reconstruction time and higher image reconstruction accuracy compared with the usually used greedy algorithm and the minimum norm algorithm.


[Expression profile of intervertebral disc degeneration-specific genes: a transcriptome sequencing-based analysis].
To identify new therapeutic targets for intervertebral disc degeneration (IDD) by analyzing gene variations in IDD. We analyzed surgical samples of intervertebral disc from 4 patients with IDD and 3 patients with non-IDD using RNA sequencing (RNA-seq) technology to identify significant differentially expressed genes (DEGs) in IDD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized for gene enrichment studies to acquire the key genes and signal pathways during IDD progression. The differential expressions of the identified genes in IDD were validated in clinical samples with qRT-PCR. The transcriptome profile revealed 512 significant DEGs, which were enriched in terms of keratinization, extracellular matrix (ECM) components, growth factor binding, and inflammatory chemotaxis in GO analysis. The top 10 terms of KEGG enrichment included amoebiasis, viral protein interaction with cytokine and cytokine receptor, ECM-receptor interaction, IL-17 signaling pathway, cytokine-cytokine receptor interaction, TNF signaling pathway, AGE-RAGE signaling pathway in diabetic complications, PI3K-Akt signaling pathway, chemokine signaling pathway and estrogen signaling pathway. Thirteen DEGs selected as the targets for qRT-PCR validation showed significant differential expressions in IDD (P < 0.001), and their expression trends were all consistent with the results of RNA-seq. Among these genes, 10 genes showed significant intergroup fold change (Log2FoldChange>1). ECM, growth factors, collagen components, inflammatory chemokines and such signal pathways as TNF-α and PI3K-Akt all have important contributions to IDD progression and may thus serve as new therapeutic targets for treatment of IDD.


[Renal mucinous tubular and spindle cell carcinoma: clinicopathological and whole exome sequencing analyses].
Objective: To explore the clinicopathological characteristics, immunophenotype, diagnosis and differential diagnosis of renal mucinous tubular and spindle cell carcinoma (MTSCC), and to explore the all-exon mutations, microsatellite stability and tumor mutational burden (TMB) in MTSCC cases. Methods: The data of 5 patients with MTSCC that were submitted to the Department of Pathology, First Affiliated Hospital of Soochow University, China from January 2008 to May 2020, were reviewed and analyzed. The whole exome sequencing (WES) was conducted in all patients, while 3 of them were subject to the analyses of microsatellite stability and TMB. Results: Among the 5 patients, 3 were males and 2 were females. They were 37-76 years old. The maximum diameter of the tumor was 3.5-6.0 cm. The borders of the tumors were well defined. Microscopically, MTSCC was characterized by tubular structure, spindle cell and mucinous stroma, and the nuclear grade of tumor cells was overall low. The average follow-up was 15 months, and no recurrence or metastasis was found. Immunohistochemistry showed that all 5 cases were positive for broad-spectrum cytokeratin (CKpan), cytokeratin (CK)7, CK19, vimentin, PAX8, and P504s (varying expression levels), and the Ki-67 positive index was low. The WES of 5 cases showed that NF2 and PTPN14 exhibited higher mutation rates, which were 3/5 and 2/5, respectively. The microsatellite stability analysis indicated that the 3 cases were all microsatellite stable, and the TMB analysis showed that the TMB of the 3 cases were all <9 mut/Mb. Conclusions: MTSCC is a unique, low-grade pleomorphic kidney tumor. The WES analyses suggest that NF2 and PTPN14 have a higher mutation rate, indicating that the occurrence and development of MTSCC may be closely related to the Hippo pathway. The analysis of microsatellite stability indicates that there is no significant relationship between microsatellite stability and MTSCC, and the TMB analysis suggests that MTSCC patients may not benefit from immunotherapy.


Anesthesia in the Yom Kippur war.
The role of the anesthetist in the treatment of battle casualties is discussed in the light of personal experience in a field hospital and in the rear during the Yom Kippur War of October 1973. Resuscitation and intensive care both before and after evacuation play an important part in reducing mortality, and the importance of providing adequate facilities for these functions in the battle area as well as at the base is emphasized.


Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant.
This prospective study assessed the endometrial effects of fulvestrant, a pure estrogen-receptor antagonist, in postmenopausal women with breast cancer. This single-center study enrolled postmenopausal patients who had an intact uterus at baseline with progressive metastatic breast cancer on tamoxifen followed by an oral aromatase inhibitor (AI). Fulvestrant (250 mg) was administered every 28 +/- 3 days via IM injection. Transvaginal ultrasonography (TVUS) was performed at baseline and after 3 months of therapy. Primary and secondary endpoints were changes from baseline in double endometrial thickness (DET) and uterine volume (UV), respectively. No interventions were performed on any asymptomatic uterine abnormalities that were detected at baseline. In total, 32 women were enrolled. Five patients had no repeat TVUS because of early progression before 3 months, leaving 27 evaluable patients for final analysis. After 3 months therapy, mean DET had significantly decreased by 23.08% (P = 0.010). Mean UV also decreased by 10.88%, although this change was not significant (P = 0.119). After 3 months of therapy, none reported vaginal bleeding, there were no changes noted in most of the uterine pathologies present at baseline and no new uterine abnormalities were detected. We observed that 3 months of fulvestrant treatment resulted in a significant decrease in endometrial growth and a non-significant decrease in UV in postmenopausal women with metastatic breast cancer previously exposed to tamoxifen and AIs. Furthermore, no new uterine pathologies were detected, indicating that fulvestrant behaves as a pure antiestrogen at the uterine level.


Age-dependent differential regulation of anxiety- and depression-related behaviors by neurabin and spinophilin.
Affective disorders impact nearly 10% of the adult population in the United States in a given year. Synaptic dysfunction has recently emerged as a key neurobiological mechanism underlying affective disorders such as anxiety and depression. In this study, we investigate the potential role of two synaptic scaffolding proteins, neurabin and spinophilin, in regulating anxiety- and depression-related behaviors at different ages using genetically deficient mice. Loss of the neurabin gene reduces anxiety-like behavior in the elevated zero maze in young adult mice (3-5 months old), but not in middle aged mice (11-13 months old), whereas loss of spinophilin decreases anxiety in middle-aged mice, but not in young adult mice. Neurabin knockout (KO) mice also show reduced immobility in the repeated force swim test (FST) at 3-5 months, but not 11-3 months, of age, compared to age- and strain-matched wild type (WT) controls. Conversely, spinophilin KO mice display a lower level of this behavioral despair than matched WT controls after repeated FST trials at the middle age (11-13 months) but not the young age (3-5 months). Together, these data indicate that, despite their structural similarities and overlapping function in regulating synaptic cytoskeleton, the two homologs neurabin and spinophilin play important yet distinct roles in the regulation of anxiety- and depression-like behaviors in an age-dependent manner. Our studies provide new insights into the complex neurobiology of affective disorders.


Office flexible cystoscopy.
Since the development of the first purpose-built flexible cystoscope in 1984, flexible cystoscopy has become an accepted diagnostic and therapeutic modality. Indeed, it is estimated that more than 10 per cent of practicing urologists are already familiar with this technology. The flexible cystoscope has markedly extended the urologist's ability to examine the bladder, and it has become a valuable adjunct to the rigid cystoscope. Although the operation of this instrument is vastly different from that of its rigid counterpart, with practice, the technique can be learned. After experience is obtained with diagnostic flexible cystoscopy, the urologist will likely prefer this new instrument for bladder inspection, as it provides for a more thorough yet less morbid and less expensive examination. In the future, the development of improved and smaller instrumentation will further extend the therapeutic indications for flexible cystoscopy. Indeed, advances in laser technology are already providing the urologist with 300- to 600-micron (0.9 to 1.8F) flexible probes capable of incision (KTP laser), fulguration (Nd:YAG laser), and stone disintegration (tunable dye laser). Lastly, the skills obtained in using the flexible cystoscope are all readily applicable to the development of dexterity with the already available flexible nephroscope and the more recently developed flexible ureteroscope.


Binding and desulfurization characteristics of pulp black liquor in biocoalbriquettes.
To control pollutant emissions from coal combustion in some developing countries, biocoalbriquette, an artificially produced solid fuel, was developed. Both the breaking strength and production costs of the biocoalbriquette have become essentially the most important factors in popularizing it in these countries. To increase the breaking strength and decrease the production costs, it is proposed in this study to use pulp black liquor, a byproduct from the pulp production industry, as a binder. The influences of pulp black liquor on the briquetting and combustion characteristics were investigated. Furthermore, the desulfurization characteristics of pulp black liquor were also evaluated through combustion experiments. The study results show that the briquetting pressure has a limited effect on the breaking strength. An increase in the briquetting pressure yields greater breaking strength of up to the 50 MPa. Above 50 MPa, the breaking strength changes very little with the briquetting pressure. The use of pulp black liquor has had a greater effect on increasing the breaking strength than on changing the briquetting pressure and also on improving the combustion characteristics of the biocoalbriquette. On the other hand, pulp black liquor has some desulfurization capabilities. When used as a binder, it not only increases the breaking strength and decreases the necessary briquetting pressure, but it also improves some characteristics of the combustion and reduces the pollutants emission.


Pediatric rehabilitation: 5. Transitioning teens with disabilities into adulthood.
This self-directed learning module focuses on preparing adolescent patients with special health care needs for adulthood by promoting their independence in their own self-care; helping them to navigate issues of sexuality, marriage, and parenting; preparing the patient and family to make guardianship decisions during the transition between childhood and adulthood; and planning for higher education or vocation. Emphasis will be on the role of the physiatrist in providing this guidance and its importance in improving the patient's quality of life. It is part of the study guide on pediatric rehabilitation in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation and pediatric medicine. The goal of this article is to refine the learner's knowledge of preparing adolescent patients with special health care needs for adulthood to improve their quality of life.


Self-Sorting of Heteroanions in the Assembly of Cross-Shaped Polyoxometalate Clusters.
Heteroanion (HA) moieties have a key role in templating of heteropolyoxometalate (HPA) architectures, but clusters templated by two different templates are rarely reported. Herein, we show how a cross-shaped HPA-based architecture can self-sort the HA templates by pairing two different guests into a divacant {XYW15O54} building block, with four of these building block units being linked together to complete the cross-shaped architecture. We exploited this observation to incorporate HA templates into well-defined positions within the clusters, leading to the isolation of a collection of mixed-HA templated cross-shaped polyanions [(XYW15O54)4(WO2)4]32-/36- (X = H-P, Y = Se, Te, As). The template positions have been unambiguously determined by single crystal X-ray diffraction, NMR spectroscopy, and high-resolution electrospray ionization mass spectrometry; these studies demonstrated that the mixed template containing HPA clusters are the preferred products which crystallize from the solution. Theoretical studies using DFT calculations suggest that the selective self-sorting originates from the coordination of the template in solution. The cross-shaped polyoxometalate clusters are redox-active, and the ability of molecules to accept electrons is slightly modulated by the HA incorporated as shown by differential pulse voltammetry experiments. These results indicate that the cross-shaped HPAs can be used to select templates from solution, and themselves have interesting geometries, which will be useful in developing functional molecular architectures based upon HPAs with well-defined structures and electronic properties.


Cost-effectiveness of an intensive group training protocol compared to physiotherapy guideline care for sub-acute and chronic low back pain: design of a randomised controlled trial with an economic evaluation. [ISRCTN45641649].
Low back pain is a common disorder in western industrialised countries and the type of treatments for low back pain vary considerably. In a randomised controlled trial the cost-effectiveness and cost-utility of an intensive group training protocol versus physiotherapy guideline care for sub-acute and chronic low back pain patients is evaluated. Patients with back pain for longer than 6 weeks who are referred to physiotherapy care by their general practitioner or medical specialist are included in the study. The intensive group training protocol combines exercise therapy with principles of behavioural therapy ("graded activity") and back school. This training protocol is compared to physiotherapy care according to the recently published Low Back Pain Guidelines of the Royal Dutch College for Physiotherapy. Primary outcome measures are general improvement, pain intensity, functional status, work absenteeism and quality of life. The direct and indirect costs will be assessed using cost diaries. Patients will complete questionnaires at baseline and 6, 13, 26 and 52 weeks after randomisation. No trials are yet available that have evaluated the effect of an intensive group training protocol including behavioural principles and back school in a primary physiotherapy care setting and no data on cost-effectiveness and cost-utility are available.


[Comparison of plasma radiofrequency ablation to the total inferior turbinate with its anterior extremity].
To compare the curative effect and complications between plasma radiofrequency ablation to the anterior extremity of the inferior turbinate and the treatment to the total of the inferior turbinate for the treatment of hypertrophic inferior turbinate. One hundred and fifty-three patients were randomly divided into two groups, and all of the patients had obviously nasal obstruction due to isolated inferior turbinate hypertrophy. In the experimental group, plasma radiofrequency ablation was only applied to the anterior extremity of the inferior turbinate, whereas the whole concha was ablated in the control group. Visual analogue scale (VAS) for nasal obstruction were obtained both before the treatment and 1 year after surgery, and during the follow-up period, their recovery of nasal mucosa and complications were evaluated. RESULT. VAS scores before and after treatment were statistically significant in both groups (P < 0.01), but decreased value of VAS scores between the two groups was insignificant (P > 0.05). Complications between the two groups were statistically significant (P < 0.01). Compare to radiofrequency ablation to the total of the inferior turbinate, the application to the anterior extremity of the inferior turbinate could provide adequate curative effect. The treatment to the anterior extremity of the inferior turbinate is simpler, which induce less complications, and which is safer for there is less risk of damage of continuity of the nasal mucosa. So it has a higher clinical application value.


The management of malignant esophago-respiratory fistulas with a cuffed prosthesis.
Peroral intubation with a standard prosthesis fails to occlude inoperable malignant esophago-respiratory fistulas located above the narrowed segment, or when there is little or no stricture at all. Ten patients with malignant esophago-respiratory fistulas were intubated perorally with a prosthesis surrounded by a foam ruber cuff contained in a silicone sheath, in which a vacuum can be created. The type of fistula was esophago-bronchial in 6 patients, esophago-tracheal in 3 patients, and gastro-tracheal in 1 patient. The fistula was located above the stricture in 8 patients and in a malignancy without a stricture in 2 patients. The diameter of the opening of the fistula ranged between 1 and 3 cm. Complications with the cuffed tube were recurrent leakage after a period of 30 days in situ in 1 patient, and compression of the trachea immediately after intubation in 1 patient. Adequate palliation, that is, no symptoms related to the fistula, good transit of food and discharge from hospital within a few days was achieved in 9 patients for an average period of 37.2 days (10-84 days). The cuffed esophageal prosthesis can improve the quality of life in patients with malignant esophago-respiratory fistulas that do not respond to conventional intubation.


Analysis of leukocyte differentiation antigens in blood and bone marrow from preleukemia (refractory anemia) patients using monoclonal antibodies.
Peripheral blood and bone marrow mononuclear cells from patients with refractory anemia (RA) or RA with sideroblasts (defined according to the revised French-American-British classification with less than 5% blast cells in the bone marrow) were analyzed using a panel of monoclonal antibodies directed against leukocyte antigens on B lymphocytes, T lymphocytes, monocytes, and myeloid cells. In the peripheral blood an increased proportion of T lymphocytes (and correspondingly a decreased proportion of B cells) could be demonstrated. However, when expressed in terms of absolute numbers, the T cell component was depressed because of severely decreased numbers of T4+ helper cells. In contrast, the absolute numbers of T8+ suppressor cells were either normal or increased in the majority of the patients. This resulted in markedly decreased ratios of T4+/T8+ cells, which were closely correlated to the number of transfusions given to the patients because of their refractory anemia. Finally, nearly all of the patients exhibited decreased numbers of cells reactive with the N901 natural killer (NK) antibody, thus explaining our earlier finding of decreased NK activity in these patients. In the bone marrow increased proportions of myeloid cells reactive with monoclonal antibodies present on immature myeloid cells (My7 and My9) were found, suggesting the presence of malignant clones. Indeed, when the numbers of My7+ cells and the morphologic evaluations of bone marrow smears at the time of diagnosis were compared to the progression of the disease, a group of patients with high numbers of My7+ cells and normal morphology could be identified that had a high probability of progression to refractory anemia with an excess of blasts or to overt acute myeloid leukemia. Thus, the use of antibodies defining leukocyte differentiation antigens might be of significant value in the diagnosis and prognostication of the myelodysplastic syndromes. These findings are discussed in relation to the pathogenesis of this potentially premalignant condition with special emphasis on possible defects in the immunologic defense mechanisms against early neoplasias.


An argyrophil III method for the demonstration of micro- and oligodendroglia.
Micro- and oligodendroglia, plasma and nucleoli of nerve cells, capillary wall and nuclei of astrocytes become visible when sections of formol fixed human brain are immersed, without any previous treatment, into a physical developer of pH 10.5. The staining is inhibited by the catalytic activity of the tissue elements involved. By means of pretreatments with 1% performic acid and 30% sodium rhodanide dissolved in 0.4% sodium hydroxide, the catalytic activity in the unwanted tissue elements is suppressed, and this results in an elective demonstration of micro- and oligodendroglia. Reducing groups of the tissue or any kind of performed nuclei play no role in this silver staining.


Can Systemic Immune-Inflammation Index Create a New Perspective for the IMDC Scoring System in Patients with Metastatic Renal Cell Carcinoma?
The aim of the study was to evaluate impact of the systemic immune-inflammation index (SII) on prognosis and survival within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score groups. The records of 187 patients with metastatic renal cell carcinoma (RCC) were reviewed retrospectively. The SII was calculated as follows: SII = Neutrophil × Platelet/Lymphocyte. The patients were categorized into 2 groups based on a median SII of 730 (×109 per 1 L) as SII low (<730) and SII high (≥730). The Kaplan-Meier method was used for survival analysis and a Cox regression model was utilized to determine independent predictors of survival. The median age was 61 years (range: 34-86 years). Kaplan-Meier tests revealed significant differences in survival between the SII-low and SII-high levels (27.0 vs. 12.0 months, respectively, p < 0.001). The Cox regression model revealed that SII was an independent prognostic factor. The implementation of the log-rank test in the IMDC groups according to the SII level provided the distinction of survival in the favorable group (SII low 49.0 months vs. SII high 11.0 months, p < 0.001), in the intermediate group (SII low 26.0 vs. SII high 15.0 months, p = 0.007), and in the poor group (SII low 19.0 vs. SII high 6.0 months, p = 0.019). The SII was an independent prognostic factor and provided significant differences in survival for the favorable, intermediate, and poor IMDC groups. Thus, the SII added to the IMDC score may be clinically beneficial in predicting survival.


Conducting research interviews with bereaved family carers: when do we ask?
Interviews with bereaved family carers to examine the end-of-life experience of the deceased are important tools for palliative care researchers, but the ethics of approaching the bereaved when they are grieving and vulnerable is often debated. The aim of this study was to explore the insights of bereaved family carers about the most appropriate time to be involved in a research interview about the end of life and death of their family member. This qualitative study used a social constructionist framework. Twenty-two bereaved family carers of people with motor neurone disease (MND) and cancer were interviewed in Western Australia. Most family carers (86%) feel comfortable being interviewed about the death of their family member within the first 5 months of bereavement, with 43% reporting they could be interviewed within weeks after death. Family carers reported that recall would be better earlier in bereavement and felt it may be helpful to them to talk about their experiences earlier. They said bereaved people should be allowed to decide for themselves when to be involved in an interview. These findings indicate that interviews with the bereaved may be most fruitful for researchers and beneficial to family carers when they are allowed to make the choice about timing for themselves, beginning weeks after the death of their family member.


Executive functioning and divergent thinking predict creative problem-solving in young adults and elderlies.
The role of executive functioning in creative thinking is under debate. Some authors suggested that increased inhibitory control, a component of executive functioning, is detrimental to creative solutions, whereas others argued that executive functions are central to creative problem-solving, thus questioning Guilford's classical distinction between divergent and convergent thinking. Executive functions decline with age. In this study, we investigated the contributions of executive functioning and its age-related decline and divergent thinking to creative problem-solving. To this aim, we divided our sample of sixty healthy adults into two age groups of young adults (20-26 years) and elderly (60-70 years) and we assessed their creative problem-solving abilities (using the compound remote associate problems) as well as other potential cognitive predictors of creative problem-solving (i.e., impulsivity, divergent thinking, verbal working memory, and decision-making style). A linear regression model revealed that the ability to solve problems creatively is negatively predicted by older age and impulsivity, while positively predicted by divergent thinking and verbal working memory. These findings reveal a combined contribution of executive functions and divergent thinking to creative problem-solving, suggesting that both convergent and divergent processes should be considered in interventions to contrast age-related decline.


Poly(lactic acid)/cellulose nanocrystal composites via the Pickering emulsion approach: Rheological, thermal and mechanical properties.
The use of nanocellulose is an attractive method to improve the characteristics of biodegradable polymers, but its effects are often affected by uneven dispersion. In this work, cellulose nanocrystals (CNCs) were evenly dispersed into poly(lactic acid) (PLA) via the Pickering emulsion approach. The PLA/CNC composites prepared were studied by rheological, thermal as well as mechanical measurements. Changes in the rheological characteristics of the composites showed that CNC promoted the transition of the composites from fluid to solid-like behavior at high temperatures. The introduction of 5 wt% CNC improved the crystallinity of PLA considerably and increased the onset temperature of crystallization by about 10 °C. The storage modulus of the composites increased throughout the entire temperature range of testing. Flexural modulus was improved considerably. All the results indicated that the Pickering emulsion approach improved the dispersion of CNC in the PLA matrix and CNC improved efficiently most properties of PLA.


Alloxan diabetes alters the rabbit transarterial wall oxygen gradient.
Atherosclerotic vascular occlusive disease is the most common complication of diabetes mellitus and accounts for 75% of deaths in diabetic patients. Determining the initiator and continuing stimulus for the cellular events in the formation of atherosclerotic lesions in diabetic patients could lead to the prevention of this common and deadly complication. Diabetes-induced arterial wall hypoxia is proposed as an initiator and continuing stimulus for atherosclerotic vascular occlusive disease. Transarterial wall oxygen gradient measurements were performed on the infrarenal aorta with an oxygen microelectrode 14 to 16 weeks after the induction of alloxan diabetes in rabbits. Both insulin-treated and untreated alloxan diabetic rabbits revealed significantly decreased oxygen tensions throughout the arterial wall compared with control rabbits. There was no significant difference in the transarterial wall oxygen gradient between the two groups of diabetic rabbits. This effect was noted despite no difference in the partial pressure of oxygen in arterial blood or visual evidence of atherosclerotic lesion formation in the three groups. These findings suggest that diabetes induces arterial wall hypoxia independent of insulin therapy and before the formation of atherosclerotic lesions. Diabetes-induced arterial wall hypoxia may contribute to the formation of atherosclerotic lesions.


In Vivo 11β-Hydroxysteroid Dehydrogenase Inhibition in Posaconazole-Induced Hypertension and Hypokalemia.
We describe a case of apparent mineralocorticoid excess (AME) secondary to posaconazole therapy and suggest the biochemical mechanism. Clinical and laboratory investigation confirmed 11β-hydroxysteroid dehydrogenase inhibition and withholding therapy led to a resolution of all clinical and laboratory abnormalities. Posaconazole was later restarted at a lower dose and prevented recurrence of this syndrome. Additional studies are necessary to determine the frequency of posaconazole-induced AME and whether other azole antifungals can be associated with this phenomenon.


Atherosclerosis and vascular aging as modifiers of tumor progression, angiogenesis, and responsiveness to therapy.
It is rarely considered that age-related common vascular co-morbidities may affect therapeutic outcomes of antiangiogenic therapy in cancer. Indeed, the accepted model of human disease consists of 4- to 8-week-old (young) tumor-bearing, but otherwise healthy, experimental mice, yet human cancers are diagnosed and treated in later decades of life when atherosclerosis and vascular diseases are highly prevalent. Here we present evidence that tumor growth and angiogenesis are profoundly altered in mice affected by natural aging and with genetically induced atherosclerosis (in ApoE(-/-) mice). Thus, transplantable tumors (Lewis lung carcinoma and B16F1) grew at higher rates in young (4 to 8 weeks old) ApoE(+/+) and ApoE(-/-) nonatherosclerotic syngeneic recipients than in their old (12 to 18 months old) or atherosclerotic (old/ApoE(-/-)) counterparts. These age-related changes were paralleled by reduced tumor vascularity, lower expression of tumor endothelial marker 1, increased acute tumor hypoxia, depletion of circulating CD45(-)/VEGFR(+) cells, and impaired endothelial sprouting ex vivo. Exposure of tumor-bearing mice to metronomic therapy with cyclophosphamide exerted antimitotic effects on tumors in young hosts, but this effect was reduced in atherosclerotic mice. Collectively, our results suggest that vascular aging and disease may affect tumor progression, angiogenesis, and responses to therapy.


Capping of aβ42 oligomers by small molecule inhibitors.
Aβ42 peptides associate into soluble oligomers and protofibrils in the process of forming the amyloid fibrils associated with Alzheimer's disease. The oligomers have been reported to be more toxic to neurons than fibrils, and have been targeted by a wide range of small molecule and peptide inhibitors. With single touch atomic force microscopy (AFM), we show that monomeric Aβ42 forms two distinct types of oligomers, low molecular weight (MW) oligomers with heights of 1-2 nm and high MW oligomers with heights of 3-5 nm. In both cases, the oligomers are disc-shaped with diameters of ~10-15 nm. The similar diameters suggest that the low MW species stack to form the high MW oligomers. The ability of Aβ42 inhibitors to interact with these oligomers is probed using atomic force microscopy and NMR spectroscopy. We show that curcumin and resveratrol bind to the N-terminus (residues 5-20) of Aβ42 monomers and cap the height of the oligomers that are formed at 1-2 nm. A second class of inhibitors, which includes sulindac sulfide and indomethacin, exhibit very weak interactions across the Aβ42 sequence and do not block the formation of the high MW oligomers. The correlation between N-terminal interactions and capping of the height of the Aβ oligomers provides insights into the mechanism of inhibition and the pathway of Aβ aggregation.


Polymorphisms of IL12RB2 May Affect the Natural History of Primary Biliary Cholangitis: A Single Centre Study.
Background. Recent GWAS in primary biliary cholangitis (PBC) showed strong associations with SNPs located within interleukin-12 receptor (IL12R) beta-2 (IL12RB2) gene. Aims. We assessed whether genetic variation of IL12RB2 is associated with laboratory and clinical features of PBC. Methods. Genomic DNA was isolated from 306 patients with PBC and 258 age/gender-matched controls. PBC-specific anti-mitochondrial antibodies (AMA) were tested in all subjects by ELISA. Two SNPs, rs3790567 and rs6679356, of IL12RB2 were genotyped using the MGB-TaqMan SNP assay. Results. Despite comparable age at diagnosis of cirrhotic and noncirrhotic PBC patients, allele A of rs3790567 and allele C of rs6679356 were overrepresented in the former rather than the latter group (p = 0.0009 and p = 0.002, resp.). The risk of cirrhosis at presentation increased when allele A and allele C coexisted. AMA-M2 titres were significantly higher in AA homozygotes of rs3790567 compared to GG homozygotes (132 ± 54 versus 103 ± 62, p = 0.02) and in rs6679356 when C allele was present (p = 0.038). There were no other significant associations between IL12RB2 polymorphisms and laboratory or clinical features. Conclusion. In this first study analyzing phenotypic features of PBC carriers of the IL12RB2 polymorphisms, we found that carriers are more frequently cirrhotic at diagnosis and have significantly higher titres of AMA.


Daily Spiritual Experiences and Adolescent Treatment Response.
The purpose of this study is to explore changes in belief orientation during treatment and the impact of increased daily spiritual experiences (DSE) on adolescent treatment response. One-hundred ninety-five adolescents court-referred to a 2-month residential treatment program were assessed at intake and discharge. Forty percent of youth who entered treatment as agnostic or atheist identified themselves as spiritual or religious at discharge. Increased DSE was associated with greater likelihood of abstinence, increased prosocial behaviors, and reduced narcissistic behaviors. Results indicate a shift in DSE that improves youth self-care and care for others that may inform intervention approaches for adolescents with addiction.


Synthesis of microtubes with a surface of "house of cards" structure via needlelike particles and control of their pore size.
The conditions for synthesizing microtubes with a surface of "house of cards" structure via needlelike particles were examined in detail. Magnesium carbonate trihydrate was formed as a metastable phase in the reaction process using magnesium hydroxide and carbon dioxide as starting materials. Subsequently, in the formation of basic magnesium carbonate from magnesium carbonate trihydrate, microtubes with a surface of house of cards structure were obtained via needlelike particles of magnesium carbonate trihydrate under certain conditions where the temperature and added amount of sodium hydroxide were properly controlled. The pore size of the microtubes could be controlled within a range of 0.5-6 microm by adjusting the condition of needlelike particle formation. In addition, the sustainability of naphthalene release from the microtube was found to be about 6 times higher than that from naphthalene crystal.


Solution structure of 6aJL2 and 6aJL2-R24G amyloidogenics light chain proteins.
AL amyloidosis is the most common amyloid systemic disease and it is characterized by the deposition of immunoglobulin light chain amyloid fibers in different organs, causing organ failure. The immunoglobulin light chain germinal line 6a has been observed to over-express in AL patients, moreover, it was observed that, out of these amyloidogenic proteins, 25% present a mutation of an Arg to Gly in position 24. In vitro studies have shown that this mutation produces proteins with a higher amyloid fiber propensity. It was proposed that this difference was due, in part, to the formation of a non-canonical structural element. In order to get a more detailed understanding of the structural and dynamic properties that govern the amyloid fibers formation process, we have determined the solution structure by NMR for the two constructs, showing that the difference in amyloid fibril formation is not due to sequence or structure.


Clinicopathologic Differences Between Micropapillary and Papillary Thyroid Carcinoma.
The aim of this study is observing the clinicopathologic features of thyroid papillary microcarcinomas (PTMs) and comparing these features with papillary thyroid carcinoma (PTC). A total of 86 surgically treated patients suffering from PTC were evaluated retrospectively. Group 1 (G1) included patients with a tumor <1 cm, while Group 2 (G2) included patients with a tumor >1 cm. The two groups were compared in terms of the preoperative thyroid-stimulating hormone (TSH) level, anti-thyroid peroxidase antibody (anti-TPO) and antithyroglobulin antibody (TgAb) values, multicentricity, the lymphovascular invasion rate, the presence of extrathyroidal extension, and central and/or lateral lymph node metastasis. There was no statistically significant difference observed between the groups in terms of the preoperative TSH level, anti-TPO, and TgAb values. The rate of multicentricity of the tumor in G2 was 66%, while it was 36% in G1 (p<0.001). The lymphovascular invasion rate in G1 was 14.2%, while it was 61% in G2 (p<0.001). The extrathyroidal extension rate of the tumor cells in G1 was 21.4%, while it was 63.6% in G2 (p<0.001). The central lymph node metastasis rate in G2 was 38.6%, while it was 4.8% in G1 (p<0.001). The lateral lymph node metastasis rate in G2 was 20.5%, while it was 0% in G1 (p<0.001). PTMs are generally associated with good prognostic factors with high survival rates. However, the risk factors such as multifocality, extrathyroidal extension, and lymphovascular invasion increasing the recurrence risk are not rare in PTM. Thus, the patients having these histopathological features of the tumor should be followed more carefully.


The analysis of the cases of circulatory and respiratory arrest in the work of the Regional Unit of Ambulance Service - Sródmieście Station.
The major causes of deaths all over the world are circulatory system diseases, neoplasms and injuries. Each man can become a participant of the event which results in life-threatening emergencies and the most immediate possible actions are essential. The period of time for starting efficient life-restoration actions is very short, estimated at 4-5 minutes. Ambulance Service is a medical organization created to apply aid in life-threatening emergencies. The standards of the developed western countries determine the arrival time at 7-10 minutes from the call time. Both first-aid applied by the accident witnesses and efficient actions of ambulance service have significance for effective pre-hospital aid and increasing the chances of survival of people in need. The study analysed emergency records of the ambulance cars of the Regional Unit of Ambulance Service - Sródmieście Station in Lublin in the year 2000. 3,723 calls were recorded. In 142 cases complete resuscitation actions were carried out due to circulatory and respiratory arrest. The records selected this way went through a detailed analysis. In 3.8% of the interventions of emergency teams the necessity of applying advanced life support was observed. The time of arrival at the scene, transport of the patient to the admission room as well as efficiency of resuscitation comply with the European standards. The efficiency of resuscitation actions estimated at 51.4% depended on the age of the patient, the cause of circulatory and respiratory arrest and ambulance arrival time. Taking up basic life support by witnesses of the event was observed in 2.8% of cases, in 8.5% aid was applied by the medical staff members who happened to be at the scene.


Clean intermittent self-catheterization.
The pathogenesis and the symptomatology of the infrequent voiding syndrome is discussed. The acceptability of clean intermittent self-catheterization as a treatment modality for women with the infrequent voiding syndrome is documented through questionnaires and retrospective study of patient records in fifty-four women. This study is part of a study already published.


Role of quercetin in protecting ARPE‑19 cells against H2O2‑induced injury via nuclear factor erythroid 2 like 2 pathway activation and endoplasmic reticulum stress inhibition.
Age‑related macular degeneration (AMD) is a common cause of irreversible blindness in the elderly in the western world. Research has demonstrated that degenerative and progressive conditions of retinal pigmented epithelial (RPE) cells are the key pathogenic mechanisms in AMD. Previous research has indicated the anti‑apoptosis, anti‑oxidant, anti‑inflammatory and anti‑cancer properties of quercetin. Therefore, the present study aimed to investigate the protective effects of quercetin on the ARPE‑19 human retinal pigment epithelial cell line. ARPE‑19 cells were pretreated with various concentrations of quercetin (0‑80 µM) before exposure to 300 µM H2O2. Cell viability was assessed and reactive oxygen species (ROS) were determined. The importance of the NF‑E2‑related factor 2 (Nrf2) signaling pathway was corroborated by western blotting and immunostaining. The protein expression levels of endoplasmic reticulum‑associated stress responsive genes and apoptotic markers were assessed by western blotting. The results demonstrated that in the H2O2 group, cell viability was weakened, but preserved in quercetin group in a dose‑dependent manner, particularly at 20 µM. The level of ROS decreased in the quercetin group compared with the control groups. In the quercetin group, the expression levels of Nrf2 and phase II enzymes (NQO1 and HO‑1) were increased, whereas the levels of ER stress markers (binding of immunoglobulin protein, CCAAT/enhancer‑binding protein homologous protein and phosphorylated eukaryotic translation initiation factor 2α) were reduced. Cell apoptosis‑associated protein expression levels were altered, with the increase of B‑cell lymphoma 2 and reduction of Bcl‑2 X‑associated protein. In conclusion, quercetin protected ARPE‑19 cells from H2O2‑induced cytotoxicity by activating the Nrf2 pathway, inhibiting ER stress and targeting anti‑apoptotic proteins.


Measurement of phenotype and absolute number of circulating heparin-binding hemagglutinin, ESAT-6 and CFP-10, and purified protein derivative antigen-specific CD4 T cells can discriminate active from latent tuberculosis infection.
The tuberculin skin test (TST) and interferon gamma (IFN-γ) release assays (IGRAs) are used as adjunctive tests for the evaluation of suspected cases of active tuberculosis (TB). However, a positive test does not differentiate latent from active TB. We investigated whether flow cytometric measurement of novel combinations of intracellular cytokines and surface makers on CD4 T cells could differentiate between active and latent TB after stimulation with Mycobacterium tuberculosis-specific proteins. Blood samples from 60 patients referred to the Singapore Tuberculosis Control Unit for evaluation for active TB or as TB contacts were stimulated with purified protein derivative (PPD), ESAT-6 and CFP-10, or heparin-binding hemagglutinin (HBHA). The CD4 T cell cytokine response (IFN-γ, interleukin-2 [IL-2], interleukin-17A [IL-17A], interleukin-22 [IL-22], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor alpha [TNF-α]) and surface marker expression (CD27, CXCR3, and CD154) were then measured. We found that the proportion of PPD-specific CD4 T cells, defined as CD154(+) TNF-α(+) cells that were negative for CD27 and positive for GM-CSF, gave the strongest discrimination between subjects with latent and those with active TB (area under the receiver operator characteristic [ROC] curve of 0.9277; P < 0.0001). Also, the proportions and absolute numbers of HBHA-specific CD4 T cells were significantly higher in those with latent TB infection, particularly CD154(+) TNF-α(+) IFN-γ(+) IL-2(+) and CD154(+) TNF-α(+) CXCR3(+). Finally, we found that the ratio of ESAT-6- and CFP-10-responding to HBHA-responding CD4 T cells was significantly different between the two study populations. In conclusion, we found novel markers of M. tuberculosis-specific CD4 cells which differentiate between active and latent TB.


Preparedness for practice. Young physicians' views of their professional education.
To describe the views of young physicians (younger than age 45 years) regarding the appropriateness of specific aspects of medical training that have often been criticized as inadequate. Proportional analysis of survey data, stratified by medical school type and graduate medical education specialty and adjusted for demographics. National sample of 4756 allopathic and osteopathic physicians trained in allopathic residencies representing a variety of practice settings. Overall satisfaction with medical training, including medical school through residency and fellowship; satisfaction with preparedness for five aspects of practice and six types of patients; and satisfaction with the amount of time spent in each of six training settings. Eighty percent of young physicians reported that their formal medical training did an excellent or good job of preparing them for medical practice. Much smaller proportions (21% to 78%) reported excellent or good preparation to treat specific conditions or types of patients, and few (3%) reported being well prepared to manage business aspects of practice. Large proportions (35% to 63%) would prefer to have received more training in settings outside of hospitals, including managed care settings (67%). Significant differences in preparedness were observed by type of training; those trained in general and family practice reported better preparedness along many dimensions than did those trained in general internal medicine. Young physicians generally confirm critiques of medical training noted by scholars and commissions. Health care reform is likely to increase the urgency for remedial action.


Designing services for frequent attenders to the emergency department: a characterisation of this population to inform service design.
Frequent attendance to the emergency department (ED) is a growing public health concern. Designing services for frequent attenders poses challenges, given the heterogeneous nature of this group. This was a two-part observational study identifying frequent attenders from ED records. The first stage studied trends and developed personas with emphasis on differentiating moderate frequent attenders (attending between 5 and 20 times per year) and extreme frequent attenders (attending more than 20 times). Stage 2 included a case note review of 100 consecutive frequent attenders. Results showed an increase in frequent attendance from 2.59% to 4.12% over 8 years. Moderate frequent attenders accounted for 97%. Of the 100 frequent attenders studied, 45% had medically unexplained symptoms (MUS), associated with younger age (p<0.001) but not with gender (p>0.05). In conclusion, the ED is a useful hub for identifying frequent attenders with MUS, particularly among moderate frequent attenders; service design for this group should consider a 'whole-systems approach' with integration between primary and secondary care, including specialist liaison psychiatry services where appropriate.


Open reduction of congenital hip dislocation by medial approach: case series.
To present the results of medial approach in open reduction of congenital hip dislocation, with the preservation of the medial femoral circumflex artery. We operated on 48 nonreducible hip dislocations diagnosed in children aged 6-27 months. Twenty-two hips (17 patients) were available for clinical and radiographic follow-up. The median age of children at the time of operation was 15 months (range 7-29), and median duration of the follow-up was 4.5 years (range 3-14). The latest radiographic evaluation of the treatment outcome was based on Severins classification. There were three hips with the loss of concentric reduction. Osteochondritis developed in three, and coxa magna in seven hips. On final evaluation, 19 hips were rated as excellent or good (Severin I or II), and three hips as poor (Severin III or IV): one hip with evident ostechondritis lesions, and two hips with the loss of concentric reduction due to treatment discontinuation. By preserving circumflex medial artery and eliminating obstacles to reduction, vascularization of the femur head is ensured. The loss of concentric reduction is prevented by complete removal of all obstacles on the way of the femur head down to the bottom of acetabulum, by postoperative cast immobilization, and by walking with abduction orthosis for an appropriate period of time. Medial approach in surgical management of congenital hip dislocation in infants under 24 months of age is considered safe and efficient procedure.


Incipient balancing selection through adaptive loss of aquaporins in natural Saccharomyces cerevisiae populations.
A major goal in evolutionary biology is to understand how adaptive evolution has influenced natural variation, but identifying loci subject to positive selection has been a challenge. Here we present the adaptive loss of a pair of paralogous genes in specific Saccharomyces cerevisiae subpopulations. We mapped natural variation in freeze-thaw tolerance to two water transporters, AQY1 and AQY2, previously implicated in freeze-thaw survival. However, whereas freeze-thaw-tolerant strains harbor functional aquaporin genes, the set of sensitive strains lost aquaporin function at least 6 independent times. Several genomic signatures at AQY1 and/or AQY2 reveal low variation surrounding these loci within strains of the same haplotype, but high variation between strain groups. This is consistent with recent adaptive loss of aquaporins in subgroups of strains, leading to incipient balancing selection. We show that, although aquaporins are critical for surviving freeze-thaw stress, loss of both genes provides a major fitness advantage on high-sugar substrates common to many strains' natural niche. Strikingly, strains with non-functional alleles have also lost the ancestral requirement for aquaporins during spore formation. Thus, the antagonistic effect of aquaporin function-providing an advantage in freeze-thaw tolerance but a fitness defect for growth in high-sugar environments-contributes to the maintenance of both functional and nonfunctional alleles in S. cerevisiae. This work also shows that gene loss through multiple missense and nonsense mutations, hallmarks of pseudogenization presumed to emerge after loss of constraint, can arise through positive selection.


External validation of severity scoring systems for acute renal failure using a multinational database.
Several different severity scoring systems specific to acute renal failure have been proposed. However, most validation studies of these scoring systems were conducted in a single center or in a small number of centers, often the same ones used for their development. Therefore, it is not known whether such severity scoring systems may be widely applied. Prospective clinical investigation. Intensive care units. One thousand seven hundred and forty-two intensive care unit patients with acute renal failure who were either treated with renal replacement therapy or fulfilled predefined criteria. Demographic and clinical information and outcomes were measured. Scores for four acute renal failure-specific scoring systems and two general scoring systems (Simplified Acute Physiology Score II and Sequential Organ Failure Assessment) were calculated, and their discrimination and calibration were tested with receiver operating characteristic curves and Hosmer-Lemeshow goodness-of fit-tests. For the receiver operating characteristic curves, blood lactate levels were also used as a reference. All scores had an area under the receiver operating characteristic curve <0.7 (Mehta 0.670, Liano 0.698, Chertow 0.610, Paganini 0.643, Simplified Acute Physiology Score II 0.645, Sequential Organ Failure Assessment 0.675, lactate 0.639). For scores that can calculate predicted mortality, the Hosmer-Lemeshow goodness-of-fit test showed poor calibration. None of the scoring systems tested had a high level of discrimination or calibration to predict mortality for patients with acute renal failure when tested in a broad cohort of patients from multiple countries. A large, multiple-center database might be needed to improve the discrimination and calibration of acute renal failure scoring system.


Glycosaminoglycan mimetic peptide nanofibers promote mineralization by osteogenic cells.
Bone tissue regeneration is accomplished by concerted regulation of protein-based extracellular matrix components, glycosaminoglycans (GAGs) and inductive growth factors. GAGs constitute a significant portion of the extracellular matrix and have a significant impact on regulating cellular behavior, either directly or through encapsulation and presentation of growth factors to the cells. In this study we utilized a supramolecular peptide nanofiber system that can emulate both the nanofibrous architecture of collagenous extracellular matrix and the major chemical composition found on GAGs. GAGs and collagen mimetic peptide nanofibers were designed and synthesized with sulfonate and carboxylate groups on the peptide scaffold. The GAG mimetic peptide nanofibers interact with bone morphogenetic protein-2 (BMP-2), which is a critical growth factor for osteogenic activity. The GAG mimicking ability of the peptide nanofibers and their interaction with BMP-2 promoted osteogenic activity and mineralization by osteoblastic cells. Alkaline phosphatase activity, Alizarin red staining and energy dispersive X-ray analysis spectroscopy indicated the efficacy of the peptide nanofibers in inducing mineralization. The multifunctional and bioactive microenvironment presented here provides osteoblastic cells with osteogenic stimuli similar to those observed in native bone tissue.


A diet-specific microbiota drives Salmonella Typhimurium to adapt its in vivo response to plant-derived substrates.
Little is known about the complex interactions between the diet, the gut microbiota, and enteropathogens. Here, the impact of two specific diets on the composition of the mouse gut microbiota and on the transcriptional response of Salmonella Typhimurium (S. Typhimurium) was analyzed in an enteritis model. Mice were fed for two weeks a fibre-rich, plant-based diet (PD), or a Westernized diet (WD) rich in animal fat and proteins and in simple sugars, and then infected with an invasin-negative S. Typhimurium strain ST4/74 following streptomycin-treatment. Seventy-two hours post infection, fecal pathogen loads were equal in both diet groups, suggesting that neither of the diets had negatively influenced the ability of this ST4/74 strain to colonize and proliferate in the gut at this time point. To define its diet-dependent gene expression pattern, S. Typhimurium was immunomagnetically isolated from the gut content, and its transcriptome was analyzed. A total of 66 genes were more strongly expressed in mice fed the plant-based diet. The majority of these genes was involved in metabolic functions degrading substrates of fruits and plants. Four of them are part of the gat gene cluster responsible for the uptake and metabolism of galactitol and D-tagatose. In line with this finding, 16S rRNA gene amplicon analysis revealed higher relative abundance of bacterial families able to degrade fiber and nutritive carbohydrates in PD-fed mice in comparison with those nourished with a WD. Competitive mice infection experiments performed with strain ST4/74 and ST4/74 ΔSTM3254 lacking tagatose-1,6-biphosphate aldolase, which is essential for galactitol and tagatose utilization, did not reveal a growth advantage of strain ST4/74 in the gastrointestinal tract of mice fed plant-based diet as compared to the deletion mutant. A Westernized diet and a plant-based diet evoke distinct transcriptional responses of S. Typhimurium during infection that allows the pathogen to adapt its metabolic activities to the diet-derived nutrients. This study therefore provides new insights into the dynamic interplay between nutrient availability, indigenous gut microbiota, and proliferation of S. Typhimurium.


The C-terminal cytoplasmic tail of claudins 1 and 5 but not its PDZ-binding motif is required for apical localization at epithelial and endothelial tight junctions.
Claudins are a family of tetraspan transmembrane proteins that represent the major constituents of epithelial and endothelial tight junctions (TJs). They form TJ strands representing the major barrier regulating paracellular transport of solutes and water. Intracellularly, claudins are connected via a C-terminal PDZ-binding motif with several TJ-associated proteins containing PDZ domains. Although these interactions can provide a link to the actin cytoskeleton, they appear to be dispensable for the TJ localization of claudins. To identify TJ-targeting elements in the C-terminal cytoplasmic domains of the claudins 1 and 5, we generated a series of C-terminal deletion mutants and analyzed their distribution in polarized epithelial (MDCK) and endothelial (HMEC-1) cells. TJ localization was revealed by establishing an in vivo cross-linking approach that stabilized claudin-TJ interactions. We show that residues located C-terminal to the last transmembrane domain are required for the proper targeting to apical TJ.s. While claudin derivatives lacking only the very C-terminal PDZ-binding motif continue to localize to TJs, mutants lacking the entire C-terminal juxtamembrane sequence do not associate with TJs and accumulate in intracellular structures. This indicates that crucial determinants for stable TJ incorporation of claudins reside in a cytoplasmic C-terminal sequence which up to now has not been implicated in specific protein-protein interactions.


Maternal Risk Factors for Stillbirth: A Registry-Based Study.
Background and Objectives: The number of stillbirths has reduced more slowly than has maternal mortality or mortality in children younger than 5 years, which were explicitly targeted in the Millennium Development Goals. Placental pathologies and infection associated with preterm birth are linked to a substantial proportion of stillbirths. Appropriate preconception care and quality antenatal care that is accessible to all women has the potential to reduce stillbirth rates. The aim of the present study was to assess potential risk factors associated with stillbirth within maternal medical diseases and obstetric complications. Materials and Methods: Retrospective cohort study (2001-2014) was used to analyse data from the Medical Birth Register on stillbirth and live births as controls. Adjusted Odds ratios (aOR) with 95% confidence intervals (CI) were estimated. Multiple regression model adjusted for maternal age, parity and gestational age. Results: The stillbirth rate was 6.2 per 1000 live and stillbirths. The presence of maternal medical diseases greatly increased the risk of stillbirth including diabetes mellitus (aOR = 2.5; p < 0.001), chronic hypertension 3.1 (aOR = 3.1; p < 0.001) and oligohydromnios/polyhydromnios (aOR = 2.4; p < 0.001). Pregnancy complications such as intrauterine growth restriction (aOR = 2.2; p < 0.001) was important risk factor for stillbirth. Abruption was associated with a 2.8 odds of stillbirth. Conclusions: Risk factors most significantly associated with stillbirth include maternal history of chronic hypertension and abruptio placenta which is a common cause of death in stillbirth. Early identification of potential risk factors and appropriate perinatal management are important issues in the prevention of adverse fetal outcomes and preventive strategies need to focus on improving antenatal detection of fetal growth restriction.


Self-pinning of silica suspension droplets on hydrophobic surfaces.
Self-pinning induced by the aggregation of particles at the edge of a pinned drop is a pre-requisite for the coffee ring formation. The edge (three-phase contact line) of a suspension drop on a hydrophobic surface would depin and shrink in the early stage of evaporation process. It is plausible to conjecture that the self-pinning of silica suspension drops depends on the particle size and surface property. Two substrate materials, the alkylsilane coated surfaces and the polydimethylsiloxane surfaces, and three different sizes of silica particles are used to explore the criterion of self-pinning of silica suspension drops on these hydrophobic surfaces. The evaporation process of droplets is recorded and further analyzed. The pinning concentration of silica suspensions of a fixed size linearly depends on the receding contact angle of the surface, irrelevant to the substrate material and initial particle concentration. The pinning concentration decreases along with an increase in particle size. In addition, the pinning concentrations of bi-dispersed silica (e.g. 400 + 1000 nm) suspensions have an excellent agreement with that of larger size (1000 nm) particle system. That implies that the larger particle dominates the system of bi-dispersed silica suspensions to initiate the self-pinning, further verified by SEM images.


Correlation between length and tilt of lipid tails.
It is becoming recognized from simulations, and to a lesser extent from experiment, that the classical Helfrich-Canham membrane continuum mechanics model can be fruitfully enriched by the inclusion of molecular tilt, even in the fluid, chain disordered, biologically relevant phase of lipid bilayers. Enriched continuum theories then add a tilt modulus κθ to accompany the well recognized bending modulus κ. Different enrichment theories largely agree for many properties, but it has been noticed that there is considerable disagreement in one prediction; one theory postulates that the average length of the hydrocarbon chain tails increases strongly with increasing tilt and another predicts no increase. Our analysis of an all-atom simulation favors the latter theory, but it also shows that the overall tail length decreases slightly with increasing tilt. We show that this deviation from continuum theory can be reconciled by consideration of the average shape of the tails, which is a descriptor not obviously includable in continuum theory.


Rehabilitation of Nose following Chemical Burn Using CAD/CAM Made Substructure for Implant Retained Nasal Prosthesis: A Clinical Report.
Insufficient knowledge of medical chemicals and their improper use have destructive effects. Accidental exposure to chemicals on facial tissue may result in large facial defect. For ages the tradition of piercing nose is common but improper use of unknown chemical for piercing has deleterious effect. Mostly rhinectomy defects are acquired caused by trauma or malignant diseases. Prosthetic rehabilitation is the preferred treatment of choice for any large rhinectomy defects as medical and surgical interventions are ineffective in developing esthetics. Main concern with the prosthesis for such defects is retention. This article describes rehabilitation of a patient with large size nasal defect created by chemical burn in childhood during piercing. Implant retained customized silicone nasal prosthesis was fabricated using simple O-ring attachments and innovative modified polyamide acrylic resin substructure acting as skeleton.


Quality of sleep for hospitalized patients in Rasoul-Akram hospital.
Sleep disturbances have negative effects on medical conditions, mental health and cognitive performance. It was shown that about 60% of inpatients suffer from sleep problems. The aim of this study was to assess the correlation between sleep quality and other factors in the inpatients of Rasoul-e-Akram hospital. In this cross-sectional study, all the hospitalized patients in twelve wards of Rasoul-e-Akram hospital during September 2012, were examined. Sleeping habits of 209 inpatients of different wards were assessed through the Persian version of Pittsburgh Sleep Questionnaire (PSQI). A self-designed 18- question questionnaire was conducted for all patients in order to assess their attitude to interior and atmosphere of wards. Content validity and test retest reliability were evaluated. The pain level was also measured by the visual analog scale (VAS) and scores analyzed by the statistical methods of frequency, percentage, chi-square and logistic regression. The mean of the total scores in PSQI was 8.8±4.8 and 70.8% of the patients were 'poor sleepers' (global PSQI> 5). Age and gender had no effect on the PSQI total score, but the number of roommates, type of the ward, hospitalization period, presence and severity of pain, taking sleep medication and attitude toward the overall atmosphere and interior of wards have caused deviation in scores. Sleep problems are quite frequent in medical inpatients. Pain management and modification of the ward interior and atmosphere can impact inpatients sleep quality.


Spontaneous abortions and twinning.
The relation between spontaneous abortions and twinning was studied in the years 1980-1981 in 22 towns of the South Moravian Region, Czechoslovakia. Each town has more than 10,000 inhabitants and less than 750 births per year. The number of spontaneous abortions and the number of twin births were evaluated separately for each town and for a time unit of three months. The comparison indicated that the group with a higher number of spontaneous abortions also had a lower number of twin births. The relation between spontaneous abortions and twinning is discussed.


Building Leadership Through Partnerships: Using Concept Mapping to Develop Community Capacity to Address Gender-Based Violence.
To address an unmet need for community-driven gender-based violence (GBV) responses in areas with high levels of precarious employment, a community-based organization partnered with academic researchers and community members to use concept mapping to inform the design of a leadership development program. The objectives of the research were to identify and prioritize the skills, knowledge, and resources that "worker-leaders" (informal activists) need to help prevent and reduce acts of GBV directed toward individuals working in low-wage and precarious employment situations. Using concept mapping as part of a community-based participatory project, the community-academic research team elicited input from Latinx and Korean residents from low-income immigrant communities. Individuals brainstormed, sorted, and rated the skills and resources necessary to reduce and respond to GBV. Quantitative analyses were jointly interpreted by community and academic researchers. Sixty-nine individuals participated in at least one concept mapping activity. Twenty-one unique skills and resources across seven thematic constructs were identified. Participants believed that skills and resources related to Workplace Violence would be most effective at building trainee capacity to address GBV, but Employee and Survivor Support topics were more likely to draw worker-leaders to a program. Access to organizations that support survivors was considered both highly effective and likely to be of great interest. This research ensures that the GBV leadership training program is grounded in community-generated evidence. The process of undertaking this research was at least as useful in the development of the leadership of the program as the results themselves.


Prevalence and Clinical Profiling of Dysglycemia and HIV Infection in Persons With Pulmonary Tuberculosis in Brazil.
There are scarce data on the prevalence and disease presentation of HIV in patients with tuberculosis (TB) and dysglycemia (diabetes [DM] and prediabetes [PDM]), especially in TB-endemic countries. We assessed the baseline epidemiological and clinical characteristics of patients with culture-confirmed pulmonary TB, enrolled in a multicenter prospective cohort in Brazil (RePORT-Brazil) during 2015-2019. Dysglycemia was defined by elevated glycated hemoglobin and stratified as PDM or DM. Additionally, we used data from TB cases obtained through the Brazilian National Notifiable Diseases Information System (SINAN), during 2015-2019. In SINAN, diagnosis of diabetes was based on self-report. Logistic regression models were performed to test independent associations between HIV, dysglycemia status, and other baseline characteristics in both cohorts. In the RePORT-Brazil cohort, the prevalence of DM and of PDM was 23.7 and 37.8%, respectively. Furthermore, the prevalence of HIV was 21.4% in the group of persons with TB-dysglycemia and 20.5% in that of patients with TBDM. In the SINAN cohort, the prevalence of DM was 9.2%, and among the TBDM group the prevalence of HIV was 4.1%. Logistic regressions demonstrated that aging was independently associated with PDM or DM in both the RePORT-Brazil and SINAN cohorts. In RePORT-Brazil, illicit drug use was associated with PDM, whereas a higher body mass index (BMI) was associated with DM occurrence. Of note, HIV was not associated with an increased risk of PDM or DM in patients with pulmonary TB in both cohorts. Moreover, in both cohorts, the TBDM-HIV group presented with a lower proportion of positive sputum smear and a higher frequency of tobacco and alcohol users. There is a high prevalence of dysglycemia in patients with pulmonary TB in Brazil, regardless of the HIV status. This reinforces the idea that DM should be systematically screened in persons with TB. Presence of HIV does not substantially impact clinical presentation in persons with TBDM, although it is associated with more frequent use of recreational drugs and smear negative sputum samples during TB screening.


Use of power spectral analysis of respiratory sinus arrhythmia to detect graft rejection.
Some evidence has suggested that graft rejection in heart transplant recipients is accompanied by sinus node dysfunction. To test this hypothesis the electrocardiograms of 21 orthotopic heart transplant recipients receiving cyclosporine were recorded at regularly scheduled biopsies. This resulted in 105 good quality recordings of at least 10 minutes each. All exhibited normal sinus rhythm. These recordings were then processed through patented digital routines that calculated the power spectrum of the RR intervals. All recordings exhibited Mayer wave and respiratory sinus arrhythmia (RSA) periodicities. Peak spectral power of RSA (PSP-RSA) demonstrated good repeatability at 2 weeks (r = 0.81). A paired t test comparing the baseline PSP-RSA in eight subjects who experienced rejection episodes with their individual average PSP-RSA during periods of rejection revealed a significant decrease (p = 0.039). As a global measure, PSP-RSA greater than 1 (natural logarithmic scales) demonstrated a sensitivity of 1.0, specificity of 0.42, positive predictive value of 0.22, and negative predictive value of 1.0. These tentative results demonstrate that PSP-RSA may be a sensitive, noninvasive marker for graft rejection of heart transplant patients receiving cyclosporine for immunosuppression. A larger, more extensive study needs to be conducted to confirm these results.


Transformation by different oncogenes relies on specific metabolic adaptations.
Metabolic adaptations are emerging as common traits of cancer cells and tumor progression. In vitro transformation of NIH 3T3 cells allows the analysis of the metabolic changes triggered by a single oncogene. In this work, we have compared the metabolic changes induced by H-RAS and by the nuclear resident mutant of histone deacetylase 4 (HDAC4). RAS-transformed cells exhibit a dominant aerobic glycolytic phenotype characterized by up-regulation of glycolytic enzymes, reduced oxygen consumption and a defect in complex I activity. In this model of transformation, glycolysis is strictly required for sustaining the ATP levels and the robust cellular proliferation. By contrast, in HDAC4/TM transformed cells, glycolysis is only modestly up-regulated, lactate secretion is not augmented and, instead, mitochondrial oxygen consumption is increased. Our results demonstrate that cellular transformation can be accomplished through different metabolic adaptations and HDAC4/TM cells can represent a useful model to investigate oncogene-driven metabolic changes besides the Warburg effect.


Real-world implementation of sequential targeted therapies for EGFR-mutated lung cancer.
Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging. EGFR+ NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib. A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, p < 0.001) associated with lack of T790M testing, whose most frequent cause (in approximately 50% of cases) was also rapid clinical decline. Among the 127 consecutive patients with failure of 1G/2G TKI started after November 2015, 47 (37%) received osimertinib, with a median overall survival of 36 months versus 24 and 21 months for patients with alternative and no subsequent therapies (p = 0.003). Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR+ NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR+ NSCLC in the future.


A free-blockage controlled release system based on the hydrophobic/hydrophilic conversion of mesoporous silica nanopores.
A pH-responsive free-blockage release system was achieved through controlling the hydrophobic/hydrophilic conversion of mesoporous silica nanopores. This system further presented pulsatile release with changing pH values between 4.0 and 7.0 for several cycles. This free-blockage release system could also release antitumor agents to induce cell death after infecting tumor cells and could have the ability of continuous infection to tumor cells with high drug-delivery efficiency and few side effects.


[Determination of lean body mass by skin fold measurements (author's transl)].
Skin folds were measured on 12 different body sites of 32 boys, aged 9--12, by using the calipers of Best, Lange, Harpenden and Holtain successively. We compared the measurements of the biceps, triceps, scapula, suprailiaca, abdominal and thigh skin folds. The results depended on body sites as well as on the type of caliper used. Therefore, conversion is recommendable only when absolute values of body fat must be taken into consideration, as when investigating population parameters in terms of functional performance capacity. Moreover conversion is necessary when using those nomograms which are built up mainly by measurements with an unusual caliper. Conversions must be omitted when comparing data by means of rank-correlations.


Influence of electroporation on chicken blastoderm cell viability in vitro.
The aim of this study was to compare two types of devices used for blastoderm cell (BC) transfection: the Nucleofector (Amaxa, Biosystems) and the Multiporator (Eppendorf). To assess the influence of electric current on BCs, different conditions of both nucleofection and electroporation were used. Next, the viability of cells was assessed. The highest number of cells (90.8%) was viable after nucleofection in the G10 program. After transfection in the presence of pmaxGFP, the A23 program was found to be most advantageous. The elecroporation experiment with the Multiporator (Eppendorf) showed a significant influence of osmotic pressure and voltage on BC viability. Namely, in the isoosmolar buffer BC viability was statistically higher (P < or = 0.05) in comparison to the hypoosmolar buffer. The, viability of cells was statistically higher (P < or = 0.05) after application of 25V as compared to 50V. The efficiency of transfection in the presence of EGFP-C 1 after electroporation in 2 pulses, 25V, 500 micros in the isoosmolar buffer was better than in the recommended conditions in the Amaxa Biosystems A23 program.


Characteristics and Impact of HPV-Associated p16 Expression on Head and Neck Squamous Cell Carcinoma in Thai Patients.
Head and neck squamous cell carcinoma (HNSCC) is a common malignancy in Asia. Infection by human papilloma virus (HPV) has been recognized as an etiological risk for HNSCC, especially oropharyngeal region. While the association between HPV and HNSCC has been well evaluated in Western countries, only a few investigated the HPV-associated HNSCC in Southeast Asia. This study evaluated the prevalence, the characteristics, and the impact of HPV on the treatment outcomes in Thai HNSCC patients. Non-nasopharyngeal HNSCC patients treated at Ramathibodi Hospital during 2007-2013 were identified through the cancer registry database. Baseline patient, treatment data and survivals were retrospectively reviewed. The formalin-fixed paraffin-embedded (FFPE) tissue sections were retrieved for p16 analysis. The HPV status was determined by p16 immunohistochemistry. The survival outcomes were analyzed in cases which p16 status was confirmed. Total of 200 FFPE tissues of HNSCC patients was evaluated for p16 expression. Positive p16 status was observed in 24 cases (12%); majority of p16-positive were men (20:4 cases). The oropharynx (37.9%) was the most common site found in p16-positive while oral cavity (3.2%) was the least common site. Interestingly, 66.7% of p16-positive were former/current smokers, and 70.8% of this subgroup was categorized as clinical AJCC stage III-IV. The p16-positive HNSCC was significantly superior in 5-year overall survival [5-yrs OS 63% vs. 40%, p=0.03], 5-year disease-free survival [5-yrs DFS 61% vs. 36%, p=0.03] and in 5-year locoregional relapse-free survival [5-yrs LRFS 93% vs. 68%, p=0.018] when compared with p16-negative. In comparison to the results from the Western countries, the prevalence of HPV-related HNSCC in Thai patients was less, and differences in some characteristics were observed. Nevertheless, improvement in OS, DFS and LRFS were observed in p16-positive patients. Our analyses suggested that p16 status is also a strong prognostic marker for HNSCC patients in Thailand.


Distinct patterns of protective antibodies are generated against Borrelia burgdorferi in mice experimentally inoculated with high and low doses of antigen.
We have studied the development of clinical arthritis and the generation of protective antibodies in two normal, inbred strains of mice either infected by ticks or experimentally (subcutaneous) inoculated with increasing numbers of Borrelia burgdorferi organisms. AKR/N mice developed only mild and DBA/2 mice only marginal clinical arthritis irrespective of the route of infection or the numbers of spirochetes (10-10(8)) inoculated. In contrast, immunodeficient SCID mice developed severe chronic arthritis under similar conditions, but with a delayed onset at lower numbers of needle-inoculated spirochetes or after tick bite. AKR/N and DBA/2 mice inoculated with either 10(4) (and fewer) B. burgdorferi organisms or via experimentally infected ticks generated antibodies with specificities for a variety of B. burgdorferi antigens except those to the outer surface proteins A and B (OspA, OspB). In contrast, mice inoculated with more than 10(4) spirochetes (10(5)-10(8)) developed in addition antibodies to OspA and OspB. Most notably, all three types of immune sera taken from DBA/2 mice showed similar capacities to confer protection on SCID mice against subsequent challenge with viable B. burgdorferi organisms. The data not only demonstrate that the quality of humoral immune responses to B. burgdorferi in mice is determined by the antigenic load, they also indicate the existence of further protective antibodies with specificities distinct from OspA and OspB.


[Changes in the legally mandated distribution of competency for mosquito control based on experience on Reunion Island].
The purpose of this article is to describe the legal framework for controlling mosquito vectors of diseases transmissible to human beings in certain locations such as Reunion Island. A distinction is made between general legal measures for insect vector control and specific measures for mosquito control. Regionalization is a major factor in the legal framework for insect vector control, thus limiting the scope of action by the prefecture. Another factor involves the increasing role of an important new player, i.e., the regional health agencies. Mosquito vector control raises the need to impose and enforce measures on the general public as well as private citizens. Failure to comply with these measures is punishable by sanctions and fines with no diminishing effect on de jure implementation of control measures by public agencies.


Synthesis of potential antifilarial agents. 1-(5-Benzoylbenzimidazol-2-yl)-3-alkyl- and -arylureas.
A series of 1-(5-benzoylbenzimidazol-2-yl)-3-substituted ureas have been synthesized by reacting an appropriate isocyanate with 2-amino-5-benzoylbenzimidazole or by reacting methyl (5-benzoylbenzimidazol-2-yl)carbamate with various amines. Several of the compounds have demonstrated antifilarial activity against Brugia pahangi and Litomosoides carinii.