Measuring diaphragm movement and respiratory frequency using a novel ultrasound device in healthy volunteers.
To evaluate the ability of a novel ultrasound (US) device, DiaMon, to monitor diaphragm movement via its proxy liver movement, and compare it with the respired flow measured with a flowmeter, in awake and healthy volunteers. We wanted to (1) establish the optimal anatomical position for attaching the DiaMon device to the abdominal wall, and (2) evaluate the accuracy of continuous monitoring of respiratory frequency. Thirty healthy subjects were recruited. The DiaMon probe was applied subcostally in four different positions with the subjects in five different postures. The subjects breathed tidal volumes into a spirometer for 30-60 s with the DiaMon recording simultaneously. The device detected a readable signal in 83-100% of the position/posture-combinations. The technical correlation between the two signals was highest in the anterior axillary-supine position (mean ± SD: 0.95 ± 0.03), followed by paramidline-supine (0.90 ± 0.09) and midclavicular-supine (0.89 ± 0.12). The frequency measurements yielded a mean difference of 0.03 (95% limits of agreement - 0.11, 0.16) breaths per minute in the anterior axillary-supine position. The DiaMon device is able to detect liver movement in most subjects, and it measures breathing frequency accurately.


Trends in the pharmacological treatment of benign prostatic hyperplasia in the UK from 1998 to 2016: a population-based cohort study.
To describe trends in the pharmacological treatment of BPH in the United Kingdom (UK) from 1998 to 2016. We created a cohort of men with a diagnosis of BPH between 1998 and 2016 using the Clinical Practice Research Datalink. Using Poisson regression, we estimated annual prescription rates of 5αRIs, α-blockers, and combination therapy (5αRIs + α-blockers). Adherence was defined by a proportion of days covered > 80%. Our cohort included 192,640 men with BPH who generated 1,176,264 person-years (PYs) of follow-up. The mean age was 68.0 (standard deviation: 10.7) years. The prescription rate of all BPH medications during the study period was 347.6 per 100 PYs (95% CI 347.2-347.9). α-Blockers had the highest prescription rate (222.9 per 100 PYs, 95% CI 222.7-223.2); prescription rates of 5αRIs and combination therapy were 69.1 per 100 PYs (95% CI 69.0-69.3) and 55.5 per 100 PYs (95% CI 55.4-55.7), respectively. The prescription rate for combination therapy was 19 times greater in 2013-2016 than in 1998-2000 (rate ratio: 19.2, 95% CI 18.6-19.7), while the prescription rates for 5αRIs and α-blockers each doubled during this period (rate ratio: 1.86, 95% CI 1.84-1.88 and rate ratio: 2.02, 95% CI 2.01-2.04, respectively). The proportion of patients who were adherent at 1 year to 5αRIs (32.3%), α-blockers (44.0%), and combination therapy (45.6%) was low. The prescription rate of BPH medications increased substantially between 1998 and 2016 in the UK, with the greatest relative increase observed with combination therapy. Adherence to BPH medications was low in this population-based study.


The properties of neurones recorded in the superficial dorsal horn of the rat spinal cord.
The physiological properties of neurones in the superficial laminae of the dorsal horn of the fourth and fifth lumbar segments of the rat spinal cord have been investigated in decerebrate spinal animals. Both extracellular recordings with platinum-plated tungsten microelectrodes (n = 72) and intracellular recordings with glass microelectrodes (N = 79) were made. Attempts were made to fill cells intracellularly with horseradish peroxidase or Lucifer Yellow. Thirty-seven percent of the intracellularly injected neurones were recovered after histological processing and their cell bodies found to be in lamina 1 or 2 and in the dorsal white matter overlying lamina 1. The dendritic spread of the stained neurones was maximal in the rostrocaudal plane with a restricted mediolateral spread. The physiological properties of the extracellularly recorded units, the intracellularly unidentified units, and the intracellularly stained units were the same. The neurones were characterized by low background activity and all had excitatory receptive fields on the lower limb. Some neurones responded only to low-threshold mechanical stimulation of the skin or only to noxious skin stimulation but the majority of units (58%) were wide-dynamic-range cells responding to both types of stimuli. Receptive field classification was made questionable, however, by the existence of cells (9%) that exhibited a spontaneous shift in the size of their receptive fields and in the type of stimulus that elicited a response. The neurones in the superficial dorsal horn commonly showed a marked inhibition to repeated cutaneous stimuli (27%) or a prolonged afterdischarge followed a single stimulus (20%). Afferent input from the sural nerve was found to be from A and C fibres in both extra-and intracellular recordings. A delta- and C-mediated excitations were most common although convergent inputs from A beta-fibres occurred in 40% of units. No correlation was found between cell structure or distribution of dendritic fields and physiological properties in our small sample of intracellularly stained cells. The morphology of the cells was highly diverse, as were the different receptive fields. There was, however, some correlation between the location of cell bodies and their responses. Neurones responding only to low-threshold stimuli were distributed either in the dorsal white matter or in inner lamina 2. Wide-dynamic-range cells were distributed throughout the superficial dorsal horn. These results suggest that neurones of different shapes and positions may subserve the same function and, conversely, that neurones of the same shape and position may subserve different functions.


Free energy difference to create the M-OH* intermediate of the oxygen evolution reaction by time-resolved optical spectroscopy.
Theoretical descriptors differentiate the catalytic activity of materials for the oxygen evolution reaction by the strength of oxygen binding in the reactive intermediate created upon electron transfer. Recently, time-resolved spectroscopy of a photo-electrochemically driven oxygen evolution reaction followed the vibrational and optical spectra of this intermediate, denoted M-OH*. However, these inherently kinetic experiments have not been connected to the relevant thermodynamic quantities. Here we discover that picosecond optical spectra of the Ti-OH* population on lightly doped SrTiO3 are ordered by the surface hydroxylation. A Langmuir isotherm as a function of pH extracts an effective equilibrium constant relatable to the free energy difference of the first oxygen evolution reaction step. Thus, time-resolved spectroscopy of the catalytic surface reveals both kinetic and energetic information of elementary reaction steps, which provides a critical new connection between theory and experiment by which to tailor the pathway of water oxidation and other surface reactions.


Custom core construction using glass-ionomer cements.
Crown loss is a frequent problem, and it is often compounded, particularly in the elderly, by fracture of the underlying natural core. Reconstructing the core in either amalgam or composite resin can have disadvantages. This article suggests a method for constructing replacement cores at one visit using glass-ionomer cements.


Contemporary views on the genetics of anorexia nervosa.
Anorexia nervosa (AN) is a serious mental illness characterized by severe dietary restriction that leads to high rates of morbidity, chronicity, and mortality. Unfortunately, effective treatment is lacking and few options are available. High rates of familial aggregation and significant heritability suggested that the complex etiology of AN is affected by both genetic and environmental factors. In this paper, we review studies that reported common and rare genetic variation that influence susceptibility of AN through candidate gene studies, genome-wide association studies, and sequencing-based studies. We also discuss gene expression, methylation, imaging genetics, and pharmacogenetics to demonstrate that these studies have collectively advanced our knowledge of how genetic variation contributes to AN susceptibility and clinical course. Lastly, we highlight the importance of gene by environment interactions (G×E) and share our enthusiasm for the use of nutritional genomic approaches to elucidate the interaction among nutrients, metabolic intermediates, and genetic variation in AN. A deeper understanding of how nutrition alters genome stability, how genetic variation influences uptake and metabolism of nutrients, and how response to food components affects disordered eating, will lead to personalized dietary interventions and effective nutraceutical and pharmacological treatments for AN.


The role of hyperthermia in the water economy of desert birds.
A number of authors have suggested that hyperthermia, the elevation of body temperature (Tb) 2 degrees-4 degrees C above normal, contributes to a reduction in total evaporative water loss (TEWL) in birds. Information about the role of hyperthermia in the water economy of birds is scattered throughout the literature. We purposed to collate the available information on this subject, to reevaluate the benefits and costs of this process, and to assess its net effect on the water economy of birds, especially species living in deserts. In this review, we first consider the current model of heat balance in birds at high ambient temperatures (Ta), and show that, in most studies performed at a high Ta, birds were increasing their Tb, a violation of the assumption of steady state conditions. Next, we incorporate the rate of heat gain into calculations of the dry heat transfer coefficient (h), below and above temperature equality (Ta=Tb). We develop a method to calculate h at Ta=Tb, using l'Hôpital's rule. The combined result of our approach suggests that birds increase their dry heat transfer even when Ta is above Ta=Tb, contrary to our prediction. Finally, we explore aspects of hyperthermia that reduce water loss, such as an improved thermal gradient and heat storage, and aspects that may augment water loss, the latter a result of increased respiratory water loss when Tb is elevated. Our analysis of the combination of these three factors suggests that, during acute exposure to high Ta (1 h), birds over a size range of 10-1,000 g save about 50% of their TEWL by becoming hyperthermic. For chronic episodes of high Ta (5 h), small birds save water by hyperthermia but large birds do not.


Osteoporosis health beliefs and self-efficacy among orthopedic nurses in Hunan Province, China.
Osteoporosis is a growing health problem worldwide. Health beliefs and self-efficacy in regard to osteoporosis may be important targets in preventive behaviours. This study aimed to describe beliefs around osteoporosis held by orthopaedic nurses as well as the nurses' self-efficacy and the associations between knowledge, health beliefs and self-efficacy. A cross-sectional study was conducted with nurses working in orthopaedic departments in 13 tertiary hospitals in Hunan Province, China. Participants completed a questionnaire consisting of the Osteoporosis Health Belief Scale (OHBS), the Osteoporosis Self-Efficacy Scale (OSES) and a survey of their socio-demographic characteristics. A total of 558 nurses completed the survey (response rate 95%). The nurses' scores regarding their perception of the susceptibility to and seriousness of osteoporosis were moderately low (mean OHBS score = 124.72, range 45-171; SD = 14.71), while their corresponding self-efficacy scores were moderately high (mean OSES score = 72.01, range 0-120; SD = 23.15). Knowledge regarding osteoporosis was positively associated with self-efficacy (r = 0.232, p = 0.000) but not with health beliefs (r = 0.030, p = 0.484). The findings of this study revealed moderately high self-efficacy and moderate health beliefs related to osteoporosis among orthopaedic nurses. Osteoporosis knowledge was not associated with health beliefs or self-efficacy. The findings indicate that educational programs should not only focus on knowledge improvement but also changes in health beliefs to improve actual behaviour in practice.


Deficiency of the sixth component of complement and susceptibility to Neisseria meningitidis infections: studies in 10 families and five isolated cases.
Complement component C6 deficiency (C6D) was diagnosed in 15 patients who presented, independently, with recurrent meningococcal infection. This condition is thus not particularly rare in the Cape. Ten of the patients belonged to multiplex families, and family studies led to the diagnosis of another 12 C6D cases among the siblings. Segregation analysis showed that C6D occurred more frequently among the siblings of affected individuals than would be expected for co-dominant inheritance. The possible reasons for this are discussed. We also observed that the 12 non-proband C6D siblings included only four with a history suggestive of meningococcal infection, and thus C6D individuals apparently differ in susceptibility to Neisseria meningitidis infection. We confirmed previous observations that primary infection occurs later in C6D individuals than amongst susceptible complement-sufficient individuals. Among 123 patients presenting with primary meningitis, one case of C6D was diagnosed. The data show that C6D is an important factor associated with susceptibility to meningococcal infection in the Cape.


[Eruptive nevi associated with sorafenib treatment].
Sorafenib is a new multikinase inhibitor recently approved for renal cell carcinoma and hepatocarcinoma. Among other targets, it blocks the kinase function of the RAF gene products including V600E mutant BRAF, which is frequently found in both melanoma and naevi. Cutaneous side effects are frequent with sorafenib, but no naevus modification has been reported until now. Five cases of eruptive naevi in patients treated with sorafenib are reported. The mean duration of sorafenib treatment was 9.2 months when naevi eruption was noticed. The patients presented with about 100 to more than 200 small, homogenous, dark-brown naevi located mainly on the trunk and upper limbs. Eruptive melanocytic naevi have been reported in association with blistering diseases, and more generally in a setting of immunosuppression. We hypothesize that naevi appearance could be linked to an anti-senescence effect of sorafenib via its action on the MAP kinase pathway. Further prospective studies are needed to explore the relationship between sorafenib and the biology of naevi.


The contribution of intrinsic disorder prediction to the elucidation of protein function.
Current knowledge of protein function stems primarily from the detailed characterization of some protein domain families and from extensive homology-based annotation transfers. Intrinsically disordered proteins exploit complementary molecular recognition mechanisms and their study has potential to make a significant contribution to the field. Building on established computational biology techniques, efforts are now aimed at unveiling their biological roles at the molecular and system level. Recent developments towards identifying functional sites in disordered regions, and analysing how the occurrence of protein disorder in a gene can provide insight into its biochemical and cellular function are discussed.


A biologically motivated neural network for phase extraction from complex sounds.
We demonstrate that natural acoustic signals like speech or music contain synchronous phase information across multiple frequency bands and show how to extract this information using a spiking neural network. This network model is motivated by common neurophysiological findings in the auditory brainstem and midbrain of several species. A computer simulation of the model was tested by applying spoken vowels and organ pipe tones. As expected, spikes occurred synchronously in the activated frequency bands. This phase information may be used for sound separation with one microphone or sound localization with two microphones.


The theory and practice of ovulation induction with gonadotropin-releasing hormone.
Gonadotropin-releasing hormone therapy has undergone sufficient basic and clinical investigation as a tool for ovulation induction that it should now be considered a safe and effective infertility therapy for office practice. Nevertheless, there remains sufficient mystique about patient selection, optimal dosage and route of delivery, and apprehension on the part of both physicians and patients about cost and inconvenience of medication pumps that gonadotropin-releasing hormone therapy has not enjoyed the widespread acceptance it deserves. This article presents straightforward guidelines for therapy that are based on a detailed review of current literature, together with new information about evolving pump technologic characteristics, that should offer reassurance to the practitioner considering use of gonadotropin-releasing hormone therapy in her/his practice.


Lead and cancer in humans: where are we now?
Lead is only weakly mutagenic, but in vitro it inhibits DNA repair and acts synergistically with other mutagens. Lead acetate administered orally, cutaneously, or intraperitoneally causes kidney cancer, brain cancer (gliomas), and lung cancer in rodents, and acts synergistically with other carcinogens. Most cytogenetic studies of exposed workers have shown increases in chromosome aberrations or sister chromatid exchange, including some studies with positive-exposure response trends. There are eight studies of cancer mortality or incidence among highly exposed workers; most are cohort studies of lead smelter or battery workers exposed decades ago. We reviewed the epidemologic studies with regard to cancer. These studies provide some evidence of increased risk of lung cancer (RR = 1.30, 1.15-1.46, 675 observed deaths) and stomach cancer (combined RR = 1.34, 1.14-1.57, 181 observed). However, the lung cancer findings are not consistent across studies, and confounding by arsenic may affect the study with the highest lung cancer RR. Exclusion of that study yields a combined lung cancer RR of 1.14 (1.04-1.73). There is little evidence of increased risk of kidney cancer (combined RR = 1.01, 0. 72-1.42, 40 observed) or brain cancer (combined RR = 1.06, 0.81-1.40, 69 observed). However, two studies show a two-fold increase in kidney cancer, and one study shows a significant excess of gliomas. IARC classified lead as a "possible human carcinogen" based on sufficient animal data and insufficient human data in 1987. Six of the eight studies cited above have been published since 1987. Overall, there is only weak evidence associating lead with cancer; the most likely candidates are lung cancer, stomach cancer, and gliomas.


Nondestructive and objective assessment of the vestibular function in rodent models: A review.
The normal function of the vestibular system is crucial for the sense of balance. The techniques used to assess the vestibular function plays a vital role in the research of the vestibular system. In this article, we have systematically reviewed some popular methods employing vestibular reflexes and vestibular evoked potentials for assessing the vestibular function in rodent models. These vestibular reflexes and vestibular evoked potentials to effective stimuli have been used as nondestructive and objective functional measures. The main types of vestibular reflexes include the vestibulo-ocular reflex (VOR), vestibulocollic reflex (VCR), and vestibulo-sympathetic reflex (VSR). They are all capable of indicating the functions of the semicircular canals and otoliths. However, the VOR assessment is much more prevalently used because of the relatively stereotypical inputoutput relationship and simple motion pattern of the ocular response. In contrast, the complicated motion pattern and small gain of the VCR response, as well as the undesired component possibly contributed from the acceleration receptors outside the labyrinths in the VSR response, restrict the widespread applications of VCR and VSR in the assessment of the vestibular system. The vestibular evoked myogenic potentials (VEMPs) and vestibular sensory evoked potentials (VsEPs) are the two typical evoked potentials that have been also employed for evaluating the vestibular function. Through exploiting different types of the VEMPs, the saccular and utricular functions can be evaluated separately. The sound-induced VEMPs, moreover, are capable of noninvasively assessing the unilateral vestibular function. The VsEPs, via the morphology of their signal waveforms, enable the access to the location-specific information that indicates the functional statuses of different components within the vestibular neural pathway.


Fluorescent and electrochemical dual-mode detection of Chikungunya virus E1 protein using fluorophore-embedded and redox probe-encapsulated liposomes.
The critical goal of sensitive virus detection should apply in the early stage of infection, which may increase the probable survival rate. To achieve the low detection limit for the early stage where a small number of viruses are present in the sample, proper amplified signals from a sensor can make readable and reliable detection. In this work, a new model of fluorescent and electrochemical dual-mode detection system has been developed to detect virus, taking recombinant Chikungunya virus E1 protein (CHIK-VP) as an example. The hydrophobic quantum dots (QDs) embedded in the lipid bilayer of liposome and methylene blue (MB) encapsulated in the inner core of liposomes played a role of dual-signaling modulator. After CHIK-VP addition, the nanocomposites and APTES-coated Fe3O4 nanoparticles (Fe3O4 NPs) were conjugated with antibodies to form a sandwich structure and separated from the medium magnetically. The nanoconjugates have been burst out by chloroform as surfactant, and both the QDs and MB are released from the liposome and were then monitored through changes in the fluorescence and electrochemical signals, respectively. These two fluorometric and electrochemical signals alteration quantified the CHIK-VP in the range of femtogram to nanogram per milliliter level with a LOD of 32 fg mL-1, making this liposomal system a potential matrix in a virus detection platform. Graphical abstract.


Two classes of binding sites for [3H]substance P in rat cerebral cortex.
The binding characteristics of [3H]substance P ([3H]SP) were investigated in membranes prepared from rat cerebral cortex. Binding of [3H]SP reached equilibrium after 50 min at 25 degrees C and was saturable at 8 nM. Saturation data could be resolved into high affinity (equilibrium dissociation constant, Kd, 0.22 nM) and low affinity sites (Kd, 2.65 nM). The low affinity sites were more numerous than the high affinity sites, with a ratio of 4:1. The non-hydrolyzable GTP analogue GppNHp had no effect on binding, indicating that the high and low affinity sites are not guanine nucleotide-regulated states of the same (NK-1) receptor. The low affinity sites are unlikely to represent NK-3 receptors since coincubation with the selective NK-3 receptor agonist senktide did not alter the biphasic nature of [3H]SP binding. The rank order of potency for inhibition of [3H]SP (2 nM) binding was SP > or = [Sar9, Met(O2)11]-SP > or = physalaemin >> SP(3-11) > NP gamma = [Ala3]-SP > or = SP(4-11) > or = NPK > or = SP(5-11) > or = NKB approximately NKA >> SP(1-9), compatible with binding to an NK-1 site. N-terminal fragments and non-amidated analogues were ineffective competitors for [3H]SP binding. However, competition data for several peptides including substance P (SP) and the NK-1 selective agonist [Sar9, Met(O2)11]-SP could be resolved into two components.(ABSTRACT TRUNCATED AT 250 WORDS)


Antimycobacterial Activities of N-Substituted-Glycinyl 1H-1,2,3-Triazolyl Oxazolidinones and Analytical Method Development and Validation for a Representative Compound.
Twelve N-substituted-glycinyl triazolyl oxazolidinone derivatives were screened for antimycobacterial activity against susceptible (Mycobacteriumtuberculosis (Mtb) H37Rv) and resistant (isoniazid (INH)-resistant Mtb (SRI 1369), rifampin (RMP)-resistant Mtb (SRI 1367), and ofloxacin (OFX)-resistant Mtb (SRI 4000)) Mtb strains. Most of the compounds showed moderate to strong antimycobacterial activity against all strains tested, with minimum inhibitory concentration (MIC) value ranges of 0.5-11.5, 0.056-11.6, 0.11-5.8, and 0.03-11.6 μM, and percent inhibition ranges of 41-79%, 51-72%, 50-75%, and 52-71% against Mtb H37Rv, INH-R, RMP-R, and OFX-R M.tuberculosis, respectively. The 3,5-dinitrobenzoyl and 5-nitrofuroyl derivatives demonstrated strong antimycobacterial activities with the N-(5-nitrofuroyl) derivatives (PH-145 and PH-189) being the most potent, with MIC value range of 0.3-0.6 μM against all strains tested. Compounds were not bactericidal, but showed intracellular (macrophage) antimycobacterial activity. A reliable validated analytical method was developed for a representative compound PH-189 using Waters Acquity ultra High-Performance Liquid Chromatography (UHPLC) system with quaternary Solvent Manager (H-Class). A simple extraction method indicated that PH-189 was stable in human plasma after 90 min at 37 °C with more than 90% successfully recovered. Moreover, stress stability studies were performed and degradants were identified by using UHPLC-ESI-QToF under acidic, basic, and oxidative simulated conditions.


Hepatitis B virus genotypes from European origin explains the high endemicity found in some areas from southern Brazil.
Southern Brazil is considered an area of low Hepatitis B endemicity, but some areas of higher endemicity have been described in the Southwest of Paraná and Santa Catarina states. The aim of this study was to evaluate viral genotypes circulating throughout Paraná state. PCR amplification and partial sequencing of the S gene was carried out in 228 samples from HBsAg positive candidate blood donors. Samples have been collected in seven different counties (Cascavel, Curitiba, Foz do Iguaçu, Francisco Beltrão, Maringá, Londrina and Paranaguá). The most common HBV genotype in Paraná state was D (82.9%; 189/228), followed by A (14.1%; 32/228). Genotypes F (1.3%; 3/228), C (1.3%; 3/228) and H (0.4%; 1/228) were also found. Distribution of genotypes was different in the studied counties, but genotype D was the most frequent in all of them. In Francisco Beltrão, all studied samples belonged to genotype D. The high prevalence of HBV genotype D in South of Brazil is explained by the intense migration of settlers from Europeans countries. Subgenotypes A1 and A2 were identified circulating in all cities where HBV/A was found. As observed in other areas of Brazil, HBV/A1 is more frequent than the HBV/A2 in Paraná state and its presence was significantly larger in black and mulatto individuals. Genotype C was found only in individuals with Asian ancestry from Londrina and Maringá. Most HBV/F sequences identified in this study were classified as subgenotype F2a that was previously described in Brazil. The sole case of subgenotype F4 was from Foz do Iguaçu city, near to Northern Argentina, where F4 is highly prevalent. The single genotype H sample was from Curitiba. This is the first case of this genotype described in Brazil. Further studies should be carried out to determine if more genotype H samples can be found in other populations from Brazil.


Intermittent sigmoid volvulus in the younger age groups.
Sigmoid volvulus is a well-recognized clinical entity, occurring more commonly in the male in middle or old age. In younger age groups the diagnosis is therefore often delayed. We report here 11 patients of an average age of 31 years (range 12-57 years), with a preponderance of females (7 : 4), who have presented to us in the past 2 years with intermittent sigmoid volvulus. The average age at onset of initial symptoms was 26 years. All had the diagnosis confirmed radiologically by colonoscopy or at operation. The diagnostic features of the condition are described.


Rates of revision and surgeon-reported graft rupture following ACL reconstruction: early results from the New Zealand ACL Registry.
There remains a lack of consensus on the patient factors associated with graft rupture following anterior cruciate ligament (ACL) reconstruction. This study aimed to identify the rate of revision and surgeon-reported graft rupture and clarify the patient risk factors for failure. Analysis was conducted on prospective data captured by the New Zealand ACL registry. All primary isolated ACL reconstructions recorded between April 2014 and December 2018 were reviewed to identify the rate of revision and surgeon-reported graft rupture. Univariate and multivariate survival analysis was performed to identify patient factors associated with revision and graft rupture. A total of 7402 primary isolated ACL reconstructions were reviewed and had a mean follow-up time of 23.1 (SD ± 13.9) months. There were 258 surgeon-reported graft ruptures (3.5%) of which 175 patients underwent subsequent revision ACL reconstruction (2.4%). Patients younger than 18 years had the highest risk of revision (adjusted HR = 7.29, p < 0.001) and graft rupture (adjusted HR = 4.26, p < 0.001) when compared to patients aged over 36 years. Male patients had a higher risk of revision (adjusted HR = 2.00, p < 0.001) and graft rupture (adjusted HR = 1.70, p < 0.001) when compared to their female counterparts. Patients who underwent ACL reconstruction within 6 months of their injury had a two times increased risk of revision compared to patients who had surgery after 12 months (adjusted HR = 2.15, p = 0.016). Younger age, male sex and a shorter injury-to-surgery time interval increased the risk of revision, while younger age and male sex increased the risk of surgeon-reported graft rupture. II.


Using n-gram method in the decomposition of compound medical diagnoses.
Our goal in this study was to find an easy to implement method to detect compound medical diagnosis in Hungarian medical language and decompose them into expressions referring to a single disease. A corpus of clinical diagnoses extracted form discharge reports (3,079 expressions, each of them referring to only one disease) was represented in an n-gram tree (a series of n consecutive word). A matching algorithm was implemented in a software, which is able to identify sensible n-grams existing both in test expressions and in the n-gram tree. A test sample of another 92 diagnoses was decomposed by two independent humans and by the software. The decompositions were compared with measure the recall and the precision of the method. There was not full agreement between the decompositions of the humans, (which underlines the relevance of the problem). A consensus was arrived in all disagreed point by a third opinion and open discussion. The resulting decomposition was used as a gold standard and compared with the decomposition produced by the computer. The recall was 82.6% the precision 37.2%. After correction of spelling errors in the test sample the recall increased to 88.6% while the precision slightly decreased to 36.7%. The proposed method seems to be useful in decomposition of compound diagnostic expressions and can improve quality of diagnostic coding of clinical cases. Other statistical methods (like vector space methods or neural networks) usually offer a ranked list of candidate codes either for single or compound expressions, and do not warn the user how many codes should be chosen. We propose our method especially in a situation where formal NLP techniques are not available, as it is the case with scarcely spoken languages like Hungarian.


Biodistribution of GB-10 (Na(2)(10)B10H10 compound for boron neutron capture therapy (BNCT) in an experimental model of oral cancer in the hamster cheek pouch.
We previously proposed the hamster cheek pouch model of oral cancer for BNCT studies. We herein present the biodistribution of a non-toxic boron compound, GB-10 (Na(2)(10)B10H10), in this model to assess its potential for BNCT or BNCT enhanced Fast Neutron Therapy. We evaluated the uptake and retention of GB-10 in tumour and precancerous tissue and in potentially dose-limiting, clinically relevant normal tissues. Mean tumour boron concentration delivered by GB-10 (50mgB/kg) peaked to 77.7+/-28.0 ppm at 20min post-administration and remained at therapeutically useful values of 31.9+/-21.4 ppm at 3h. The clearance rate for normal tissues was faster than for tumour tissue. The consistently low brain and spinal cord values would preclude normal tissue toxicity. The uptake of GB-10 by precancerous tissue may be of potential use in the treatment of field cancerized areas. GB-10 was deposited homogeneously in different tumour areas, an asset when treating heterogenous tumours. The data suggests that the joint administration of BPA and GB-10 may improve the therapeutic efficacy of BNCT. GB-10 is a potential boron carrier for BNCT of head and neck tumours and for BNCT-FNT.


Implantable cardioverter/defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: single-center experience of long-term follow-up and complications in 60 patients.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of ventricular tachycardia (VT) and cardiac arrest in young patients. We hypothesized that treatment with implantable cardioverter/defibrillators (ICDs) is safe and improves the long-term prognosis of ARVC patients at high risk of sudden death. Sixty patients with ARVC (aged 43+/-16 years) were treated with transvenous ICD systems. Despite a higher number of right ventricular sites tested for adequate lead positions (P<0.05), lower R-wave amplitudes (P<0.001) were achieved in ARVC patients compared with other entities. During follow-up of 80+/-43 months (396 patient-years), event-free survival was 49%, 30%, 26%, and 26% for appropriate ICD therapies and 79%, 64%, 59%, and 56% for potentially fatal VT (>240 bpm) after 1, 3, 5, and 7 years, respectively. Multivariate analysis identified extensive right ventricular dysfunction as an independent predictor of appropriate ICD discharge. Fifty-three adverse events occurred in 37 patients during the perioperative (n=10) or follow-up (n=43) period, mainly related to the leads (n=31 in 21 patients). No lead perforation was observed. Freedom from adverse events was 90%, 78%, 56%, and 42% and freedom from lead-related complications was 95%, 85%, 74%, and 63% after 1, 3, 5, and 7 years, respectively. These results strongly suggest an improvement in long-term prognosis by ICD therapy in high-risk patients with ARVC. However, meticulous placement and long-term observation of transvenous lead performance with focus on sensing function are required for the prevention and/or early recognition of disease progression and lead-related morbidity during long-term follow-up of ICD therapy in ARVC.


Association between use of specific drugs and antiretroviral adherence: findings from MACH 14.
To determine the association between individual substances of abuse and antiretroviral adherence, analyses require a large sample assessed using electronic data monitoring (EDM). In this analysis, EDM data from 1,636 participants in 12 US adherence-focused studies were analyzed to determine the associations between recent use of various substances and adherence during the preceding 4 weeks. In bivariate analyses comparing adherence among patients who had used a specific substance to those who had not, adherence was significantly lower among those who had recently used cocaine, other stimulants or heroin but not among those who had used cannabis or alcohol. In multivariate analyses controlling for sociodemographics, amount of alcohol use and recent use of any alcohol, cocaine, other stimulants and heroin each was significantly negatively associated with adherence. The significant associations of cocaine, other stimulants, heroin, and alcohol use with adherence suggest that these are important substances to target with adherence-focused interventions.


[Vital microscopy and histochemical study of the autonomic nervous system of the small intestine in animals with thermal burns].
By means of vital microscopy a possibility of histochemical detection of redox enzymes and of study of changes in their activity in intramural nerve plexuses of the small intestine on a live animal was demonstrated. Severe thermal trauma induced a disturbance of permeability of mitochondrial membranes of the Auerbach's plexus nerve cells; as a result, there was a change in the activity of redox enzymes localized within the mitochondria. Lumbar novocain block performed soon after the burn trauma normalized the state of the mitochondrial membranes of the nerve cells.


TGF-β3 Protects Neurons Against Intermittent Hypoxia-Induced Oxidative Stress and Apoptosis Through Activation of the Nrf-2/KEAP1/HO-1 Pathway via Binding to TGF-βRI.
Intermittent hypoxia (IH) is the primary pathological manifestation of obstructive sleep apnea (OSA) and the main cause of OSA-induced cognitive impairment. Hippocampal neurons are considered to be critical cells affected by IH. Transforming growth factor-β3 (TGF-β3) is a cytokine with a neuroprotective effect, which plays a crucial role in resisting hypoxic brain injury, while its role in IH-induced neuronal injury is still unclear. Here, we aimed to clarify the mechanism of TGF-β3 protecting IH-exposed neurons by regulating oxidative stress and secondary apoptosis. Morris water maze results revealed that IH exposure was unable to affect the vision and motor ability of rats, but significantly affected their spatial cognition. Second-generation sequencing (RNA-seq) and subsequent experiments supported that IH decreased TGF-β3 expression and stimulated reactive oxygen species (ROS)-induced oxidative stress and apoptosis in rat hippocampus. In vitro, IH exposure significantly activated oxidative stress within HT-22 cells. Exogenous administration of Recombinant Human Transforming Growth Factor-β3 (rhTGF-β3) prevented ROS surge and secondary apoptosis in HT-22 cells caused by IH, while TGF-β type receptor I (TGF-βRI) inhibitor SB431542 blocked the neuroprotective effect of rhTGF-β3. Nuclear factor erythroid 2-related factor 2 (Nrf-2) is a transcription factor preserving intracellular redox homeostasis. rhTGF-β3 improved the nuclear translocation of Nrf-2 and activated downstream pathway. However, Nrf-2 inhibitor ML385 suppressed the activation of the Nrf-2 mechanism by rhTGF-3 and restored the effects of oxidative stress damage. These results indicate that TGF-β3 binding to TGF-βRI activates the intracellular Nrf-2/KEAP1/HO-1 pathway, reduces ROS creation, and attenuates oxidative stress and apoptosis in IH-exposed HT-22 cells.


Validation of a screening method based on liquid chromatography coupled to high-resolution mass spectrometry for analysis of perfluoroalkylated substances in biota.
A screening method for analysis of perfluoroalkylated substances (PFAS) in biota samples has been developed and validated using liver samples from polar cod (Boreogadus saida) and glaucous gull (Larus hyperboreus). The method was based on extraction of target compounds from homogenised samples into the solvent mixture used as mobile phase in high-performance liquid chromatography (HPLC), i.e. methanol/water (50:50; 2 mM ammonium acetate). The extract was filtered and directly injected into a HPLC/time-of-flight mass spectrometry (TOF-MS) system. Quantification was performed using 7H-perfluoroheptanoic acid as internal standard and a calibration standard solution dissolved in sample extract for each matrix type (matrix-matched calibration standard). The method is very time and cost efficient. Except for long-chain compounds and perfluorooctane sulfonamide (which cannot be covered by this method), recoveries were between 60% and 115% and method detection limits were in the range 0.04-1.3 ng/g wet weight. Blank values could be neglected with the exception of perfluorooctane sulfonate (PFOS), perfluorohexanoic acid (PFHxA) and perfluorooctanoic acid (PFOA). One of the major challenges in PFAS analysis is ionisation disturbance by co-eluting matrix in the ion source of the mass spectrometer. Both matrix and analyte specific signal enhancement and suppression was observed and quantified. Repeated extractions (n = 3) gave relative standard deviations (RSD) <35% for all PFAS. Accuracy was examined by comparing the screening method to the generally applied ion pair extraction (IPE) method. PFAS concentration values of a glaucous gull liver sample deviated by less than 30% for the two methods, provided that matrix-matched calibration standards were employed in both methods.


Development of morphological changes in the small intestine of lambs continuously infected with Trichostrongylus vitrinus.
Groups of three-month-old worm-free Suffolk cross lambs were given 2500 Trichostrongylus vitrinus larvae on five days each week for four, six, eight and 13 weeks and killed one week later. Severe villous atrophy, epithelial erosion and cellular infiltration were common features in the duodenum and the following 2 to 3 m of intestine of lambs killed at weeks 5 and 7. There was evidence of intestinal recovery in the lambs killed at weeks 9 and 14; five of the seven lambs had large areas of intestine which appeared relatively normal and worm activity appeared to be confined largely within focal areas ("fingerprint lesions'). There was no change in the linear distribution of the worms in the intestine over the course of the experiment. The highest percentage of the larval challenge was recovered from lambs killed at week 5 and worm burdens were not cumulative. Lambs killed at week 14 were resistant to larval reinfection.


Reliable gas-phase tautomer equilibria of drug-like molecule scaffolds and the issue of continuum solvation.
Accurate calculation of relative tautomer energies in different environments is a prerequisite to many parameters of relevance in drug discovery. This work provides a thorough benchmark of the semiempirical methods AM1, PM3 and GFN2-xTB, the force-field OPLS4, Hartree-Fock and HF-3c, the density functionals PBEh-3c, B97-3c, r2SCAN-3c, PBE, PBE0, TPSS, r2SCAN, ω-B97X-V, M06-2X, B3LYP, B2PLYP, and second-order perturbation theory MP2 versus the gold-standard coupled-cluster DLPNO-CCSD(T) using the def2-QZVPP basis set. The outperforming method identified is M06-2X, whereas r2SCAN-3c is the best-perfoming one in the set of cost-optimized methods. Application of the two methods on a challenging subset from the SAMPL2 challenge provides evidence that deviations from experiment are caused by deficiencies of current continuum solvation methods.


Compensatory muscle activation caused by tendon lengthening post-Achilles tendon rupture.
The purpose of this study was to establish a relationship between the lengthening of the Achilles tendon post-rupture and surgical repair to muscle activation patterns during walking in order to serve as a reference for post-surgical assessment. The Achilles tendon lengths were collected from 4 patients with an Achilles tendon rupture 6 and 12 months post-surgery along with 5 healthy controls via ultrasound. EMG was collected from the triceps surae muscles and tibialis anterior during overground walking. Achilles lengths at 6 and 12 months post-surgery were significantly longer (p < 0.05) on the involved side compared to the uninvolved side, but there were no side-to-side differences in the healthy controls. The integrated EMG (iEMG) of the involved side was significantly higher than the uninvolved side in the lateral gastrocnemius at 6 months and for the medial gastrocnemius at 12 months in the patients with Achilles tendon rupture; no side-to-side difference was found in the healthy controls. The triceps surae muscles' activations were fair to moderately correlated to the Achilles lengths (0.38 < r < 0.52). The increased Achilles tendon length and iEMG from the triceps surae muscles indicate that loss of function is primarily caused by anatomical changes in the tendon and the appearance of muscle weakness is due to a lack of force transmission capability. This study indicates that when aiming for full return of function and strength, an important treatment goal appears to be to minimize tendon elongation.


Incidence and aetiology of serious viral infections in young febrile infants.
While the incidence and aetiology of serious bacterial infections among febrile infants younger than 90 days old are well studied, those concerning viral infection are not. There are severe life-threatening viral infections requiring immediate intense therapy. The objective of the study is to describe the incidence and aetiology of serious viral infections (SVI) among young febrile infants. A retrospective audit was performed covering all the febrile infants younger than 90 days old admitted to a paediatric emergency department in Japan from 2011 to 2013. SVI was defined as a viral illness that may result in permanent organ dysfunctions or life-threatening complications. Diagnostic investigation consisted of urine and blood culture for all infants, cerebrospinal fluid cultures for infants who do not fulfil the low-risk criteria, rapid antigen tests for several viruses in infants with specific symptoms and blood and/or cerebrospinal fluid polymerase chain reaction of possible viruses for infants with fever without a localising source. Of 275 cases, 32 and 45 cases were diagnosed as serious viral and bacterial infections, respectively. Intensive care unit admission occurred for three viral and four bacterial infections. Viral aetiology consisted of respiratory syncytial virus (11 cases), aseptic meningitis (9 cases), enterovirus (6 cases), influenza virus (3 cases), rotavirus (2 cases) and herpes simplex virus-1 (1 case). Respiratory (14 cases), central nervous (12 cases) and circulatory (6 cases) systems were affected. SVI was observed in 11.6% of febrile young infants in a paediatric emergency department.


Neural correlates of a magnetic sense.
Many animals rely on Earth's magnetic field for spatial orientation and navigation. However, how the brain receives and interprets magnetic field information is unknown. Support for the existence of magnetic receptors in the vertebrate retina, beak, nose, and inner ear has been proposed, and immediate gene expression markers have identified several brain regions activated by magnetic stimulation, but the central neural mechanisms underlying magnetoreception remain unknown. Here we describe neuronal responses in the pigeon's brainstem that show how single cells encode magnetic field direction, intensity, and polarity; qualities that are necessary to derive an internal model representing directional heading and geosurface location. Our findings demonstrate that there is a neural substrate for a vertebrate magnetic sense.


Effects of transmission delays and noise in recurrent excitatory neural networks.
Random perturbations, referred to as noise, are omnipresent in the nervous system. We investigate how noise modifies the dynamics of the neural networks according to the delay. In this report, we examine the effect of transmission delay on both the dynamics of a single neuron receiving a recurrent excitation and the dynamics of fully interconnected excitatory networks. In the case of the single neuron with a recurrent connection, depending on the value of the delay, the discharge pattern changes from regular to multiplets. More complicated patterns appears when noise is added, and depends on both the delay and the noise intensity, but classification can be described. In certain conditions, noise reduces the synchronization, whereas in others it increases the regularity of the network activity. Finally, the same network codes the input amplitude either using mean activity amplitude coding when short delays exist, and using frequency modulation when long delays exist.


[Is there a connection between intraocular pressure and blood pressure? Results of the Gutenberg Health Study and review of the current study situation].
Intraocular pressure (IOD) is the most important risk factor for the occurrence and progression of glaucoma because it is the only measurable risk factor. There is a positive connection between IOD and both systolic and diastolic blood pressure. The clinical relevance is, however, limited because the moderate alterations in IOD are less than the known measurement error and daily physiological oscillation.


The transcribed ultraconserved element uc.51 promotes the proliferation and metastasis of breast cancer by stabilizing NONO.
Long noncoding RNAs have recently emerged as significant contributors to cancers, including breast cancer (BC). One class of long noncoding RNAs called transcribed ultraconserved regions (T-UCRs) is highly conserved in many species and closely related to diverse physiological and pathological processes. However, the function of T-UCRs in BC remains largely unclear. In this study, we identified uc.51, a T-UCR that is overexpressed in both BC tissues and cell lines and is correlated with larger tumor size. Loss- and gain-of-function assays were performed in vitro and demonstrated that uc.51 promotes the proliferation, migration, and invasion of BC cells. Mechanistically, non-POU domain-containing octamer-binding protein (NONO) was found to physically interact with uc.51 by RNA pulldown followed by mass spectrometry. This interaction was further verified by RNA immunoprecipitation. Moreover, uc.51 positively regulated the expression of NONO, maintained its stability through the ubiquitin-proteasome system, and activated the phosphorylation of CREB. Rescue experiments demonstrated that NONO overexpression compensated for the attenuated influence on BC progression resulting from downregulation of uc.51, indicating that NONO functions downstream of uc.51. In vivo functional experiments also revealed a positive correlation between uc.51 expression and tumor size. Ki-67 and NONO levels in the lv-uc.51-shRNA group were decreased compared with those in the lv-con-shRNA group, according to the immunohistochemical staining results, and a decreased incidence of distant metastasis was observed in the lv-uc.51-shRNA group in the xenograft model. Collectively, our results reveal a substantial role for the uc.51-NONO axis in BC progression and indicate that the uc.51-NONO axis has potential to be a therapeutic target for BC.


Electrophoresis of a charge-regulated spheroid along the axis of an uncharged cylindrical pore.
Boundary effects can have a profound influence on the electrophoretic behavior of a charged entity, in particular, when the entity is nonspherical and its surface conditions are dependent upon the nearby environment. In this study, the electrophoresis of a spheroid along the axis of an uncharged cylindrical pore is analyzed for the case where the electrical potential is low and the applied electric field is weak. We consider the case where the surface of a particle contains dissociable acidic and basic functional groups, which simulate biological colloids and entities covered by an artificial membrane. This leads to a mixed-type boundary value problem, which extends the conventional constant-surface-potential and constant-surface-charge-density models to a more general case. The effects of the particle aspect ratio, the relative magnitudes of particle and pore, the thickness of the double layer surrounding a particle, and the pH of the liquid phase on the electrophoretic mobility of a particle are investigated. Several interesting results are observed; for example, if the volume of a particle is fixed, its mobility may have a local maximum as the relative magnitudes of its two axes vary.


Understanding and Optimizing Ocular Biometry for Cataract Surgery in Dry Eye Disease: A Review.
To understand the impact of dry eye disease (DED) on the components of ocular biometry and ways to optimize the visual outcomes of cataract surgery in eyes with DED. A thorough literature review of the components pertaining to this review was undertaken using the databases, PubMed (from the year 2000), MEDLINE, CENTRAL (including Cochrane Eyes and Vision Trials Register; Cochrane Library: Issue 12 of 12 December 2019), metaRegister of Controlled Trials (mRCT) (www.controlled-trials. com), ClinicalTrials.gov (www.clinicaltrial.gov) and WHO International Clinical Trials Registry Platform (www.who.int/ictrp/search/en). The keywords used for the search included "cataract surgery" or "phacoemulsification" combined with "dry eye", "dry eye disease","biometry", "keratometry". Publications considered for this review included meta-analysis, systematic reviews, case-control and cohort studies, case series, and laboratory-based studies. Published articles reporting tear film alteration in DED, its impact on the quality of vision and optical aberrations, the effect of topical medications on keratometry variations, and reports on optimizing the ocular surface before cataract surgery were included. DED is a common entity seen in patients presenting to routine cataract clinics and is known to impact the accuracy, reliability, and repeatability of ocular biometry and IOL power calculations in them. This review intends to emphasize the preoperative screening for the presence of DED, initiation of appropriate medical management for optimization of the ocular surface before cataract surgery, and recommendations for performing biometry. The algorithmic approach proposed will help the general ophthalmologists in routine practice to provide quality care and acceptable visual outcomes in patients with pre-existing DED.


Role of trap-induced scales in non-equilibrium dynamics of strongly interacting trapped bosons.
We use a time-dependent hopping expansion technique to study the non-equilibrium dynamics of strongly interacting bosons in an optical lattice in the presence of a harmonic trap characterized by a force constant K. We show that after a sudden quench of the hopping amplitude J across the superfluid (SF)-Mott insulator (MI) transition, the SF order parameter [Formula: see text] and the local density fluctuation [Formula: see text] exhibit sudden decoherence beyond a trap-induced time scale [Formula: see text]. We also show that after a slow linear ramp down of J, [Formula: see text] and the boson defect density [Formula: see text] display a novel non-monotonic spatial profile. Both these phenomena can be explained as consequences of trap-induced time and length scales affecting the dynamics and can be tested by concrete experiments.


Direct social perception and dual process theories of mindreading.
The direct social perception (DSP) thesis claims that we can directly perceive some mental states of other people. The direct perception of mental states has been formulated phenomenologically and psychologically, and typically restricted to the mental state types of intentions and emotions. I will compare DSP to another account of mindreading: dual process accounts that posit a fast, automatic "Type 1" form of mindreading and a slow, effortful "Type 2" form. I will here analyze whether dual process accounts' Type 1 mindreading serves as a rival to DSP or whether some Type 1 mindreading can be perceptual. I will focus on Apperly and Butterfill's dual process account of mindreading epistemic states such as perception, knowledge, and belief. This account posits a minimal form of Type 1 mindreading of belief-like states called registrations. I will argue that general dual process theories fit well with a modular view of perception that is considered a kind of Type 1 process. I will show that this modular view of perception challenges and has significant advantages over DSP's phenomenological and psychological theses. Finally, I will argue that if such a modular view of perception is accepted, there is significant reason for thinking Type 1 mindreading of belief-like states is perceptual in nature. This would mean extending the scope of DSP to at least one type of epistemic state.


Antioxidant biomarkers and food intake in elderly women.
To investigate the relationship between antioxidant biomarkers and food intake in elderly women. Cross-sectional study. Recreation Center for the Elderly in the city of Itajaí, Santa Catarina, Brazil. 73 elderly women with an average age of 71 years, 93% caucasian, average body weight 68.7 ± 13.1 kg and average BMI 28.5 ± 2.3 kg/m². Nutritional status was assessed based on the Body Mass Index (BMI). Data on food intake were obtained by applying the 24h diet recall method in three non-consecutive days, including Sunday. The assessment of antioxidant biomarkers was performed based on tests for total plasma thiols and phenolic compounds. The linear regression analysis was used to assess the effect of the consumption of food groups on antioxidant biomarkers. A positive association was found between thiols and intake of carotenoid-rich vegetables (p=0.03), oils, fats and oilseeds (p=0.03); a negative association was observed between total concentrations of phenolic compounds and intake of cereals (p=0.04). The intake of foods from the carotenoid-rich vegetables, oils, fats and oilseeds food groups increased the levels of plasma thiols, and the intake of foods from the group of cereals decreased the plasma concentration of phenols. Studies should be conducted to investigate the association between the intake of antioxidant-rich foods and the plasma antioxidant profile, as a way to protect against the aging process.


Regulation of CD44 expression by tumor necrosis factor-α and its potential role in breast cancer cell migration.
CD44 molecule plays critical role in distant malignant metastasis. It is expressed in standard form (CD44s) or variant form (CD44v). Tumor necrosis factor-α (TNF-α) is highly expressed in the cancer microenvironment. TNF-α was reported to modulate CD44 expression in several kinds of cancer. However, little is known about pathological role of TNF-α in breast cancer (BC) cells. In the current investigation, we investigated the effect of TNF-α on BC cells (MCF-7 and MDA-MB-231) viability, CD44 expression, and in vitro migration. We found that TNF-α down-regulated CD44s expression, up-regulated CD44v3 and CD44v6 expression through JNK pathway in MCF-7 cells. In MDA-MB-231 cells, TNF-α up-regulated CD44s, CD44v3 and CD44v6 expression via p38 pathway. These data indicate important role of CD44 molecule in BC pathology.


A method for incorporating three-dimensional residual stretches/stresses into patient-specific finite element simulations of arteries.
The existence of residual stresses in human arteries has long been shown experimentally. Researchers have also demonstrated that residual stresses have a significant effect on the distribution of physiological stresses within arterial tissues, and hence on their development, e.g., stress-modulated remodeling. Through progress in medical imaging, image analysis and finite element (FE) meshing tools it is now possible to construct in vivo patient-specific geometries and thus to study specific, clinically relevant problems in arterial mechanics via FE simulations. Classical continuum mechanics and FE methods assume that constitutive models and the corresponding simulations start from unloaded, stress-free reference configurations while the boundary-value problem of interest represents a loaded geometry and includes residual stresses. We present a pragmatic methodology to simultaneously account for both (i) the three-dimensional (3-D) residual stress distributions in the arterial tissue layers, and (ii) the equilibrium of the in vivo patient-specific geometry with the known boundary conditions. We base our methodology on analytically determined residual stress distributions (Holzapfel and Ogden, 2010, J. R. Soc. Interface 7, 787-799) and calibrate it using data on residual deformations (Holzapfel et al., 2007, Ann. Biomed. Eng. 35, 530-545). We demonstrate our methodology on three patient-specific FE simulations calibrated using experimental data. All data employed here are generated from human tissues - both the aorta and thrombus, and their respective layers - including the geometries determined from magnetic resonance images, and material properties and 3-D residual stretches determined from mechanical experiments. We study the effect of 3-D residual stresses on the distribution of physiological stresses in the aortic layers (intima, media, adventitia) and the layers of the intraluminal thrombus (luminal, medial, abluminal) by comparing three types of FE simulations: (i) conventional calculations; (ii) calculations accounting only for prestresses; (iii) calculations including both 3-D residual stresses and prestresses. Our results show that including residual stresses in patient-specific simulations of arterial tissues significantly impacts both the global (organ-level) deformations and the stress distributions within the arterial tissue (and its layers). Our method produces circumferential Cauchy stress distributions that are more uniform through the tissue thickness (i.e., smaller stress gradients in the local radial directions) compared to both the conventional and prestressing calculations. Such methods, combined with appropriate experimental data, aim at increasing the accuracy of classical FE analyses for patient-specific studies in computational biomechanics and may lead to increased clinical application of simulation tools.


Prediction of post-operative adding-on or compensatory lumbar curve correction after anterior vertebral body tethering.
Anterior Vertebral Body Tethering (AVBT), a fusionless surgical technique based on growth modulation, aims to correct pediatric scoliosis over time. However, medium-term curvature changes of the non-instrumented distal lumbar curve remains difficult to predict. The objective was to biomechanically analyze the level below the LIV to evaluate whether adding-on or compensatory lumbar curve after AVBT can be predicted by intervertebral disc (ID) wedging and force asymmetry. 33 retrospective scoliotic cases instrumented with AVBT were used to computationally simulate their surgery and 2-year post-operative growth modulation using a finite element model. The cohort was divided into two subgroups according to the lumbar curvature evolution over 2 years: (1) correction > 10° (C); (2) maintaining ± 10° (M). The lumbar Cobb angle and residual ID wedging angle under LIV were measured. Simulated pressures and moments at the superior endplate of LIV + 1 were post-processed. These parameters were correlated at 2 years postoperatively. On average, the LIV + 1 simulated moment was 538 Nmm for subgroup C, 155 Nmm for subgroup M with lumbar Cobb angle > 20° and 34 Nmm for angle < 20° whereas the ID angle was 1° for C and 0° for M. On average, a positive moment on the LIV + 1 superior growth plate led to correction of the lumbar curvature, whereas a null moment kept it stable, and a parallel immediate postoperative ID under LIV contributed to its correction or preservation. Nevertheless, the significant interindividual variability suggested that other parameters are involved in the distal non-instrumented curvature evolution. IV.


Effects of paleogeographic changes and CO2 variability on northern mid-latitudinal temperature gradients in the Cretaceous.
The Cretaceous 'greenhouse' period (~145 to ~66 million years ago, Ma) in Earth's history is relatively well documented by multiple paleoproxy records, which indicate that the meridional sea surface temperature (SST) gradient increased (non-monotonically) from the Valanginian (~135 Ma) to the Maastrichtian (~68 Ma). Changes in atmospheric CO2 concentration, solar constant, and paleogeography are the primary drivers of variations in the spatiotemporal distribution of SST. However, the particular contribution of each of these drivers (and their underlying mechanisms) to changes in the SST distribution remains poorly understood. Here we use data from a suite of paleoclimate simulations to compare the relative effects of atmospheric CO2 variability and paleogeographic changes on mid-latitudinal SST gradient through the Cretaceous. Further, we use a fundamental model of wind-driven ocean gyres to quantify how changes in the Northern Hemisphere paleogeography weaken the circulation in subtropical ocean gyres, leading to an increase in extratropical SSTs.


Distortion of mental body representations.
Our body is central to our sense of self, and distorted body representations are found in several serious medical conditions. This paper reviews evidence that distortions of body representations are also common in healthy individuals, and occur in domains including tactile spatial perception, proprioception, and the conscious body image. Across domains, there is a general tendency for body width to be overestimated compared to body length. Intriguingly, distortions in both eating disorders and chronic pain appear to be exaggerations of this baseline pattern of distortions, suggesting that these conditions may relate to dysfunction of mechanisms for body perception. Distortions of body representations provide a revealing window into basic aspects of self-perception.


Psychometric Properties of the Patient Health Questionnaire-9 in Patients With Heart Failure and Gastrointestinal Symptoms.
Patients who have coexisting medical conditions tend to be more depressed. The purpose of this study was to examine the reliability, validity, and dimensionality of the Patient Health Questionnaire-9 (PHQ-9) in patients with heart failure and gastrointestinal (GI) symptoms. The cross-sectional data for this secondary analysis were collected in four studies. Cronbach's alpha was used to examine reliability. Concurrent validity with the Beck Depression Inventory-II (BDI-II) was examined. Cronbach's alpha for the PHQ-9 was .87. Concurrent validity with BDI-II was excellent (r = .78, p < .01). The evidence from this study supports the reliability and validity of the PHQ-9 as a measure of depression in patients with heart failure and GI symptoms.


Removal of chromium (VI) from aqueous solution using walnut hull.
In this study, removal of chromium (VI) from aqueous solution by walnut hull (a local low-cost adsorbent) was studied. The extent of adsorption was investigated as a function of solution pH, contact time, adsorbent and adsorbate concentration, reaction temperature and supporting electrolyte (sodium chloride). The Cr (VI) removal was pH-dependent, reaching a maximum (97.3%) at pH 1.0. The kinetic experimental data were fitted to the first-order, modified Freundlich, intraparticle diffusion and Elovich models and the corresponding parameters were obtained. A 102.78 kJ/mol Ea (activation energy) for the reaction of chromium (VI) adsorption onto walnut indicated that the rate-limiting step in this case might be a chemically controlled process. Both the Langmuir and Freundlich isotherms were suitable for describing the biosorption of chromium (VI) onto walnut hull. The uptake of chromium (VI) per weight of adsorbent increased with increasing initial chromium (VI) concentration up to 240-480 mg/L, and decreased sharply with increasing adsorbent concentration ranging from 1.0 to 5.0 g/L. An increase in sodium chloride (as supporting electrolyte) concentration was found to induce a negative effect while an increase in temperature was found to give rise to a positive effect on the chromium (VI) adsorption process. Compared to the various other adsorbents reported in the literature, the walnut hull in this study shows very good promise for practical applicability.


Peptide microarrays on coated silicon slides for highly sensitive antibody detection.
Peptides, with their well-established chemistry and fully automated synthesis, provide an invaluable tool for the screening of protein ligands, for epitope mapping, and for antibody diagnostics on the microarray format.The method described in this chapter shows that the sensitivity of a peptide-based microimmunoassay is greatly improved by using a new, specifically developed substrate made of silicon coated by an optimized layer of silicon oxide. A set of six peptides corresponding to the sequences of human and rat acetylcholine receptor subunits was immobilized on glass and silicon slides coated by a copolymer of N,N-dimethylacrylamide, N-acryloyloxysuccinimide, and 3-(trimethoxysilyl) propyl methacrylate, copoly(DMA-NAS-MAPS). The spotted probes were incubated with rabbit anti-sera and with purified antibodies raised against the corresponding peptides. The coated silicon slides, in comparison against the glass substrates, showed a five- to tenfold enhancement of the fluorescence signals, leading to the specific detection of the full set of antibodies down to a concentration of 0.5-1 ng/mL in serum. The sensitivity provided by the test allows its use for the diagnosis of antibodies in clinical samples.


Comparison of the mucoadhesive properties of various polymers.
In this study the mucoadhesive potential of nineteen different, most often referred mucoadhesive polymers was evaluated and characterized by adhesion time and total work of adhesion (TWA) of the polymer to porcine small intestinal mucosa. In addition, the influence of pH of the polymer and of method of drying on adhesion was evaluated. Aqueous polymer solutions were therefore adjusted to pH 3.0 and 7.0. Solutions were either dried by lyophilization (lyo.) or precipitated (pr.) in organic solvent and air-dried. Results of this study led to the following rank order of adhesion time: chitosan-4-thiobuthylamidine pH 3 lyo. >chitosan-4-thiobuthylamidine pH 6.5 pr.>polycarbophil-cysteine pH 3 lyo.>chitosan-4-thiobuthylamidine pH 6.5 lyo.>PAA450-cysteine pH 3 lyo.>pH 7 pr.>Carbopol 980 pH 7 pr.>Carbopol 974P pH 7 pr.>polycarbophil pH 7 pr.>980 pH 3 lyo. The rank order obtained for adhesion time was in agreement with the rank order obtained for total work of adhesion. The highest mucoadhesion was shown by thiolated polymers at pH 3.0, dried by lyophilization. In contrary, polyacrylates were most mucoadhesive in form of precipitated neutral sodium salts. Other tested polymers like natural polysaccharides, cellulose derivatives, polyvinylpirrolidone and polyethylenglycole, although previously reported as good mucoadhesives, showed low to almost no mucoadhesion. The pH of polymer and drying method were found to be important factors influencing the mucoadhesive potential of polymers.


Which patients become seizure free with antiepileptic drugs? An observational study in 821 patients with epilepsy.
Analysis of factors influencing seizure outcome in antiepileptic drug treatment of epilepsy. Retrospective analysis of 500 patients with complete seizure control and 321 patients with refractory epilepsy (mean ages 33.3 and 32.1 years respectively). The seizure-free group consisted of 377 patients with symptomatic/cryptogenic epilepsy (SCE; mean seizure control 45 months) and 123 patients with idiopathic generalized epilepsy (IGE; mean seizure control 61 months) (P = 0.02). Of the patients with SCE, 35.7% had achieved seizure control with monotherapy (MT), 29.6% with >or=2 AEDs. No single AED was superior in MT. Of the patients with IGE, 35.9% had become seizure free with MT, 15.6% on combination therapy (CT). Valproate MT was more commonly associated with seizure freedom than lamotrigine (P < 0.05). The results indicate that, in SCE, seizures can be controlled with carefully selected CT more commonly than suggested by previous studies. The seizure prognosis of patients with IGE presenting to a specialist in epilepsy may be worse than previously thought.


Protein, Creatine, and Dieting Supplements Among Adolescents: Use and Associations With Eating Disorder Risk Factors, Exercise-, and Sports Participation, and Immigrant Status.
Objective: This study aimed to estimate the number of weekly users of protein, creatine, and dieting supplements and to explore whether weekly use was related to eating disorder (ED) risk factors, exercise, sports participation, and immigrant status. Methods: In total, 629 and 1,060 high school boys and girls, respectively, self-reported weekly frequency of protein, creatine, and dieting supplement use, and weight and shape concerns, appearance internalization and pressure, self-esteem, mental distress, physical activity level, exercise context, and the type and weekly frequency of sport played. Multiple hierarchical regression analyses were performed to investigate explanatory factors for supplement use. Results: More boys than girls used protein and creatine supplements. Immigrant boys had more frequent use of all supplements than non-immigrant boys, and immigrant girls used creatine supplements more frequently than non-immigrant girls. In total, 23-40 and 5-6% of the variation in the weekly frequency of supplement use in boys and girls, respectively, was explained by immigrant status, ED risk factors, and exercise and sports participation. More frequent use of protein, creatine and dieting supplements in boys was significantly explained by more weight and shape concerns, fitness center exercise, and weight-sensitive sports participation. Depending on the type of supplement, more frequent use of supplements in girls was significantly explained by lower self-esteem, more engagement in weight-sensitive sports, and less engagement in general sport and exercise activities. Conclusion: Weekly supplement use was common and more frequent among boys than girls. The weekly use of protein, creatine, and dieting supplements was related to ED risk factors, exercise and sports participation, and immigrant status in boys but not in girls.


Continuous infusion of 5-azacytidine as induction for acute nonlymphocytic leukemia in patients with previous exposure to 5-azacytidine.
5 children with acute nonlymphocytic leukemia in relapse who had received 5-azacytidine as a part of previous multiagent chemotherapy received continuous infusion of 5-azacytidine, 150-200 mg/m2/day, for 5-7 days every 2 weeks. 2 achieved remission marrows with good peripheral counts (duration 1 and 3 months). 1 achieved a transient remission marrow but remained pancytopenic and 1 achieved reduction from 91% blasts to 18% blasts in the marrow. Principal toxicities were severe myelosuppression, diarrhea, and phlebitis.


Selective extraction and determination of Cr(VI) in food samples based on tandem electromembrane extraction followed by electrothermal atomic absorption spectrometry.
In this study, electromembrane extraction (EME) combined with micro-EME (µ-EME) was used for the selective extraction of Cr(VI) from food samples (milk powder, Ocimum basilicum, and fish samples). Electrothermal atomic absorption spectrometry was used for the quantification of Cr(VI). Under the optimized extraction conditions, the extraction recovery of Cr(VI) was 73.7%. This proposed method provided a linear range from 0.01 to 5.0 ng/mL and the limit of detection (LOD) and limit of quantification (LOQ) were 0.003 and 0.010 ng/mL. The %RSD (n = 5) was in the range of 11.2-11.8% at 0.05, 1.0 and 2.5 ng/mL of Cr(VI), and the enrichment factor was 584. The accuracy of the method was evaluated by analysis of SRM 2700 as a certified reference material (CRM) and result was in good agreement with the certified value.


MRI-apparent localized deformation of the median nerve within the carpal tunnel during functional hand loading.
In MR images, the median nerve of carpal tunnel syndrome (CTS) patients frequently appears flatter than in healthy subjects. The purpose of this work was to develop a metric to quantify localized median nerve deformation rather than global nerve flattening, the hypothesis being that localized median nerve deformation would be elevated in CTS patients. Twelve patients with CTS and 12 matched normals underwent MRI scanning in eight isometrically loaded hand conditions. 2D cross sections of the proximal and distal tunnel were analyzed for nerve cross sectional area, flattening ratio, and a position shift to the dorsal side of the tunnel. Additionally, new metrics based on the angulation of the nerve perimeter in 0.5-mm lengths around the boundary were calculated. The localized deformation metrics were able to detect differences between CTS patients and healthy subjects that could not be appreciated from the flattening ratio. During most hand activities, normal subjects had a higher average percentage of locally deformed nerve boundary than did CTS patients, despite having a rounder overall shape. Less local nerve deformation in the CTS patient group resulting from its interaction with flexor tendons suggests that the nerve may be less compliant in CTS patients.


MUC1 and CD147 Are Promising Markers for the Detection of Circulating Tumor Cells in Small Cell Lung Cancer.
Lung cancer is the most prevalent type of cancer globally and small cell lung cancer (SCLC) accounts for only 15% of all cases but exhibits a dismal prognosis. The standard of care of SCLC has not changed for decades and novel biomarkers and novel strategies for patient's care are urgently needed. The expression of the two potential markers MUC1 and CD147 was evaluated in circulating tumor cells (CTCs) and CTC-derived SCLC cell lines using qRT PCR, western blotting, immunohistochemistry, and ELISA assays. Both CTCs enriched from patient blood samples by Parsortix isolation technology and SCLC/CTC cell lines exhibited significant expression of MUC1 and CD147. Silencing of MUC1 increased chemosensitivity of an SCLC line to topotecan. Both markers, MUC1 and CD147, are highly expressed in patient-derived SCLC and SCLC CTC cell lines and show promise as potential biomarkers in SCLC.


A decrease in IL-33 regulates matrix degradation and apoptosis in intervertebral disc degeneration via HIF-1alpha.
Low back pain (LBP) is a common aging-associated disease that can cause disability in old people. Previous research revealed that an imbalance in the extracellular matrix (ECM) via abnormal hypoxia-inducible factor-1alpha (HIF-1α) expression in nucleus pulposus (NP) cells was one of the key factors in the pathogenesis of intervertebral disc degeneration (IDD). However, the mechanism by which the ECM is reduced in patients with IDD is not fully understood. Here, we reported that a new member of the interleukin (IL)-1 family, IL-33, was positively correlated with HIF-1α and was decreased in the NP cells of individuals with IDD. IL-33 overexpression in degenerative NP cells decreased the levels of matrix metalloproteinase-3/13 (MMP-3/13), a disintegrin and metallo-proteinase with thrombospondin motifs-4/5 (ADAMTS-4/5), and promoted ECM expression in vitro. Furthermore, we preliminarily explored the antiapoptotic effects of IL-33, which could reduce the expression of Caspase-3 and promote the level of Bcl-2 in degenerative NP cells. Furthermore, when HIF-1α expression was silenced, IL-33-mediated upregulation of ECM expression was weakened. Thus, IL-33-induced HIF-1α upregulation may represent a novel therapeutic strategy to ameliorate IDD in patients with LBP.


Comparison of efficiency of commercially available phototherapy units.
The efficiency of two phototherapy units was compared by exposing solutions of bilirubin in vitro. Both units are commercially available.


An investigation into academic career pathways across Radiography education centres internationally.
Robust academic pathways are critical to support of radiography faculty within third level education. As the profession of Radiography grows its' research activity, it is important that academic opportunities meet the needs of the profession. The purpose of this research was to investigate current academic career pathways across radiography education centres internationally. An online survey was developed and administered to radiography academics and clinical/academic staff members internationally. The survey questions (n = 28) include demographic data; teaching and research requirements; academic promotion criteria; identification of the challenges and benefits of being an academic, including equality, diversity and inclusion (EDI) matters. A total of 175 responses were obtained (6 continents and 39 countries), with a variety of experience levels amongst academics that primarily held permanent work contracts. Regarding the highest qualifications held, 31.4% (n = 55) had a Doctorate and 45.7% (n = 80) a Master's degree, and most respondents were employed as academic lecturers (40.6%; n = 71), with 17.7% (n = 31) employed at professorial level. The minimum time requirement to achieve a permanent contract was variable, ranging from no delay (5.7%; n = 10) to more than 10 years (12.6%; n = 22). Doctorate qualification is currently not necessary in order to career progression for 126 (72%) respondents, while 52% (n = 91) provided specific research requirements. 106 (60.6%) respondents indicated that their institution has EDI policy. This study has captured details related to academic pathways across international radiography education centres. Whilst some heterogeneity exists, there are numerous differences impacting standardised academic career opportunities for Radiography academics. These may challenge academic career opportunities and discourage those interested in an academic career. The profile and educational background of these academics has been highlighted as well as the perceived barriers and advantages of a career in academic.


CXCR3 enables recruitment and site-specific bystander activation of memory CD8+ T cells.
Bystander activation of memory T cells occurs in the absence of cognate antigen during infections that elicit strong systemic inflammatory responses, which subsequently affect host immune responses. Here we report that memory T cell bystander activation is not limited to induction by systemic inflammation. We initially observe potential T cell bystander activation in a cohort of human vaccine recipients. Using a mouse model system, we then find that memory CD8+ T cells are specifically recruited to sites with activated antigen-presenting cells (APCs) in a CXCR3-dependent manner. In addition, CXCR3 is also necessary for T cell clustering around APCs and T cell bystander activation, which temporospatially overlaps with the subsequent antigen-specific T cell response. Our data thus suggest that bystander activation is part of the initial localized immune response, and is mediated by a site-specific recruitment process of memory T cells.


Feeding ecology and seasonal movements of giant tortoises on Aldabra atoll.
We investigated seasonal changes in diet and distribution of giant tortoises (Geochelone gigantea (Schweigger)) on Aldabra atoll in the Indian Ocean. Animals were counted and their activity and feeding behaviour recorded on transects where vegetation composition and primary production had been studied (Gibson and Phillipson in press a, b).There were striking seasonal shifts in tortoise distribution, and male, female, and juvenile tortoises were found in different proportions in different vegetation types.Tortoises are selective grazers, feeding on a wide range of foodstuffs of which the most important (61% of feeding observations) was tortoise turf. Diet varied seasonally, with shrub leaves (mostly litter) overtaking tortoise turf in importance in the late dry season; diet broadened as the dry season progressed. Male and female diets were not significantly different but juveniles fed on herbs and mosaic rock vegetation more often than adults.Seasonal shifts in distribution are due to movements in response to changes in food availability, measured by the foods' cover abundances and production phenologies. Tortoises concentrate on preferred foods when available, but become less selective as production falls. Some differences in size and sex class distribution between habitats can also be explained by food availability.In the late dry season density peaks on the coastal Sporobolus virginicus (L.) Kunth sward. A detailed study showed that, while at least 20% of the population uses the sward each year, visit times are short and turnover of tortoises high, as would be expected on a non-preferred food.The giant tortoise interacts with its food supply similarly to other large herbivores, except that the low maintenance needs of this large poikilotherm allow it to develop unusually high population densities.


[Effect of mixed edaphic bacterial inoculants in the early development of improved cocoa cultivars (Theobroma cacao L.) in a traditional agroforestry system of Oaxaca, Mexico].
Cocoa plant (Theobroma cacao L.) is native from South America and it represents one of the most significant "bio-cultural" resources of Mesoamerica, since it is a region where it was domesticated and had a relevance as ritual drink and as currency in many pre-hispanic cultures until the arrival of the Spaniards who spread its use worldwide, and became it one of the most consumed commodity goods. Through this research, an alternative is proposed to address the problem of cultivars through the introduction of a wide variety of cocoa plants in traditional agroforestry systems, in synergy with the inoculation of nitrogen-fixing and insoluble phosphor solubilizing edaphic bacterial consortia. Four cultivars of improved grafted cocoa plants were introduced in a traditional agroforestry plot and three fertilization treatments were applied: application of biofertilizer, application of chemical fertilizer and control. Measurements of height, stem diameter, number of leaves and branches were recorded at 2 and 12 months after planting and rhizosphere microbial populations were characterized. Growth results showed good potential for all studied cultivars and it was observed that biofertilization foresees significant effects in some of the growth indicators of cocoa plant. Thereby, plant associations in an agroforestry system could be favorable to promote fruit development and resistance to pests and diseases.


Immunocytochemical identification of electroneutral Na⁺-coupled HCO₃⁻ transporters in freshly dissociated mouse medullary raphé neurons.
The medullary raphé (MR) of the medulla oblongata contains chemosensitive neurons that respond to increases in arterial [CO₂], by altering firing rate, with increases being associated with serotonergic (5-hydroxytryptamine [5HT]) neurons and decreases, with GABAergic neurons. Both types of neurons contribute to increased alveolar ventilation. Decreases in intracellular pH are thought to link the rise in [CO₂] to increased ventilation. Because electroneutral Na(+)-coupled HCO₃(-) transporters (nNCBTs), which help protect cells from intracellular acidosis, are expressed robustly in the neurons of the central nervous system, a key question is whether these transporters are present in chemosensitive neurons. Therefore, we used an immunocytochemistry approach to identify neurons (using a microtubule associated protein-2 monoclonal antibody) and specifically 5HT neurons (TPH monoclonal antibody) or GABAergic neurons (GAD2 monoclonal antibody) in freshly dissociated cells from the mouse MR. We also co-labeled with polyclonal antibodies against the three nNCBTs: NBCn1, NDCBE, and NBCn2. We exploited ePet-EYFP (enhanced yellow fluorescent protein) mice (with EYFP-labeled 5HT neurons) as well as mice genetically deficient in each of the three nNCBTs. Quantitative image analysis distinguished positively stained cells from background signals. We found that >80% of GAD2(+) cells also were positive for NDCBE, and >90% of the TPH(+) and GAD2(+) cells were positive for the other nNCBTs. Assuming that the transporters are independently distributed among neurons, we can conclude that virtually all chemosensitive MR neurons contain at least one nNCBT.


Peptide Vaccination Against PD-L1 With IO103 a Novel Immune Modulatory Vaccine in Multiple Myeloma: A Phase I First-in-Human Trial.
Immune checkpoint blockade with monoclonal antibodies targeting programmed death 1 (PD-1) and its ligand PD-L1 has played a major role in the rise of cancer immune therapy. We have identified naturally occurring self-reactive T cells specific to PD-L1 in both healthy donors and cancer patients. Stimulation with a PD-L1 peptide (IO103), activates these cells to exhibit inflammatory and anti-regulatory functions that include cytotoxicity against PD-L1-expressing target cells. This prompted the initiation of the present first-in-human study of vaccination with IO103, registered at clinicaltrials.org (NCT03042793). Ten patients with multiple myeloma who were up to 6 months after high dose chemotherapy with autologous stem cell support, were enrolled. Subcutaneous vaccinations with IO103 with the adjuvant Montanide ISA 51 was given up to fifteen times during 1 year. Safety was assessed by the common toxicity criteria for adverse events (CTCAE). Immunogenicity of the vaccine was evaluated using IFNγ enzyme linked immunospot and intracellular cytokine staining on blood and skin infiltrating lymphocytes from sites of delayed-type hypersensitivity. The clinical course was described. All adverse reactions to the PD-L1 vaccine were below CTCAE grade 3, and most were grade 1-2 injection site reactions. The total rate of adverse events was as expected for the population. All patients exhibited peptide specific immune responses in peripheral blood mononuclear cells and in skin-infiltrating lymphocytes after a delayed-type hypersensitivity test. The clinical course was as expected for the population. Three of 10 patients had improvements of responses which coincided with the vaccinations. Vaccination against PD-L1 was associated with low toxicity and high immunogenicity. This study has prompted the initiation of later phase trials to assess the vaccines efficacy. clinicaltrials.org, identifier NCT03042793.


Does pregnancy or pregnancy loss increase later maternal risk of diabetes?
Evidence that childbearing is associated with future development of diabetes remains conflicting and the role of pregnancy loss in this association has not been investigated. We aimed to examine whether pregnancy and/or pregnancy loss (miscarriage, abortion, or stillbirth) are associated with maternal higher risk of diabetes later in life, using a population-based prospective cohort study (mean follow-up = 10.7 years), including 13,612 women (aged 35-65 at baseline). We found pregnancy per se did not change the risk of diabetes after considering the effect of education, smoking, alcohol consumption, physical activity, BMI, waist/hip ratio, hypertension, and hyperlipidemia (fully-adjusted OR: 1.04, 95 % CI: 0.82-1.31). Having more than four live births was associated with around two times higher risk of diabetes later in life (fully-adjusted OR: 1.77, 95 % CI: 1.12-2.80). Having more than two miscarriages was associated with about two-fold higher risk of diabetes (fully-adjusted Odd ratio (OR): 1.85, 95 % CI: 1.17-2.93). After further adjustment for parity, the higher risk of diabetes in those who had history of more than two miscarriages did not change substantially (OR: 1.82; 95 % CI: 1.15-2.88), but the association between more than four live births and diabetes disappeared when the role of pregnancy loss was considered (fully-adjusted HR: 1.06; 95 % CI: 0.54-2.08). No significant association was found between abortion, stillbirth and risk of maternal diabetes. Pregnancy per se did not increase risk of diabetes. Women who experience more than two miscarriages are at around two times higher risk of diabetes later in life. The association between high parity and diabetes is mediated by history of miscarriages and known risk factors of diabetes. The underlying reason for association between miscarriage and diabetes needs further investigation.


The Only Constant Is Change: Next Generation Materials and Medical Device Design for Physical and Mental Health.
Cell health and cell network patency dictate human physical and mental health throughout life. Cutting edge multiscale imaging and mapping of cell to organ structure and function is unravelling the remarkable plasticity of cellular networks, from bone to brain. Insights from these studies will enable the development of next generation implants to replace, repair and reprogram cellular networks, for promotion of mental and physical health.


Whole genome amplification--applications and advances.
The concept of whole genome amplification is something that has arisen in the past few years as the polymerase chain reaction (PCR) has been adapted to replicate regions of genomes that are of biological interest. The applications are many--forensic science, embryonic disease diagnosis, bioterrorism genome detection, "immortalization" of clinical samples, microbial diversity, and genotyping. Several recent papers suggest that whole genomes can be replicated without bias or non-random distribution of the target, these findings open up a new avenue to molecular biology.


Improved method for the analysis of estrogenic steroids in pregnancy urine by high-performance liquid chromatography.
The use of microparticulate packing materials and large injection volumes gives significant improvements in the analysis of complex samples, such as urine extracts by high-performance liquid chromatography. Lower detection limits and improved accuracy can now be attained. In addition, the combined use of adsorption and reversed-phase chromatography leads to reduced uncertainty in peak identification and gives more reliable quantification.


Development of knowledge about osteoporosis in the world of orthopedics and traumatology.
The development of Orthopedics and Traumatology in the last 50 years have been characterized by the concurrence of several milestone events, such as the disappearance of polio and osteoarticular tuberculosis, the progress of some disciplines such as Anesthesia and Intensive Care, Diagnostic Imaging and technology development. As for other common diseases, also for osteoporosis the evolution of knowledge about pathophysiology and treatment represents a "must" to know for the orthopaedic surgeons.


ROBO2-mediated RALDH2 signaling is required for common nephric duct fusion with primitive bladder.
Congenital anomalies of the urinary tract are a significant cause of morbidity in infancy, and many congenital anomalies are linked to ureter development; however, the mechanism by which congenital anomalies control ureter development remains unknown. The loss of Robo2 can cause ureter defects and vesicoureteral reflux. However, how Robo2 impacts ureter development is unclear. We found that ROBO2 is expressed in the common nephric duct (CND) and primitive bladder, and impacts CND migration and fusion with the primitive bladder via its novel binding partner retinaldehyde dehydrogenase-2 (RALDH2). Delayed apoptosis that is due to the failure of CND fusion with the primitive bladder in the Robo2-/-embryo results in an abnormal ureter connection to the CND, which is required for ureter development. We define a novel pathway in which the CND is remodeled by ROBO2 and retinoic acid rescued the ureter anomalies in the Robo2-/-embryo. These findings may be relevant to diverse disease conditions that are associated with altered signaling in the primitive bladder.


Effects of acute resistance exercise on exhaled nitric oxide levels in non-asthmatic male.
Fractional nitric oxide (FeNO) is an index of eosinophilic airway inflammation. However, the effect of acute resistance exercise on FeNO is not completely known, in non-asthmatics. In this study, we aimed to assess the effects of acute resistance exercise on FeNO levels in non-asthmatics. Ten participants completed both exercise and control sessions. The resistance exercise routine consisted of three sets of 10 repetitions, each at 75 % of the one-repetition maximum, including vertical chest press, lateral pull-down, leg press, leg extension, and abdominal exercises. Additionally, FeNO levels and respiratory impedance were measured, and blood samples were collected from each participant at baseline, immediately after exercise (post), and 30 min after exercise (post 30). At baseline, post, and post 30, the FeNO levels did not significantly differ between the exercise and control sessions (17.1 ± 4.7 vs. 18.5 ± 3.8 vs. 16.9 ± 3.8 ppb, respectively) and exercise sessions (16.6 ± 3.4 vs. 19.3 ± 7.6 vs. 18.3 ± 5.6 ppb, respectively). Therefore, acute resistance exercise lasting approximately 30 min did not exert an impact on FeNO levels.


One-step fabrication of inorganic/organic hybrid microspheres with tunable surface texture for controlled drug release application.
In this paper, we report one-step fabrication of poly(lactide-co-glycolic acid)/titanium oxide (PLGA/TiO2) hybrid microspheres with tunable surface texture via droplet-based microfluidics. Surface texture of microspheres can be continuously tuned by changing the mass ratio between titanium tetraisopropoxide (TTIP) and PLGA in the dispersed phase. The fast hydrolysis of TTIP on the droplet surface can generate a thin shell membrane, resulting in a wrinkled surface after extraction of organic solvent. In vitro drug release monitoring of tanshinone IIA-loaded PLGA/TiO2 hybrid microsphere reveals that surface texture can affect the drug release rate to a large extent without sacrificing the drug encapsulation efficiency. Our finding might benefit the sustained drug delivery where variable drug release rate and high drug encapsulation efficiency are both required.


Measurement of sucrose in beverages using a blood glucose meter with cascade-catalysis enzyme particle.
In this paper, we developed a sensor for on-site measuring beverage sucrose level based on cascade enzyme particles and a blood glucose meter. The cascade enzyme particles with sucrose hydrolyzing capability were prepared by co-precipitation of manganese carbonate, in which the stability of the enzymes was substantially enhanced by the particle encapsulation effect. The quantitative measurement of glucose produced by the hydrolysis of sucrose was performed using a commercial glucose meter, a commonly owned electrochemical device in homes, greatly improving detection accuracy and expanding applications. Actual sample testing demonstrated the high sensitivity and selectivity of the sensor, allowing for accurate detection of sucrose in beverages. This sensing strategy can also be further expanded to a variety of analytical assays, using blood glucose meters for portable quantitative testing.