Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision.
Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000-13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support.


Public Preferences for Digital Health Data Sharing: Discrete Choice Experiment Study in 12 European Countries.
With new technologies, health data can be collected in a variety of different clinical, research, and public health contexts, and then can be used for a range of new purposes. Establishing the public's views about digital health data sharing is essential for policy makers to develop effective harmonization initiatives for digital health data governance at the European level. This study investigated public preferences for digital health data sharing. A discrete choice experiment survey was administered to a sample of European residents in 12 European countries (Austria, Denmark, France, Germany, Iceland, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom) from August 2020 to August 2021. Respondents answered whether hypothetical situations of data sharing were acceptable for them. Each hypothetical scenario was defined by 5 attributes ("data collector," "data user," "reason for data use," "information on data sharing and consent," and "availability of review process"), which had 3 to 4 attribute levels each. A latent class model was run across the whole data set and separately for different European regions (Northern, Central, and Southern Europe). Attribute relative importance was calculated for each latent class's pooled and regional data sets. A total of 5015 completed surveys were analyzed. In general, the most important attribute for respondents was the availability of information and consent during health data sharing. In the latent class model, 4 classes of preference patterns were identified. While respondents in 2 classes strongly expressed their preferences for data sharing with opposing positions, respondents in the other 2 classes preferred not to share their data, but attribute levels of the situation could have had an impact on their preferences. Respondents generally found the following to be the most acceptable: a national authority or academic research project as the data user; being informed and asked to consent; and a review process for data transfer and use, or transfer only. On the other hand, collection of their data by a technological company and data use for commercial communication were the least acceptable. There was preference heterogeneity across Europe and within European regions. This study showed the importance of transparency in data use and oversight of health-related data sharing for European respondents. Regional and intraregional preference heterogeneity for "data collector," "data user," "reason," "type of consent," and "review" calls for governance solutions that would grant data subjects the ability to control their digital health data being shared within different contexts. These results suggest that the use of data without consent will demand weighty and exceptional reasons. An interactive and dynamic informed consent model combined with oversight mechanisms may be a solution for policy initiatives aiming to harmonize health data use across Europe.


The Effect of Backpack Load Carriage on the Kinetics and Kinematics of Ankle and Knee Joints During Uphill Walking.
The purpose of this study was to investigate the effect of load carriage on the kinematics and kinetics of the ankle and knee joints during uphill walking, including joint work, range of motion (ROM), and stance time. Fourteen males walked at a self-selected speed on an uphill (15°) slope wearing military boots and carrying a rifle in hand without a backpack (control condition) and with a backpack. The results showed that the stance time significantly decreased with backpack carriage (p < .05). The mediolateral impulse significantly increased with backpack carriage (p < .05). In the ankle joints, the inversion-eversion, and dorsi-plantar flexion ROM in the ankle joints increased with backpack carriage (p < .05). The greater dorsi-plantar flexion ROM with backpack carriage suggested 1 strategy for obtaining high plantar flexor power during uphill walking. The result of the increased mediolateral impulse and inversion-eversion ROM in the ankle joints indicated an increase in body instability caused by an elevated center of mass with backpack carriage during uphill walking. The decreased stance time indicated that an increase in walking speed could be a compensatory mechanism for reducing the instability of the body during uphill walking while carrying a heavy backpack.


Sticky platelet syndrome.
The sticky platelet syndrome (SPS) is an autosomal dominant platelet disorder associated with arterial and venous thromboembolic events. It is characterized by hyperaggregability of platelets in platelet-rich plasma with adenosine diphosphate (ADP) and epinephrine (type I), epinephrine alone (type II), or ADP alone (type III). Clinically, patients may present with angina pectoris, acute myocardial infarction (MI), transient cerebral ischemic attacks, stroke, retinal thrombosis, peripheral arterial thrombosis, and venous thrombosis, frequently recurrent under oral anticoagulant therapy. Clinical symptoms, especially arterial, often present following emotional stress. Combinations of SPS with other congenital thrombophilic defects have been described. Low-dose aspirin treatment (80 to 100 mg) ameliorates the clinical symptoms and normalizes hyperaggregability. The precise etiology of this defect is at present not known, but receptors on the platelet surface may be involved. Normal levels of platelet factor 4 (PF4) and beta-thromboglobulin in plasma suggest that the platelets are not activated at all times; they appear to become hyperactive upon ADP or adrenaline release. In vivo clumping could temporarily or permanently occlude a vessel, leading to the described clinical manifestations. The syndrome appears to be prominent especially in patients with unexplained arterial vascular occlusions.


Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.


Estimating the accuracy of the MARTINI model towards the investigation of peripheral protein-membrane interactions.
Peripheral membrane proteins play a major role in numerous biological processes by transiently associating with cellular membranes, often with extreme membrane specificity. Because of the short-lived nature of these interactions, molecular dynamics (MD) simulations have emerged as an appealing tool to characterize at the structural level the molecular details of the protein-membrane interface. Transferable coarse-grained (CG) MD simulations, in particular, offer the possibility to investigate the spontaneous association of peripheral proteins with lipid bilayers of different compositions at limited computational cost, but they are hampered by the lack of a reliable a priori estimation of their accuracy and thus typically require a posteriori experimental validation. In this article, we investigate the ability of the MARTINI CG force field, specifically the 3 open-beta version, to reproduce known experimental observations regarding the membrane binding behavior of 12 peripheral membrane proteins and peptides. Based on observations of multiple binding and unbinding events in several independent replicas, we found that, despite the presence of false positives and false negatives, this model is mostly able to correctly characterize the membrane binding behavior of peripheral proteins, and to identify key residues found to disrupt membrane binding in mutagenesis experiments. While preliminary, our investigations suggest that transferable chemical-specific CG force fields have enormous potential in the characterization of the membrane binding process by peripheral proteins, and that the identification of negative results could help drive future force field development efforts.


Ultrasound and salt reduction effect on physicochemical and rheological properties of meat emulsions.
Power ultrasound and salt reduction effects on meat emulsions' physicochemical and rheological properties were determined. Therefore, meat emulsions with different NaCl concentrations (1, 1.5, 2, and 2.5%) were treated in an ultrasonic bath (40 kHz, 200 W, & 9.34 W/cm2 ) at different times (0, 15, and 45 min). Results showed that salt reduction and ultrasound time significantly (p < 0.05) affected the cooking loss, water holding capacity, water activity, pH, color, hardness, viscosity, storage modulus (G'), loss modulus (G″), and phase angle δ. Meat emulsions with low salt content (1 and 1.5% NaCl) showed significantly higher values of cooking loss than standard emulsions (2.5% NaCl), while ultrasound duration of 15 min reduced the cooking loss (12 to 27%). Hardness, color, pH, and water activity (aw) decreased with salt reduction. Ultrasounds increased the hardness, viscosity, G', and G'' values in reduced-salt meat. The experimental data of apparent viscosity were properly fitted to the mathematical model of Ostwald-de-Waele. Ultrasound increased consistency (k) and decreased flow behavior index (n) in emulsions with 1.5 to 2.5% NaCl. Ultrasound at 15 min induced gelation in emulsions with 1.5 and 2.0% NaCl (40 and 20% NaCl reduction). The formulation with 2.0% NaCl was found to be the maximum concentration that did not sacrifice meat emulsion quality. When combined with 15 min of ultrasound, this formulation yielded results comparable to the standard formulation. PRACTICAL APPLICATION: Results contribute to developing reduced-salt meat emulsions using power ultrasounds. Therefore, using ultrasounds allows for a 20% reduction in salt content while maintaining the quality of the meat emulsion.


Thoracolumbar spinal deformity: Part I. A historical passage to 1990: historical vignette.
Seven millennia of anthropological artifacts and historical tales reference human spinal deformity, its diagnosis, and treatment-many of the latter of which turned out to be worse than the deformity itself. From Hippocrates to Harrington to the 21st century, the literature base has expanded in exponential fashion to yield an imperfect but constantly improving body of evidence, experience, and understanding of this challenging disease phenomenon. This review details the pre-1990 innovations, whose failures and successes have equally contributed to the advancement and dissemination of the increasingly evidence-based field of spinal deformity.


A world without the olfactory dimension.
This article aims to describe what is it like to perceive reality when suffering from congenital anosmia. Nevertheless, this objective entails a fundamental difficulty. Since I have never had the experience of olfaction, it seems natural to me to live in a world lacking the olfactory dimension; this subjective perception is the only one I know and in consequence it is difficult to describe. For this reason, in recent years I have begun to develop long conversations with other people suffering from congenital anosmia, people who have lost their sense of olfaction in adulthood and also people with a good sense of smell. My goal is to draw a map showing the principal differences that might allow us to develop a systematic comparison. Obviously, this is not an experimental or quantitative scientific procedure, but only a modest attempt to compare personal stories about subjective experiences. It is a philosophical-literary exercise, and does not aim to be anything other than that. But I hope it will help to formulate meaningful questions, which would then need a properly scientific approach. In the first part of this article I want to try to describe how I became aware that other people could smell; and in a second part, I will try to examine the consequences of anosmia in different areas of everyday life: nourishment, relationships with people, own body perception, natural or urban environments perception, time perception, and finally aesthetic appreciation and the implications of living in a world without stench.


Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma.
A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein, we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naïve patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the MCL International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33-68%) and the 5-year OS was 85% (95% CI 73-97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis, respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL.


Developing and Using Big Data Archives to Quantify Disfluency and Stuttering in Bilingual Children.
Worldwide, bilingualism is the rule rather than the exception, and yet we have surprisingly little research data on the fluency development of bilingual children, and even less information on their potential risk for stuttering. Many variables influence a bilingual child's language, speech, and fluency development (e.g., amount of exposure to each language); controlling these variables in research studies necessitates large numbers of bilingual participants. The frequency and types of typical disfluencies in the speech of young children are also varied. In addition, stuttering is also variable in its presentation, and when we assess bilingual children for the presence of stuttering we are adding yet another layer of complexity. This article reviews research on typical disfluencies in monolingual and bilingual speakers, and how this information might be useful clinically. We provide examples from our laboratory to illustrate how computerized language analysis (CLAN) can be used over time to track the behaviors of research participants. We also present data on the identification of stuttering in bilingual children. We discuss challenges to studying bilingual speakers and how big data initiatives such as TalkBank address these challenges to increase our understanding of bilingual fluency development.


The synthetic hepatic peptides pyroglutamylglutamylglycylserylasparagine and pyroglutamylglutamylglycylserylaspartic acid inhibit growth of MH1C1 rat hepatoma cells transplanted into Buffalo rats or athymic mice.
Repeated i.p. injections of the synthetic peptides pyroglutamylglutamylglycylserylasparagine and pyroglutamylglutamylglycylserylaspartic acid inhibited the long-term growth of MH1C1 rat hepatoma cells by 50-70% in three in vivo models: metastatic colony growth in the lungs of young Buffalo rats; s.c. tumor growth in young Buffalo rats; and s.c. tumor growth in athymic mice. The amide free peptide pyroglutamylglutamylglycylserylaspartic acid which inhibited the tumor growth in all the models showed a curvilinear dose-response relationship with a maximal effect at 1000 pmol/animal in mice and at 100 pmol/animal in rats. The amidated peptide pyroglutamylglutamylglycylserylasparagine, which was only tested in the lung model, showed growth inhibition with 2, 20, or 200 pmol/animal, but 200 pmol/animal was most effective. We have recently reported that these peptides show cochromatography with hepatic growth inhibitory peptides, isolated from mouse liver.


Development and validation of a Patient-Reported Oral Mucositis Symptom (PROMS) scale.
Oral mucositis, a painful condition with potentially life-threatening sequelae, often develops in association with allogeneic bone marrow transplantation. This condition has an adverse impact on the oral-health-related quality of life of patients undergoing marrow transplantation therapy. The purpose of this study was to create and validate a Patient-Reported Oral Mucositis Symptom (PROMS) scale. This scale allows evaluation of symptoms of oral mucositis that threaten quality of life. The PROMS scale was compared with previously validated tools measuring quality of life (Functional Assessment of Cancer Therapy--Bone Marrow Transplant), symptoms of depression (Center for Epidemiologic Studies Depression Scale), psychological well-being (Affect Balance Scale) and stressful life events, as well as an objective, clinician-rated assessment of oral mucositis (Visual Analogue Scale--Oral Mucositis Assessment Scale). Thirty-four patients who were to undergo allogeneic bone marrow transplantation at Princess Margaret Hospital in Toronto, Ontario, were enrolled in this validation study. The PROMS scale had high internal reliability, as well as good convergent and discriminant validity relative to subjective measures of well-being. Longitudinal assessments showed that changes in PROMS scores were strongly correlated with changes in clinical assessment of oral mucositis over the first 2 weeks after transplantation, when the onset of oral mucositis typically occurs and the lesions are most severe. Oral mucositis in patients who have undergone bone marrow transplantation can be quantified reliably with the easily administered PROMS scale. The PROMSscale provides a valid measure of the impact of oral mucositis on the oral-health-related quality of life of patients affected by this malady.


Light energy transmission through cured resin composite and human dentin.
This study determined the amount of light energy transmitted through various densities of cured resin composite and human dentin when 2 different light intensities were used. The maximum light energy (mW/cm2) transmitted through disks (0.46 to 5.85 mm thick) of 7 resin composites and human dentin was measured when either a Standard or a Turbo light guide was attached to a curing light. The effects of the 2 light guides, the specimen thickness, and type of specimen dentin on light energy transmission were determined. The mean light energy reading at the surface of the specimens was 682.1 mW/cm2 with the Standard light guide and 1,014 mW/cm2 with the Turbo light guide. For all the specimens, there was an exponential decrease in light energy transmitted as the specimen thickness increased. The analysis of covariance showed that the specimen, thickness, and light guide all had a statistically significant effect. Significantly more light energy (about 42%) was transmitted through the specimens when the Turbo light guide was used. When the Turbo light guide was used, about 42% more light energy was transmitted through the cured composite specimens. There was an exponential decrease in the light energy transmitted through 7 resin composites and dentin as the specimen thickness increased.


Lab-on-a-bubble: synthesis, characterization, and evaluation of buoyant gold nanoparticle-coated silica spheres.
This paper describes the development and preparation of a new class of materials for surface-enhanced Raman scattering (SERS) consisting of gold nanoparticles coated onto hollow, buoyant silica microspheres. These materials allow for a new type of molecular assay designated as a lab-on-a-bubble (LoB). LoB materials serve as a convenient platform for the detection of analytes in solution and offer several advantages over traditional colloidal gold and planar SERS substrates, such as the ability to localize and concentrate analytes for detection. An example assay is presented using the LoB method and cyanide detection. Cyanide binds to SERS-active, gold-coated LoBs and is detected directly from the corresponding SERS signal. The abilities of LoBs and a gold colloid to detect cyanide are compared, and in both cases, a detection limit of ~170 ppt was determined. Differences in measurement error using LoBs versus gold colloid are also described, as well as an assay for 5,5'-dithiobis(2-nitrobenzoic acid) that shows the benefit of using LoBs over SERS analyses in colloids, which are often plagued by particle aggregation.


Effects of interaction between Escherichia coli verotoxin and lipopolysaccharide on cytokine induction and lethality in mice.
In Escherichia coli 0157 infections, verotoxins (VT) play a critical role in causing the disease, although other factors such as lipopolysaccharide (LPS) and inflammatory cytokines may affect the progression and course of the disease. The present study examined the roles of VT and LPS in induction of serum cytokines and lethality in mice. LD50 of VT2 (13 ng) was c. 10(4)-fold smaller than that of LPS (400 microg). Although the lethal toxicity of these toxins was examined in several experimental conditions, such as VT2 (5, 10, 20, 40 ng/mouse) alone or in combination with LPS (100 microg/mouse) at various times (-2 days to +2 days), no evidence of synergy was observed. VT2 did not augment LPS-induced tumour necrosis factor-alpha (TNF-alpha) or interleukin-6 production, and conversely suppressed TNF-alpha production when it was injected 2 days before LPS challenge. The data failed to indicate either synergic or additive effects of VT and LPS on cytokine production or lethality in mice. In contrast, antagonistic interactions were clearly observed in cytokine production in certain conditions. The results suggested that these toxins may be co-operatively involvedin the pathology of VT-related diseases, but not through synergic interactions.


How Does Aging Affect Whole-brain Functional Network Connectivity? Evidence from An ICA Method.
Many studies have shown that changes in the functional connectivity are diverse along with aging. However, few studies have addressed how aging affects connectivity among large-scale brain networks, and it is challenging to examine gradual aging trajectories from middle adulthood to old age. In this work, based on large-sample fMRI data from 6300 subjects aged between 49 to 73 years, we apply an independent component analysis-based method called NeuroMark to extract brain functional networks and their connectivity (i.e., functional network connectivity (FNC)), and then propose a two-level statistical analysis method to explore robust aging-related changes in functional network connectivity. We found that the enhanced FNCs mainly occur between different functional domains, involving the default mode and cognitive control networks, while the reduced FNCs come from not only between different domains but also within the same domain, primarily relating to the visual network, cognitive control network and cerebellum. Our results emphasize the diversity of brain aging and provide new evidence for non-pathological aging of the whole brain.Clinical Relevance-This provides new evidence for non-pathological aging of functional network connectivity in the whole brain.


Identifying who will benefit from non-invasive ventilation in amyotrophic lateral sclerosis/motor neurone disease in a clinical cohort.
Respiratory failure is associated with significant morbidity and is the predominant cause of death in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). This study aimed to determine the effect of non-invasive ventilatory (NIV) support on survival and pulmonary function decline across MND/ALS phenotypes. Cohort recruited via a specialist, multidisciplinary clinic. Patients were categorised into four clinical phenotypes (ALS, flail arm, flail leg and primary lateral sclerosis) according to site of presenting symptom and the pattern of upper versus lower motor neurone involvement. NIV was initiated according to current consensus practice guidelines. Between 1991 and 2011, 1198 patients diagnosed with ALS/MND were registered. 929 patients (77.5%) fulfilled the selection criteria and their data were analysed. Median tracheostomy free survival from symptom onset was 28 months in NIV-treated patients compared to 15 months in untreated (Univariate Cox regression HR=0.61 (0.51 to 0.73), p<0.001). The positive survival effect of NIV persisted when the model was adjusted for age, gender, riluzole and percutaneous endoscopic gastrostomy use (HR=0.72 (0.60 to 0.88, p=0.001). In contrast with the only randomised controlled trial, NIV statistically significantly increased survival by 19 months in those with ALS-bulbar onset (Univariate HR=0.50 (0.36 to 0.70), multivariate HR=0.59 (0.41 to 0.83)). These data confirm that NIV improves survival in MND/ALS. The overall magnitude of benefit is 13 months and was largest in those with ALS-bulbar disease. Future research should explore the optimal timing of NIV initiation within phenotypes in order to optimise respiratory function, quality of life and survival.


Experiential and cosmopolitan knowledge: The transcontinental field practices of the U.S. Bureau of Biological Survey.
Before many of the global environmental knowledge producing networks and technologies emerged later in the twentieth century, another spatially extended form of field science was implemented at a continental scale by the U.S. Bureau of Biological Survey, revealing similar tensions and dynamics. Specimens and observations from across continental spaces were integrated through railroad-based transportation and communications networks in order to map distributions of birds and mammals and delineate "life zones" stretching across the continent. At the same time that field zoologists of the Biological Survey produced this cosmopolitan scientific knowledge, they also developed an intimate, experiential knowledge of many of the places where they traveled. By following the travels of Biological Survey field parties, especially the agency's long-time chief field naturalist Vernon Bailey, during the late nineteenth and early twentieth centuries when the railroad was dominant, this paper traces the interconnections between the two ways of knowing in the Biological Survey's practice. However, the integration of these different forms of knowledge was ultimately partial and incomplete, as seen through the Survey's daily practices such as food consumption, the seasonality of survey field practice, and limitations on what types of knowledge were incorporated from lay network collaborators and field assistants.


An Application for Skin Macules Characterization Based on a 3-Stage Image-Processing Algorithm for Patients with Diabetes.
Diabetic skin manifestations, previous to ulcers and wounds, are not highly accounted as part of diagnosis even when they represent the first symptom of vascular damage and are present in up to 70% of patients with diabetes mellitus type II. Here, an application for skin macules characterization based on a three-stage segmentation and characterization algorithm used to classify vascular, petechiae, trophic changes, and trauma macules from digital photographs of the lower limbs is presented. First, in order to find the skin region, a logical multiplication is performed on two skin masks obtained from color space transformations; dynamic thresholds are stabilised to self-adjust to a variety of skin tones. Then, in order to locate the lesion region, illumination enhancement is performed using a chromatic model color space, followed by a principal component analysis gray-scale transformation. Finally, characteristics of each type of macule are considered and classified; morphologic properties (area, axes, perimeter, and solidity), intensity properties, and a set of shade indices (red, green, blue, and brown) are proposed as a measure to obviate skin color differences among subjects. The values calculated show differences between macules with a statistical significance, which agree with the physician's diagnosis. Later, macule properties are fed to an artificial neural network classifier, which proved a 97.5% accuracy, to differentiate between them. Characterization is useful in order to track macule changes and development along time, provides meaningful information to provide early treatments, and offers support in the prevention of amputations due to diabetic feet. A graphical user interface was designed to show the properties of the macules; this application could be the background of a future Diagnosis Assistance Tool for educational (i.e., untrained physicians) and preventive assistance technology purposes.


An AP-1 binding site in the enhancer/core element of the HIV-1 promoter controls the ability of HIV-1 to establish latent infection.
Following integration, HIV-1 in most cases produces active infection events; however, in some rare instances, latent infection events are established. The latter have major clinical implications, as latent infection allows the virus to persist despite antiretroviral therapy. Both the cellular factors and the viral elements that potentially determine whether HIV-1 establishes active or latent infection events remain largely elusive. We detail here the contribution of different long terminal repeat (LTR) sequences for the establishment of latent HIV-1 infection. Using a panel of full-length replication-competent virus constructs that reflect naturally occurring differences of HIV-1 subtype-specific LTRs and targeted LTR mutants, we found the primary ability of HIV-1 to establish latent infection in this system to be controlled by a four-nucleotide (nt) AP-1 element just upstream of the NF-κB element in the viral promoter. Deletion of this AP-1 site mostly deprived HIV-1 of the ability to establish latent HIV-1 infection. Extension of this site to a 7-nt AP-1 sequence massively promoted latency establishment, suggesting that this promoter region represents a latency establishment element (LEE). Given that these minimal changes in a transcription factor binding site affect latency establishment to such large extent, our data support the notion that HIV-1 latency is a transcription factor restriction phenomenon.


Detailed fluid resuscitation profiles in patients with severe acute pancreatitis.
Appropriate and timely initial fluid resuscitation in acute pancreatitis (AP) is critical. The aim of this retrospective study was to evaluate fluid therapy on an hour-by-hour basis in relation to standard indices of adequate resuscitation during AP. Emergency room shock charts, fluid balance sheets and intensive care (ICU) charts for all patients with AP admitted to ICU in a large acute hospital were examined. Vital signs, clinical course and fluid administered during the first 72 h after admission were tabulated against urine output, central venous pressure (CVP) and inotrope/vasopressor therapy. Sixty-three consecutive patients with AP were initially evaluated. Inter-hospital transfers with established organ dysfunction (n= 11) or where records had insufficient detail (n= 22) were excluded. In the remaining 30 patients, in-hospital death occurred in 7. The cumulative volume of crystalloid given was significantly less at 48 h in patients who died in hospital (3331 ± 800 ml vs. survivors, 7287 ± 544 ml; P < 0.001). Non-survivors had a higher CVP, and received more inotropes/vasopressors. In severe AP-associated organ failure, fluid resuscitation profiles differ between survivors and non-survivors. CVP alone as a crude indicator of adequate resuscitation may be unreliable, potentially leading to the use of inotropes/vasopressors in the inadequately filled patient.


When should we operate on elderly patients with a hip fracture? It's about time!
Demographic predictions indicate the annual incidence of hip fractures will rise to 100,000 per annum in 2020. The annual costs to the NHS are approximately two billion pounds. Despite significant advances in the operating technique and management of these fractures, controversies still exist. One such matter for debate is the ideal timing for hip fracture surgery. There are arguments for and against early stabilization, yet all this evidence comes from observational studies. We present data from an often overlooked source, the largest patient safety reporting system in the world housed at the National Patient Safety Agency. Since 2003, 4325/4521 (96%) patients suffered some harm due to their operation being delayed. The issue of the ideal timing for hip surgery warrants an answer. This could be in the form of a controlled trial. A randomized trial comparing early surgery versus standard of care (site dependent) in hip fracture repair may provide some future guidance. In the meantime, current evidence suggests that we should stratify the elderly according to their medical morbidities; both new and old; optimize patient's who develop hypovolemia, accelerated hypertension, untreated infection, symptomatic arrhythmia or cardiopulmonary dysfunction; and attempt to bring patient's suffering from chronic diseases as close to their baseline level of functioning as normal. Hip fracture repair should then occur as soon as possible.


Fifty Years of Research in ARDS. Is Extracorporeal Circulation the Future of Acute Respiratory Distress Syndrome Management?
Mechanical ventilation (MV) remains the cornerstone of acute respiratory distress syndrome (ARDS) management. It guarantees sufficient alveolar ventilation, high FiO2 concentration, and high positive end-expiratory pressure levels. However, experimental and clinical studies have accumulated, demonstrating that MV also contributes to the high mortality observed in patients with ARDS by creating ventilator-induced lung injury. Under these circumstances, extracorporeal lung support (ECLS) may be beneficial in two distinct clinical settings: to rescue patients from the high risk for death associated with severe hypoxemia, hypercapnia, or both not responding to maximized conventional MV, and to replace MV and minimize/abolish the harmful effects of ventilator-induced lung injury. High extracorporeal blood flow venovenous extracorporeal membrane oxygenation (ECMO) may therefore rescue the sickest patients with ARDS from the high risk for death associated with severe hypoxemia, hypercapnia, or both not responding to maximized conventional MV. Successful venovenous ECMO treatment in patients with extremely severe H1N1-associated ARDS and positive results of the CESAR trial have led to an exponential use of the technology in recent years. Alternatively, lower-flow extracorporeal CO2 removal devices may be used to reduce the intensity of MV (by reducing Vt from 6 to 3-4 ml/kg) and to minimize or even abolish the harmful effects of ventilator-induced lung injury if used as an alternative to conventional MV in nonintubated, nonsedated, and spontaneously breathing patients. Although conceptually very attractive, the use of ECLS in patients with ARDS remains controversial, and high-quality research is needed to further advance our knowledge in the field.


Dacomitinib in EGFR-mutant non-small-cell lung cancer with brain metastasis: a single-arm, phase II study.
Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations in the ARCHER1050 study. However, because that study did not include patients with brain metastases, the efficacy of dacomitinib in patients with brain metastases has not been clarified. This single-arm phase II study enrolled 30 patients with treatment-naïve advanced NSCLC harboring activating EGFR mutations from January 2021 to June 2021 and started them on dacomitinib (45 mg/day). All patients had non-irradiated brain metastases with a diameter of ≥5 mm. The primary endpoint was confirmed intracranial objective response rate (iORR). Patients had exon 19 deletions (46.7%) and L858R mutations in exon 21 (55.3%). The confirmed iORR was 96.7% (29/30), with an intracranial complete response of 63.3%. Median intracranial PFS (iPFS) was not reached, with 12- and 18-month iPFS rates of 78.6% [95% confidence interval (CI) 64.8% to 95.4%] and 70.4% (95% CI 54.9% to 90.1%), respectively. In the competing risk analysis, the 12-month cumulative incidence of intracranial progression was 16.7%. Regarding the overall efficacy for intracranial and extracranial lesions, the overall ORR was 96.7%, and the median PFS was 17.5 months (95% CI 15.2 months-not reached). Grade 3 or higher treatment-related adverse events were reported in 16.7% of patients, and 83.3% required a reduced dacomitinib dose to manage adverse events. However, none permanently discontinued dacomitinib treatment due to treatment-related adverse events. Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.


BACE-1 Inhibitors: From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease.
The amyloid hypothesis has long been the central dogma in drug discovery for Alzheimer's disease (AD), leading to many small-molecule and biological drug candidates. One major target has been the β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great resources in the search for BACE-1 inhibitors. The lack of efficacy of verubecestat in mild-to-moderate AD raises important questions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general, in AD treatment. It also suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms of actions and improved efficacy. Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule inhibitors to multitarget compounds. We discuss these compounds as innovative tools for better understanding the complexity of AD and for identifying efficacious drug candidates to treat this devastating disease.


Rapid diagnostic testing as an indicator of malaria prevalence in Rorya District, Tanzania.
Rapid Diagnostic Testing (RDT), a point-of-care, qualitative test for Plasmodium antigen, has been a catalyst in the diagnosis of patients in malaria-endemic regions. While blood-smear microscopy remains the gold standard, RDT allows for swift diagnosis in resource-poor settings. Our study sought to utilize RDT to quantify local malaria prevalence in the Rorya district of Tanzania. Two field clinics were established and 1,032 patients were screened. Those that described malaria symptoms were tested via RDT. The percentage of positive tests was compared to national data from the World Health Organization's 2019 World Malaria report and the President's Malaria Initiative Report for Tanzania. Intake data (sex, age, heart rate (HR), and temperature) were compared between the malaria-positive and malaria-negative groups. 772 patients received RDT of whom 487 tested positive. There was a statistically significant difference in the percentage of positive patients between the two sites (52.0% vs 38.2%). Sixty percent of malaria-positives were female and the median age of this group was 10 yrs (range 5-15 yrs). Intake data showed a notable difference in median heart rates between malaria-positive and malaria-negative persons, 84.0 (72-100) and 72.0 (74-84) beats per minute (bpm), respectively. The prevalence of malaria in Rorya was significantly higher than the reported Tanzanian average. Additionally, children were at a statistically higher risk of contracting malaria. Our data indicates that RDT offers enhanced insight into the local malarial burden that may be valuable to (governmental) health providers for the disbursement of resources in malaria-endemic regions.


Sequential carcinoembryonic antigen levels. A predictor of response and relapse in combination chemotherapy of advanced gastrointestinal cancer.
Serial determinations of plasma carcinoembryonic antigen (CEA) levels were assayed for 34 patients with advanced gastrointestinal cancer undergoing 5-fluorouracil and mitomycin C combination chemotherapy. 21 patients (62%) had an objective response and the CEA level was decreased in 12. After chemotherapy was initiated a rise in CEA level occurred on the average 6.5 months later, while the mean time to clinical relapse was 8 months. 5 patients (15%) had stable disease; the CEA level was decreased in 2. In 8 patients (24%) with progressive disease, the mean time for a rising CEA level was 3 months. In our view, a change in the CEA level reflects the effectiveness of combination chemotherapy in patients with advanced gastrointestinal cancer.


Fish facing global change: are early stages the lifeline?
The role of phenotypic plasticity in the acclimation and adaptive potential of an organism to global change is not currently accounted for in prediction models. The high plasticity of marine fishes is mainly attributed to their early stages, during which morphological, structural and behavioural functions are particularly sensitive to environmental constraints. This developmental plasticity can determine later physiological performances and fitness, and may further affect population dynamics and ecosystem functioning. This review asks the essential question of what role early stages play in the ability of fish to later cope with the effects of global change, considering three key environmental factors (temperature, hypoxia and acidification). After having identified the carry-over effects of early exposure reported in the literature, we propose areas that we believe warrant the most urgent attention for further research to better understand the role of developmental plasticity in the responses of marine organisms to global change.


[Chemonucleolysis with chymopapain in lumbar disk hernia. Randomized comparative study with operated patients].
We carried out a randomized comparison study with 69 patients, one group of whom had been operated on (41) and the other group treated by chemonucleolysis with chymopapain (25) in order to arrive at an objective picture of the latter recently much criticised method. 88% of the patients who were treated with chymopapain showed lasting success, and almost 90% of the operated patients are also in a good condition. In our opinion, complications can be avoided and the patient can be spared a surgical operation by the correct choice of patients and proper performance of the method in standby anaesthesia. This justifies the performance of chemonucleolysis with chymopapain.


Identification and biological activities of a new antiangiogenic small molecule that suppresses mitochondrial reactive oxygen species.
Mitochondrial reactive oxygen species (ROS) are associated with multiple cellular functions such as cell proliferation, differentiation, and apoptosis. In particular, high levels of mitochondrial ROS in hypoxic cells regulate many angiogenesis-related diseases, including cancer and ischemic disorders. Here we report a new angiogenesis inhibitor, YCG063, which suppressed mitochondrial ROS generation in a phenotypic cell-based screening of a small molecule-focused library with an ArrayScan HCS reader. YCG063 suppressed mitochondrial ROS generation under a hypoxic condition in a dose-dependent manner, leading to the inhibition of in vitro angiogenic tube formation and chemoinvasion as well as in vivo angiogenesis of the chorioallantoic membrane (CAM) at non-toxic doses. In addition, YCG063 decreased the expression levels of HIF-1α and its target gene, VEGF. Collectively, a new antiangiogenic small molecule that suppresses mitochondrial ROS was identified. This new small molecule tool will provide a basis for a better understanding of angiogenesis driven under hypoxic conditions.


Discerning an effective balance between equine infectious anemia virus attenuation and vaccine efficacy.
Among the diverse experimental vaccines evaluated in various animal lentivirus models, live attenuated vaccines have proven to be the most effective, thus providing an important model for examining critical immune correlates of protective vaccine immunity. We previously reported that an experimental live attenuated vaccine for equine infectious anemia virus (EIAV), based on mutation of the viral S2 accessory gene, elicited protection from detectable infection by virulent virus challenge (F. Li et al., J. Virol. 77:7244-7253, 2003). To better understand the critical components of EIAV vaccine efficacy, we examine here the relationship between the extent of virus attenuation, the maturation of host immune responses, and vaccine efficacy in a comparative study of three related attenuated EIAV proviral vaccine strains: the previously described EIAV(UK)DeltaS2 derived from a virulent proviral clone, EIAV(UK)DeltaS2/DU containing a second gene mutation in the virulent proviral clone, and EIAV(PR)DeltaS2 derived from a reference avirulent proviral clone. Inoculations of parallel groups of eight horses resulted in relatively low levels of viral replication (average of 10(2) to 10(3) RNA copies/ml) and a similar maturation of EIAV envelope-specific antibody responses as determined in quantitative and qualitative serological assays. However, experimental challenge of the experimentally immunized horses by our standard virulent EIAV(PV) strain by using a low-dose multiple exposure protocol (three inoculations with 10 median horse infective doses, administered intravenously) revealed a marked difference in the protective efficacy of the various attenuated proviral vaccine strains that was evidently associated with the extent of vaccine virus attenuation, time of viral challenge, and the apparent maturation of virus-specific immunity.


Optically amplified detection for biomedical sensing and imaging.
Optical sensing and imaging methods for biomedical applications, such as spectroscopy and laser-scanning fluorescence microscopy, are incapable of performing sensitive detection at high scan rates due to the fundamental trade-off between sensitivity and speed. This is because fewer photons are detected during short integration times and hence the signal falls below the detector noise. Optical postamplification can, however, overcome this challenge by amplifying the collected optical signal after collection and before photodetection. Here we present a theoretical analysis of the sensitivity of high-speed biomedical sensing and imaging systems enhanced by optical postamplifiers. As a case study, we focus on Raman amplifiers because they produce gain at any wavelength within the gain medium's transparency window and are hence suitable for biomedical applications. Our analytical model shows that when limited by detector noise, such optically postamplified systems can achieve a sensitivity improvement of up to 20 dB in the visible to near-infrared spectral range without sacrificing speed. This analysis is expected to be valuable for design of fast real-time biomedical sensing and imaging systems.


COVID-19, Anxiety, and Hopelessness: Quality of Life Among Healthcare Workers in Turkey.
The aim of the study is to investigate the effects of intense anxiety and hopelessness experienced by healthcare workers during the pandemic on their quality of life. This cross-sectional, online questionnaire-based study was conducted between August 31, 2020 and October 31, 2020, with 729 healthcare workers in Turkey. The study showed that hopelessness, the weekly working time, fatigue, and the workload of healthcare workers negatively affected their quality of life, those who found the pandemic measures inadequate had a lower quality of life and higher hopelessness levels, and those who needed knowledge on various issues to improve their skills had lower quality of life and higher levels of anxiety and hopelessness. Increasing the measures to make healthcare workers feel competent and ready during the COVID-19 pandemic and meet their information needs to improve their skills will reduce their anxiety and hopelessness and improve their quality of life. Identifying the factors affecting anxiety, hopelessness, and quality of life will help achieve sustainable success in the delivery of health services and promote employee health and safety.


Electrospun PHEA-PLA/PCL Scaffold for Vascular Regeneration: A Preliminary in Vivo Evaluation.
There is increasing interest in the development of vessel substitutes, and many studies are currently focusing on the development of biodegradable scaffolds capable of fostering vascular regeneration. We tested a new biocompatible and biodegradable material with mechanical properties similar to those of blood vessels. The material used comprises a mixture of α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) and polylactic acid (PLA), combined with polycaprolactone (PCL) by means of electrospinning technique. Low-molecular-weight heparin was also linked to the copolymer. A tubular PHEA-PLA/PCL sample was used to create an arteriovenous fistula in a pig model with the use of the external iliac vessels. The flow was assessed by means of Doppler ultrasound examination weekly, and 1 month after the implantation we removed the scaffold for histopathologic evaluation. The implants showed a perfect leak-proof seal and adequate elastic tension to blood pressure. About ∼3 weeks after the implantation, Doppler examination revealed thrombosis of the graft, so we proceeded to its removal. Histologic examination showed chronic inflammation, with the presence of foreign body cells and marked neovascularization. The material had been largely absorbed, leaving some isolated spot residues. The biocompatibility of PHEA-PLA/PCL and its physical properties make it suitable for the replacement of vessels. In the future, the possibility of functionalizing the material with a variety of molecules, to modulate the inflammatory and coagulative responses, will allow obtaining devices suitable for the replacement of native vessels.


Axial spondyloarthritis in the USA: diagnostic challenges and missed opportunities.
Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease that primarily affects the sacroiliac joints and spine. Delayed or inadequate treatment may decrease quality of life and lead to poor long-term outcomes, including irreversible loss of spinal function. In this review, we discuss clinical practice related to axSpA within the USA, including prevalence, diagnosis, reasons for delayed/missed diagnosis, and suggestions for making early diagnosis. The US population prevalence of axSpA (0.9-1.4%) is higher than the diagnostic prevalence (0.2-0.7%). Although the estimated diagnostic delay for axSpA is 14 years in the USA, the disease can be identified earlier if appropriately preselected patients are quickly referred to rheumatologists. Only 37% of patients with ankylosing spondylitis in the USA are diagnosed by rheumatologists; the remaining 63% are diagnosed by primary care (26%), chiropractic/physical therapy (7%), orthopedic surgery (4%), pain clinics (4%), acute care (3%), and other settings (19%). To help reduce diagnostic delay, non-rheumatologist-healthcare professionals are urged to refer patients with back pain and ≥ 1 of 3 SpA features (HLA-B27 positivity, current inflammatory back pain, or x-ray/MRI evidence of sacroiliitis) to a rheumatologist. Prevalence and diagnosis rates of axSpA are disparate in the USA due to the lack of awareness and knowledge among non-rheumatologists. Progress has been made in identifying hurdles causing diagnostic delays. Public health initiatives are needed to guide primary care physicians, physical therapists, chiropractors, and other specialists seeing patients with chronic back pain on methods for suspecting or identifying axSpA and early referral to rheumatologists.


Measurement of the first ionization potential of lawrencium, element 103.
The chemical properties of an element are primarily governed by the configuration of electrons in the valence shell. Relativistic effects influence the electronic structure of heavy elements in the sixth row of the periodic table, and these effects increase dramatically in the seventh row--including the actinides--even affecting ground-state configurations. Atomic s and p1/2 orbitals are stabilized by relativistic effects, whereas p3/2, d and f orbitals are destabilized, so that ground-state configurations of heavy elements may differ from those of lighter elements in the same group. The first ionization potential (IP1) is a measure of the energy required to remove one valence electron from a neutral atom, and is an atomic property that reflects the outermost electronic configuration. Precise and accurate experimental determination of IP1 gives information on the binding energy of valence electrons, and also, therefore, on the degree of relativistic stabilization. However, such measurements are hampered by the difficulty in obtaining the heaviest elements on scales of more than one atom at a time. Here we report that the experimentally obtained IP1 of the heaviest actinide, lawrencium (Lr, atomic number 103), is 4.96(+0.08)(-0.07) electronvolts. The IP1 of Lr was measured with (256)Lr (half-life 27 seconds) using an efficient surface ion-source and a radioisotope detection system coupled to a mass separator. The measured IP1 is in excellent agreement with the value of 4.963(15) electronvolts predicted here by state-of-the-art relativistic calculations. The present work provides a reliable benchmark for theoretical calculations and also opens the way for IP1 measurements of superheavy elements (that is, transactinides) on an atom-at-a-time scale.


Clinical Relevance of Blood Glucose and Gastroesophageal Reflux Symptoms to Depressive Status in Patients with Type 2 Diabetes Mellitus.
A relationship between diabetes and depression is apparent. To clarify the clinical relevance of diabetic patients' gastroesophageal symptoms to their psychological status, we retrospectively analyzed the data from a Selfrating Depression Scale (SDS) and a Frequency Scale for Symptoms of Gastroesophageal reflux disease (FSSG) among 143 type 2 diabetic patients who visited a general medicine department. Among the 45 Japanese patients enrolled, the group with relatively high SDS scores (≥ 36) showed higher (FSSG) dysmotility symptom scores versus the low-SDS (< 36) group, although the 2 groups' characteristics and laboratory data were not significantly different. Positive correlations of postprandial plasma glucose (PPG) levels with FSSG scores (R=0.321, p<0.05), particularly with reflux scores (R=0.455, p<0.01) were revealed. PPG and HbA1c levels were not correlated with SDS scores. The patients' SDS scores were significantly correlated with their FSSG scores (R=0.41, p<0.01), suggesting that depressive status is linked to GERD-related manifestations. Considering that the patients' PPG levels were correlated with GERD-related symptoms, diabetic patients' blood glucose levels are associated with depressive status. Collectively, key symptoms related to GERD and glucose level values would be helpful.


Securing cooperation from persons supplying statistical data.
Securing the co-operation of persons supplying information required for medical statistics is essentially a problem in human relations, and an understanding of the motivations, attitudes, and behaviour of the respondents is necessary.Before any new statistical survey is undertaken, it is suggested by Aubenque and Harris that a preliminary review be made so that the maximum use is made of existing information. Care should also be taken not to burden respondents with an overloaded questionnaire. Aubenque and Harris recommend simplified reporting. Complete population coverage is not necessary.Neurdenburg suggests that the co-operation and support of such organizations as medical associations and social security boards are important and that propaganda should be directed specifically to the groups whose co-operation is sought. Informal personal contacts are valuable and desirable, according to Blaikley, but may have adverse effects if the right kind of approach is not made.Financial payments as an incentive in securing co-operation are opposed by Neurdenburg, who proposes that only postage-free envelopes or similar small favours be granted. Blaikley and Harris, on the other hand, express the view that financial incentives may do much to gain the support of those required to furnish data; there are, however, other incentives, and full use should be made of the natural inclinations of respondents. Compulsion may be necessary in certain instances, but administrative rather than statutory measures should be adopted. Penalties, according to Aubenque, should be inflicted only when justified by imperative health requirements.The results of surveys should be made available as soon as possible to those who co-operated, and Aubenque and Harris point out that they should also be of practical value to the suppliers of the information.Greater co-operation can be secured from medical persons who have an understanding of the statistical principles involved; Aubenque and Neurdenburg suggest that a course in elementary statistical methodology be introduced in the curriculum of medical schools.Methods for improving co-operation, and thus the compilation of statistics, in particular countries are discussed by Lal and de Shelly Hernández, who deal with India and Venezuela respectively.


"Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer.
Erlotinib is effective for epidermal growth factor receptor (EGFR) mutant lung cancer, but CNS penetration at standard daily dosing is limited. We previously reported that intermittent "pulsatile" administration of high-dose (1500 mg) erlotinib once weekly was tolerable and achieved concentrations in cerebrospinal fluid exceeding the half maximal inhibitory concentration for EGFR mutant lung cancer cells in a patient with leptomeningeal metastases; we now expand this paradigm to a series of 9 patients. We retrospectively identified patients with EGFR mutant lung cancer treated with pulsatile erlotinib for CNS metastases (brain and/or leptomeningeal) that occurred despite conventional daily erlotinib or other EGFR tyrosine kinase inhibitors. Mutations in available lung and CNS tissue were correlated with efficacy. Erlotinib was administered as monotherapy at a median dose of 1500 mg weekly. Best CNS radiographic response was partial in 67% (6/9, including 2 with isolated leptomeningeal metastases), stable disease in 11% (1/9), and progressive disease in 22% (2/9). Median time to CNS progression was 2.7 months (range, 0.8-14.5 months) and median overall survival was 12 months (range, 2.5 months-not reached). Treatment was well tolerated. No acquired resistance mutations in EGFR were identified in the CNS metastases of 4 patients, including 1 harboring T790M outside the CNS. Pulsatile erlotinib can control CNS metastases from EGFR mutant lung cancer after failure of standard daily dosing. CNS disease may not harbor acquired resistance mutations that develop systemically. A prospective trial is planned.


Protein synthesis in the perfused rat liver.
1. When the rat livers are perfused under the conditions of these experiments with rat blood diluted with saline, the livers remain capable of removing colloidal chromic phosphate normally for 4 hours or more; that is, the reticuloendothelial system continues to function normally. 2. Good rates of bile flow continue, generally for 4 hours. 3. The livers incorporate radioactivity from the amino acids methionine, lysine, and histidine at rapid rates for 1 or 2 hours. Thereafter the rates fall. 4. The specific activity of the free lysine and histidine in the perfusate falls rapidly during the experiments (to 25 or 35 per cent of its original value at 10 minutes). 5. The fall in rate of incorporation of radioactivity is attributable to the fall in amino acid specific activity. 6. Addition of a complete amino acid mixture to the perfusate does not appear to have any stimulatory effect on incorporation of radioactivity from labelled amino acids. 7. With lysine, on the assumption that incorporation is due to new protein formation, there is a rate of synthesis equivalent to 230 mg. of plasma protein per 100 gm. of rat per day. This result is in agreement with turnover data obtained from rats in vivo. 8. The results emphasize once again the importance of precursor specific activity in the interpretation of metabolic experiments with labelled amino acids.


Dizygotic twinning is not associated with methylenetetrahydrofolate reductase haplotypes.
Folate metabolism is critical to embryonic development, influencing neural tube defects (NTD) and recurrent early pregnancy loss. Polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) have been associated with dizygotic (DZ) twinning through pregnancy loss. The C677T and A1298C polymorphisms in MTHFR were genotyped in 258 Australasian families (1016 individuals) and 118 Dutch families (462 individuals) of mothers of DZ twins and a population sample of 462 adolescent twin families (1861 individuals). Haplotypes were constructed from the alleles, and transmission of the MTHFR haplotypes to mothers of DZ twins and from parents to twins in the adolescent twin families analysed. The C677T and A1298C were common in all three populations (frequencies > 0.29). There was strong linkage disequilibrium (D' = 1) between the variants, showing that specific combinations of alleles (haplotypes) were transmitted together. Three haplotypes accounted for nearly all the variation. There was no evidence of any association between MTHFR genotype and twinning in mothers of twins, or of the loss of specific MTHFR genotypes during twin pregnancies. It is concluded that variation in twinning frequency is not associated with MTHFR genotype.


Efficacy and safety of statins and exercise combination therapy compared to statin monotherapy in patients with dyslipidaemia: A systematic review and meta-analysis.
Background Statin treatment in association with physical exercise can substantially reduce mortality in dyslipidaemic individuals. However, the available data to compare the efficacy and safety of statins and exercise combination therapy with statin monotherapy are limited. Design Systematic review and meta-analysis. Methods We systematically searched PubMed, Embase and the Cochrane Library from database inception until December 2016. We included randomised and non-randomised studies that compared the efficacy and safety of statins and exercise combination therapy with statin monotherapy in patients with dyslipidaemia. Standardised mean differences were calculated and pooled by means of fixed effects models. The risk of bias and heterogeneity among trials was also assessed. Seven articles were assessed in terms of the efficacy of therapy and 13 from the viewpoint of therapeutic safety. Results In terms of efficacy, statins and exercise combination decreased the incidence of diabetes mellitus, improved insulin sensitivity and inflammation, but caused no change in lipid profile compared to statins alone. In terms of safety, statins and exercise combination increased peak oxygen uptake (standardised mean difference 1.01, 95% confidence interval 0.46 to 1.57) compared to statins alone. In contrast to statin-induced myopathy, chronic exercise training prior to statin treatment could counteract statin-induced adverse effects in skeletal muscle. Conclusion Statins and exercise combination therapy is more effective than statin monotherapy in terms of insulin sensitivity, inflammation and exercise capacity. The small number of studies warrants the need for more randomised controlled trials evaluating the efficacy and safety of combination therapy.


Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury.
Hypercapnic acidosis is commonly permitted in patients with acute respiratory distress syndrome during the use of protective ventilation strategies. Hypercapnic acidosis is also a common complication of multiple lung diseases and is associated with a poor prognosis, although the mechanisms by which it leads to increased mortality is not known. Previous studies using noninfective models of lung injury show that acute (<6 hrs) hypercapnic acidosis reduced lung damage by an anti-inflammatory effect. We hypothesized that this anti-inflammatory effect would be detrimental in vivo in the presence of untreated bacterial infection and sustained hypercapnia (>48 hrs) and, furthermore, that if bacterial reproduction were controlled by antibiotic therapy, then the anti-inflammatory effects of hypercapnic acidosis would no longer prove detrimental. This study was a prospective, randomized animal study. This study was conducted at a university research laboratory. Study subjects were adult male Wistar-Kyoto rats. After intratracheal instillation of Escherichia coli under general anesthesia, rats were housed in normocapnic (21% O2, 0% CO2) or hypercapnic (21% O2, 5% CO2) environments for 2 days. Rats were then reanesthetized for assessment of physiological and quantitative stereologic indices of lung damage, quantitative bacterial counts, and neutrophil phagocytosis. Hypercapnic acidosis was associated with higher lung bacterial colony counts, more structural damage, and lower static lung compliance than normocapnia. Neutrophils isolated from hypercapnic rats demonstrated impaired phagocytosis. In a further separate series of experiments, in which rats were given antibiotic therapy, lung damage was not different between normocapnic and hypercapnic acidosis groups. Prolonged hypercapnic acidosis worsened bacterial infection-induced lung injury. Our findings suggest an immunosuppressive effect of hypercapnic acidosis and have important implications for protective ventilation strategies that permit hypercapnic acidosis in patients with adult respiratory distress syndrome and in the management of hypercapnic acidosis during infective exacerbations of chronic obstructive pulmonary disease and other lung diseases.


[Effects of therapies on childhood systemic lupus erythematosus].
We analyzed the effects of three therapies on 30 patients with childhood systemic lupus erythematosus, and classified the patients into three groups. The therapies were as follows; Group A (8 cases), methylpredni-solone (mPSL) pulses plus oral prednisolone (PSL) alone, Group B (10 cases), mPSL pulses plus oral PSL and mizoribine (MZB) or azathioprine (AZP), Group C (12 cases), mPSL pulses and intravenous cyclophosphamide (IVCY) pulse therapy plus oral PSL and MZB or AZP. Three years after treatment, we compared the laboratory data (C3, C4, CH50 and anti-DNA antibody), the SLEDAI scores and numbers of relapses in these three groups. We demonstrated that group C had the best data, and this data indicated that the median C3, C4 and CH50 increased and that the median anti-DNA antibody and the mean of the numbers of relapses decreased. In conclusion, the combination of immunosuppressants and IVCY appeared to offer great benefits in childhood systemic lupus erythematosus.


Sustaining Nurse-Led Task-Shifting Strategies for Hypertension Control: A Concept Mapping Study to Inform Evidence-Based Practice.
The use of task-shifting is an increasingly widespread delivery approach for health interventions targeting prevention, treatment, and control of hypertension in adults living in sub-Saharan Africa (SSA). Addressing a gap in the literature, this research examined the sustainability of an ongoing task-shifting strategy for hypertension (TASSH) from the perspectives of community health nurses (CHNs) implementing the program. We used concept-mapping, a mixed-methods participatory approach to understand CHNs' perceptions of barriers and enablers to sustaining a task-shifting program. Participants responded to focal prompts, eliciting statements regarding perceived barriers and enablers to sustaining TASSH, and then rated these ideas based on importance to the research questions and feasibility to address. Twenty-eight community health nurses (21 women, 7 men) from the Ashanti region of Ghana completed the concept-mapping process. Factors influencing sustainability were grouped into five categories: Limited Drug Supply, Financial Support, Provision of Primary Health Care, Personnel Training, and Patient-Provider Communication. The limited supply of antihypertensive medication was considered by CHNs as the most important item to address, while providing training for intervention personnel was considered most feasible to address. This study's findings highlight the importance of examining nurses' perceptions of factors likely to influence the sustainability of evidence-based, task-shifting interventions. Nurses' perceptions can guide the widespread uptake and dissemination of these interventions in resource-limited settings.


Pharmacology and molecular action of retinoids and vitamin D in skin.
All-trans retinoic acid and 1,25-dihydroxyvitamin D3 are biologically active hormones derived from metabolism of vitamins A and D, respectively. Their cellular effects in physiology and pharmacology are mediated mainly through their nuclear receptors, retinoic acid receptors (RARs), and vitamin D receptor (VDR), which are members of the steroid/thyroid hormone receptor superfamily. The nuclear receptor superfamily is a group of hormone (ligand)-dependent transcription factors that bind to specific DNA recognition sequences located in the promotor region of target genes and modulate the gene transcription. Both RARs and VDR bind to DNA in the form of heterodimers with retinoid X receptor (RXR) as the key partner. In human skin epidermis, endogenous RAR and VDR bind to their respective enhancer elements as heterodimers (RAR-RXR, VDR-RXR) and not as homodimers. 9-cis retinoic acid is the natural ligand for RXRs. Because RXR heterodimerizes with either RARs or VDR, it functions as a key protein in the overall retinoid or vitamin D response of a given biological system. The contribution of RXRs in coregulating these signaling pathways is likely to depend on the abundance of the RXRs within target cells, the relative amounts of other receptors with which they can dimerize, and the availability of their ligands (hormones). Understanding each of these components in human skin in vivo will lead to practical applications in dermatologic therapeutics.


Optimal Modeling and Simulation of the Relationship between Athletes' High-Intensity Training and Sports Injuries.
In order to take into account the physical health of athletes and the quality of sports training, an optimization modeling and simulation method for the relationship between high-intensity training and sports injuries of athletes is proposed. The research of the specific content of the method is based on the two-dimensional and three-dimensional registration principles. In the research process, the program is written strictly according to the registration principle, and the correctness of the method is effectively tested by means of experimental methods. Digital image reconstruction measures based on 3D models may be based on ray tracing methods. The experimental results show that the number of accurate cases of this method is 77, and the accuracy rate is 96.3%. The proposed method can formulate a scientific and effective injury prevention strategy for athletes during high-intensity training.


Acquired hypertrichosis lanuginosa. A case report.
A 62-year-old, postmenopausal woman had rapidly appearing lanugo-type hair on her face and extremities. Adenocarcinoma of the colon was diagnosed. The patient underwent partial hemicolectomy and liver biopsy. Serum androgen levels were normal. Carcinoembryonic antigen and alpha-fetoprotein were undetected. These cases are rare, and acquired hypertrichosis lanuginosa can be a clinical tumor marker.


Bone acquisition in healthy young females is reciprocally related to marrow adiposity.
Considerable evidence indicates that osteoblasts and adipocytes share a common progenitor cell in the bone marrow that is capable of mutually exclusive differentiation into the cell lineages responsible for bone and fat formation. The purpose of this study was to examine the relation between bone acquisition and changes in marrow adiposity. This was a longitudinal study. OUTCOME MEASURES AND SUBJECTS: Computed tomography measurements of femoral cortical bone area (CBA), cross-sectional area (CSA), and marrow density, and dual-energy x-ray absorptiometry (DXA) measurements of total body fat and lean mass (LM) were obtained in 39 healthy females (15-20 yr of age) at baseline and 18-24 months later. Marrow adiposity was inversely related to CBA at baseline and follow-up (r = 0.39 and 0.33; P = 0.015 and 0.039, respectively) but was not associated to CSA (r = 0.19 and 0.17; P = 0.24 and 0.32, respectively). The association between marrow fat and CBA persisted, even after controlling for body mass and DXA values of LM and femoral CSA. Gains in CBA during the course of the study were related to decreases in marrow fat (r = 0.41; P = 0.009), a relation that persisted, even after accounting for changes in bone size. Marrow fat was not associated to anthropometric measures or DXA values of body fat and LM (all r's between -0.15 and 0.19; P > 0.05). Bone acquisition in the appendicular skeleton of healthy young females is inversely related to changes in marrow adiposity. These results provide support for the growing body of evidence indicating an inversely coupled relationship between osteogenesis and adipogenesis in the skeleton.


Perceptions of barriers and facilitators of cancer early detection among low-income minority women in community health centers.
African-American and Hispanic women receive fewer indicated cancer early detection services than do majority women. Low rates of cancer screening may, in part, explain the disproportionately higher rates of cancer deaths in this population. The aim of this qualitative study was to explore through individual interviews the perceptions of barriers and facilitators of colorectal, cervical and breast cancer screening among 187 low-income, primarily minority women in four New-York-City-based community/migrant health centers. We identified various barriers and facilitators within each of these categories. Clinician recommendation was the most commonly cited encouragement to cancer screening. Other facilitators of cancer screening identified by patients included personal medical history, such as the presence of a symptom. The perception of screening as routine was cited as a facilitator far more commonly for mammography and Pap tests than for either of the colorectal screenings. Less commonly cited facilitators were insurance coverage and information from the media. The most common barriers were a lack of cancer screening knowledge, patients' perception of good health or absence of symptoms attributable to ill health, fear of pain from the cancer test and a lack of a clinician recommendation. Using standard qualitative techniques, patients' responses were analyzed and grouped into a taxonomy of three major categories reflecting: (1) patients' attitudes and beliefs, (2) their social network experience and (3) accessibility of services. This taxonomy may serve as a useful framework for primary care providers to educate and counsel their patients about cancer screening behaviors.


Purification and antifungal activity of a basic 34 kDa beta-1,3-glucanase from soybean hypocotyls inoculated with Phytophthora sojae f. sp. glycines.
Inoculation of soybean (Glycine max L. cv. Jangyup) hypocotyls with Phytophthora sojae f. sp. glycines results in a marked accumulation of some pathogenesis-related (PR) proteins. A basic beta-1,3-glucanase (34 kDa) was purified from soybean hypocotyls infected by an incompatible race of P. sojae f. sp. glycines using CM-cellulose cation exchange chromatography and Bio-gel P-60 gel filtration. The purified soybean beta-1,3-glucanase cross-reacted with polyclonal antibody raised against a tomato beta-1,3-glucanase. The activity of beta-1,3-glucanase was much higher in the infected soybean hypocotyls than the healthy ones. The beta-1, 3-glucanase purified from soybean inhibited spore germination and hyphal growth of the chitin-negative fungus P. sojae f. sp. glycines, but did not show any antifungal activity against the chitin-containing fungi Alternaria mali, Colletotrichum gloeosporioides, and Magnaporthe grisea.


The bZIP protein from Tamarix hispida, ThbZIP1, is ACGT elements binding factor that enhances abiotic stress signaling in transgenic Arabidopsis.
Tamarix spp. are woody halophyte, which are very tolerant to abiotic stresses such as salinity and drought, but little is known about their specific stress response systems. Basic leucine zipper proteins (bZIPs) play important roles in the ability of plants to withstand adverse environmental conditions. However, their exact roles in abiotic stress tolerance are still not fully known. In the current study, we functionally characterized a bZIP gene (ThbZIP1) from Tamarix hispida in response to abiotic stresses. We addressed the regulatory network of ThbZIP1 in three levels, i.e. its upstream regulators, the cis-acting elements recognized by ThbZIP1, and its downstream target genes. Two MYCs were found to bind to E-box, in the promoter of ThbZIP1 to activate its expression. Expression of ThbZIP1 is induced by ABA, salt, drought, methyl viologen and cold. ThbZIP1 can specifically bind to ACGT elements, with the highest binding affinity to the C-box, followed by the G-box and lastly the A-box. Compared with wild-type (Col-0) Arabidopsis, transgenic plants expressing ThbZIP1 had an increased tolerance to drought and salt, but had an increased sensitivity to ABA during seed germination and root growth; meanwhile, ROS level, cell death and water loss rate in transgenic plants were significantly reduced. Microarray analyses showed that many ROS scavenging genes were up-regulated by ThbZIP1 under salt stress conditions. Based on these data, we suggest that ThbZIP1 confers abiotic stress tolerance through activating stress tolerance genes to modulate ROS scavenging ability and other physiological changes involved in stress tolerance, and plays an important role in the ABA-mediated stress response of T. hispida.


GSK3 in Alzheimer's disease: mind the isoforms.
Understanding the molecular signaling pathways that go awry in Alzheimer's disease (AD) would provide insights into developing novel therapies for this devastating neurodegenerative disease. Previous work has established that hyperactive glycogen synthase kinase-3 (GSK3) is linked to both "sporadic" and "genetic" forms of AD, suggesting a crucial role of GSK3 in AD pathogenesis. Therefore, inhibition of GSK3 activity has been intensely investigated as a potential therapeutic intervention for AD. GSK3 exists in two isoforms: GSK3α and GSK3β. Markedly, recent studies indicate specific contributions of each of the α and β isoforms of GSK3 to AD pathogenesis, suggesting a role of both isoforms in the disease. Here I review recent relevant work investigating isoform-specific roles of GSK3 in AD pathophysiology, highlighting the emerging role of GSK3α, which has been largely overlooked in favor of the more extensive studies of GSK3β.


Open science in psychophysiology: An overview of challenges and emerging solutions.
The present review is the result of a one-day workshop on open science, held at the Annual Meeting of the Society for Psychophysiological Research in Washington, DC, September 2019. The contributors represent psychophysiological researchers at different career stages and from a wide spectrum of institutions. The state of open science in psychophysiology is discussed from different perspectives, highlighting key challenges, potential benefits, and emerging solutions that are intended to facilitate open science practices. Three domains are emphasized: data sharing, preregistration, and multi-site studies. In the context of these broader domains, we present potential implementations of specific open science procedures such as data format harmonization, power analysis, data, presentation code and analysis pipeline sharing, suitable for psychophysiological research. Practical steps are discussed that may be taken to facilitate the adoption of open science practices in psychophysiology. These steps include (1) promoting broad and accessible training in the skills needed to implement open science practices, such as collaborative research and computational reproducibility initiatives, (2) establishing mechanisms that provide practical assistance in sharing of processing pipelines, presentation code, and data in an efficient way, and (3) improving the incentive structure for open science approaches. Throughout the manuscript, we provide references and links to available resources for those interested in adopting open science practices in their research.


Epitaxial Aluminum Surface-Enhanced Raman Spectroscopy Substrates for Large-Scale 2D Material Characterization.
Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive technique to identify vibrational fingerprints of trace analytes. However, present SERS techniques suffer from the lack of uniform, reproducible, and stable substrates to control the plasmonic hotspots in a wide spectral range. Here, we report the promising application of epitaxial aluminum films as a scalable plasmonic platform for SERS applications. To assess the uniformity of aluminum substrates, atomically thin transition metal dichalcogenide monolayers are used as the benchmark analyte due to their inherent two-dimensional homogeneity. Besides the distinctive spectral capability of aluminum in the ultraviolet (325 nm), we demonstrate that the aluminum substrates can even perform comparably with the silver counterparts made from single-crystalline colloidal silver crystals using the same SERS substrate design in the visible range (532 nm). This is unexpected from the prediction solely based on optical dielectric functions and illustrate the superior surface and interface properties of epitaxial aluminum SERS substrates.


[Influence of enhanced UV-B radiation on chlorophyll fluorescence characteristics of soybean].
To investigate the influence of enhanced UV-B radiation on chlorophyll fluorescence characteristics of soybean, pulse amplitude modulation fluorometer was employed to measure the fluorescence parameters and rapid light curves during different growth stages under the condition of simulating 20% enhancement of UV-B. Results showed that enhanced UV-B radiation reduced the chlorophyll contents by 5.03%, 7.70% and 10.38% in seedling, branching-flowering and pod-setting periods, respectively. In branching-flowering period, the value of Fv/Fm decreased by 6.13%. In seedling and branching-flowering periods, effective quantum yield(Y) diminished significantly during PAR >366 micromol x (m2 x s)(-1), the maximal potential relative electron transport rate (Pm) diminished by 28.92% and 15.49%, respectively. But Y and Pm had no significant difference in 3-leave and pod setting periods. Semi-light saturation points (l(k)) were diminished by 21.18% and 23.17% in 3-leave and seedling periods. Initial slope (a) was decreased by 21.05% in branching-flowering period. Enhanced UV-B radiation also significantly reduced non-photochemical quenching (NPQ) during PAR >366 micromol x (m2 x s)(-1) in seedling period and photochemical quenching (qP) during PAR >366 micromol x (m2 x s)(-1) in branching-flowering period. The results of this study suggested that enhanced UV-B radiation inhibited electron transport activity of PS II, injured light-harvesting systems and dissipative protection mechanisms, damaged photosynthesis system, thus diminished photosynthetic efficiency of soybean.


Treatment of non-specific vaginitis with a single dose of tinidazole.
In a double-blind, randomized trial twenty-six patients with non-specific vaginitis were treated with tinidazole/placebo (4 X 500 mg in one single dose). Thirteen patients received placebo, of which one was cured. Thirteen patients received tinidazole, of which six were cured. The nineteen non-responders received tinidazole (4 X 500 mg in one single dose), which resulted in the cure of eight patients (seven from the original placebo-group and one from the original tinidazole-group). Of the eleven patients not responding to tinidazole seven were successfully treated with metronidazole (250 mg, 4 times daily, for one week).


Patient Use of Cardiovascular Devices and Apps: Are We Getting Our Money's Worth?
The evolution of technology makes it likely that a large number of people will invest in and use health-related mobile applications and wearable devices. Yet the question remains: Do these technology-based interventions modify health behavior and improve health…and are we getting our money's worth? The vast majority of studies concerning health-related apps and wearable devices have small sample sizes and short time spans of 6 months or less, so it is not clear if these durations were determined by lack of consistent use over time. Furthermore, many of the most popular applications have not been subjected to randomized trials. Overall, the small demonstrated improvements in outcomes are often associated with professional involvement from clinicians, coaches, or diabetes educators provided in conjunction with use of mobile health (mHealth) platforms. This paper explores the use of mHealth technologies that address cardiovascular disease/prevention (eg, diabetes, diet, physical activity, and associated weight loss) and discusses the lack of adequate evidence to support even minimal patient investment in mobile applications or wearable devices at this time.


Stemness Potency of Human Gingival Cells-Application in Anticancer Therapies and Clinical Trials.
Gingivae, as the part of periodontium, are involved in tooth support and possess the ability to heal rapidly, without scar formation. Recently, dental tissues have been identified as a potential source of mesenchymal stem cells (MSCs) and several populations of MSCs were isolated from the orofacial region, including gingival mesenchymal stem cells (GMSCs). GMSCs exhibit robust immunomodulatory and differentiation potential and are easily obtainable, which make them promising candidates for cellular therapies. Apart from being tested for application in immunologic- and inflammatory-related disorders and various tissue regeneration, GMSCs promise to be a valuable tool in cancer treatment, especially in tongue squamous cell carcinoma (TSCC) with the use of targeted therapy, since GMSCs are able to selectively migrate towards the cancerous cells both in vitro and in vivo. In addition to their ability to uptake and release anti-neoplastic drugs, GMSCs may be transduced with apoptosis-inducing factors and used for cancer growth inhibition. Moreover, GMSCs, as most mammalian cells, secrete exosomes, which are a subset of extracellular vesicles with a diameter of 40-160 nm, containing DNA, RNA, lipids, metabolites, and proteins. Such GMSCs-derived exosomes may be useful therapeutic tool in cell-free therapy, as well as their culture medium. GMSCs exhibit molecular and stem-cell properties that make them well suited in preclinical and clinical studies.


Contamination by antimicrobial-resistant enterobacteria isolated from cell phones and hands in a veterinary hospital.
Hospital infections are of great relevance in human and animal health, and fomites are important in the spread of pathogens in hospital units. The aim of this study was to investigate the frequency of enterobacteria in the operating room of a veterinary hospital, the potential cross-contamination of samples, and to characterise the susceptibility profile of the isolates to antimicrobials. Sixty-five samples were collected from five different surgical procedures. These samples came from the hands and cell phones of the surgical team and pet owners, operating tables, and patients. Species detection was performed through polymerase chain reaction, genetic diversity by pulsed-field gel electrophoresis (PFGE), and susceptibility to antimicrobials through an antibiogram. Escherichia coli and Proteus mirabilis isolates were obtained from eight samples, from the hands of the anaesthesiologist, the pet owner, and the surgeon; the surgeon's, the nurse's and the anaesthesiologist's cell phones, and two surgical tables. Furthermore, PFGE showed high genetic diversity among the isolates, which showed multidrug resistance. The identification of multidrug-resistant E. coli and P. mirabilis on cell phones of the surgical team is a major concern and, although no direct correlation was found, the isolation of these bacteria inside the clean area of the operating room shows the possibility of nosocomial transmission from cell phones to susceptible patients.


Electrical Conductivity of Doped Organic Semiconductors Limited by Carrier-Carrier Interactions.
High electrical conductivity is a prerequisite for improving the performance of organic semiconductors for various applications and can be achieved through molecular doping. However, often the conductivity is enhanced only up to a certain optimum doping concentration, beyond which it decreases significantly. We combine analytical work and Monte Carlo simulations to demonstrate that carrier-carrier interactions can cause this conductivity decrease and reduce the maximum conductivity by orders of magnitude, possibly in a broad range of materials. Using Monte Carlo simulations, we disentangle the effect of carrier-carrier interactions from carrier-dopant interactions. Coulomb potentials of ionized dopants are shown to decrease the conductivity, but barely influence the trend of conductivity versus doping concentration. We illustrate these findings using a doped fullerene derivative for which we can correctly estimate the carrier density at which the conductivity maximizes. We use grazing-incidence wide-angle X-ray scattering to show that the decrease of the conductivity cannot be explained by changes to the microstructure. We propose the reduction of carrier-carrier interactions as a strategy to unlock higher-conductivity organic semiconductors.


[Isolation of thermophilic bacteria Thermus sp. YBJ-1 and cloning of amylase gene].
Thermophilic bacteria strain YBJ-1 was isolated from hot spring samples collected from Yangbajing, Tibet. The 16sr DNA sequence of YBJ-1 (1511bp in length) shares 98% identity with that of Thermus scotoductus strain ITI-252T. The full-length ORF of amylase gene of YBJ-1 (amyT) was amplified by PCR technique and cloned into T-vector. The complete sequence of amyT is 1767bp in length, coding for 588 amino acids. The deduced amino acids share 99% similarity with alpha-cyclodextrinse of Bacillus sterothermophilus, 96% with maltogenic amylse of Thermus. sp IM6501, and 81% with neopullulanase of Bacillus sterothermophlus.


Assessing the Reliability and Validity of the Persian Version of the Chronic Pelvic Pain Questionnaire in Women.
There is a need for developing a standard and approved tool to assess chronic pelvic pain (CPP) in Iranian women. The aim of this study was to investigate the reliability and validity of the Persian version of the pelvic pain and urinary/frequency (PUF) questionnaire in Iranian women with CPP. This cross-sectional study was performed on 50 females with CPP referred to the urology clinic of Kerman University of Medical Sciences from 2018 to 2019. Initially, the PUF questionnaire was translated into Persian and then back translated into English. The face validity of the tool was evaluated by being tested on 50 patients who had different literacy levels to ensure its understandability and acceptability by patients. The construct validity was evaluated through both exploratory and confirmatory factor analyses. The internal consistency was also analyzed by determining Cronbach's alpha coefficient and test-retest method. The Persian version of the questionnaire was compatible with the original English version. The Kisser sampling adequacy index was calculated on the data before extracting the factors indicating good factor accessibility of the questionnaire statements. The construct validity of the questionnaire was confirmed using exploratory and confirmatory factor analyses. The internal consistency parameters were also acceptable. Cronbach's alpha coefficient of the whole questionnaire, as well as the coefficients of the "signs/symptoms" and "unpleasant feelings" domains were 77%, 74%, and 78%, respectively. The developed Persian version of the PUF questionnaire retrieved a good validity and reliability.


Platelet-induced enhancement of LS174T colon carcinoma and THP-1 monocytoid cell adhesion to vascular endothelium under flow.
This study was undertaken to characterize the adhesion of LS174T colon adenocarcinoma cells to 4-h TNF-alpha-stimulated human umbilical vein endothelial cells (HUVECs) under flow in the presence and absence of platelets and erythrocytes. Cell binding to HUVECs was significantly enhanced by simultaneous perfusion of thrombin-activated, but not resting, platelets. This increase was achieved via a platelet bridging mechanism whereby a previously tethered LS174T cell (primary tether) captures a free-flowing cell (secondary tether) that subsequently attaches to the endothelium downstream of the already adherent cell. The total number of tumor cells tethering to HUVECs and the percentage of secondary tethers relative to the total amount of cell tethering depended on platelet concentration and wall shear stress. At 0.8 dyn/cm(2) and a platelet-to-LS174T cell ratio of 25:1, the total amount of cell tethering nearly doubled as a result of platelet-induced enhancement compared with the amount without platelet perfusion. Moreover, the percentage of secondary tethers increased from background levels (<5%) in the absence of platelets to approximately 60% at a platelet-to-LS174T cell ratio of 25:1. Platelet-mediated secondary tethering is not limited to LS174T colon carcinoma cells, as THP-1 monocytoid cells also displayed this pattern of interaction. Secondary tethering was dependent on both platelet P-selectin and alpha(IIb)beta(3)-integrin for LS174T cells and P-selectin alone for THP-1 cells. Furthermore, platelet-mediated secondary tethering of both cell types occurred in the presence of red blood cells. Altogether, these results reveal a novel role for platelets in promoting cell binding to endothelium through a secondary tethering mechanism.