A strain of Saccharomyces cerevisiae evolved for fermentation of lignocellulosic biomass displays improved growth and fermentative ability in high solids concentrations and in the presence of inhibitory compounds.
Softwoods are the dominant source of lignocellulosic biomass in the northern hemisphere, and have been investigated worldwide as a renewable substrate for cellulosic ethanol production. One challenge to using softwoods, which is particularly acute with pine, is that the pretreatment process produces inhibitory compounds detrimental to the growth and metabolic activity of fermenting organisms. To overcome the challenge of bioconversion in the presence of inhibitory compounds, especially at high solids loading, a strain of Saccharomyces cerevisiae was subjected to evolutionary engineering and adaptation for fermentation of pretreated pine wood (Pinus taeda). An industrial strain of Saccharomyces, XR122N, was evolved using pretreated pine; the resulting daughter strain, AJP50, produced ethanol much more rapidly than its parent in fermentations of pretreated pine. Adaptation, by preculturing of the industrial yeast XR122N and the evolved strains in 7% dry weight per volume (w/v) pretreated pine solids prior to inoculation into higher solids concentrations, improved fermentation performance of all strains compared with direct inoculation into high solids. Growth comparisons between XR122N and AJP50 in model hydrolysate media containing inhibitory compounds found in pretreated biomass showed that AJP50 exited lag phase faster under all conditions tested. This was due, in part, to the ability of AJP50 to rapidly convert furfural and hydroxymethylfurfural to their less toxic alcohol derivatives, and to recover from reactive oxygen species damage more quickly than XR122N. Under industrially relevant conditions of 17.5% w/v pretreated pine solids loading, additional evolutionary engineering was required to decrease the pronounced lag phase. Using a combination of adaptation by inoculation first into a solids loading of 7% w/v for 24 hours, followed by a 10% v/v inoculum (approximately equivalent to 1 g/L dry cell weight) into 17.5% w/v solids, the final strain (AJP50) produced ethanol at more than 80% of the maximum theoretical yield after 72 hours of fermentation, and reached more than 90% of the maximum theoretical yield after 120 hours of fermentation. Our results show that fermentation of pretreated pine containing liquid and solids, including any inhibitory compounds generated during pretreatment, is possible at higher solids loadings than those previously reported in the literature. Using our evolved strain, efficient fermentation with reduced inoculum sizes and shortened process times was possible, thereby improving the overall economic viability of a woody biomass-to-ethanol conversion process.


Insights into the role of Val45 and Gln182 of Escherichia coli MutY in DNA substrate binding and specificity.
Escherichia coli MutY (EcMutY) reduces mutagenesis by removing adenines paired with guanines or 7,8-dihydro-8-oxo-guanines (8-oxoG). V45 and Q182 of EcMutY are considered to be the key determinants of adenine specificity. Both residues are spatially close to each other in the active site and are conserved in MutY family proteins but not in Methanobacterium thermoautotrophicum Mig.MthI T/G mismatch DNA glycosylase (A50 and L187 at the corresponding respective positions). Targeted mutagenesis study was performed to determine the substrate specificities of V45A, Q182L, and V45A/Q182L double mutant of EcMutY. All three mutants had significantly lower binding and glycosylase activities for A/G and A/8-oxoG mismatches than the wild-type enzyme. The double mutant exhibited an additive reduction in binding to both the A/G and A/GO in comparison to the single mutants. These mutants were also tested for binding and glycosylase activities with T/G- or T/8-oxoG-containing DNA. Both V45A and Q182L mutants had substantially increased affinities towards T/G, however, they did not exhibit any T/G or T/8-oxoG glycosylase activity. Surprisingly, the V45A/Q182L double mutant had similar binding affinities to T/G as the wild-type EcMutY. V45A, Q182L, and V45A/Q182L EcMutY mutants could not reduce the G:C to T:A mutation frequency of a mutY mutant. Expression of the V45A mutant protein caused a dominant negative phenotype with an increased G:C to A:T mutation frequency. The substrate specificities are altered in V45A, Q182L, and V45A/Q182L EcMutY mutants. V45A and Q182L mutants had reduced binding and glycosylase activities for A/G and A/8-oxoG mismatches and increased affinities towards T/G mismatch. However, in contrast to a previous report that Mig.MthI thymine DNA glycosylase can be converted to a MutY-like adenine glycosylase by replacing two residues (A50V and L187Q), both V45A and Q182L EcMutY mutants did not exhibit any T/G or T/8-oxoG glycosylase activity. The dominant negative phenotype of V45A EcMutY mutant protein is probably caused by its increased binding affinity to T/G mismatch and thus inhibiting other repair pathways.


Resource security impacts men's female breast size preferences.
It has been suggested human female breast size may act as signal of fat reserves, which in turn indicates access to resources. Based on this perspective, two studies were conducted to test the hypothesis that men experiencing relative resource insecurity should perceive larger breast size as more physically attractive than men experiencing resource security. In Study 1, 266 men from three sites in Malaysia varying in relative socioeconomic status (high to low) rated a series of animated figures varying in breast size for physical attractiveness. Results showed that men from the low socioeconomic context rated larger breasts as more attractive than did men from the medium socioeconomic context, who in turn perceived larger breasts as attractive than men from a high socioeconomic context. Study 2 compared the breast size judgements of 66 hungry versus 58 satiated men within the same environmental context in Britain. Results showed that hungry men rated larger breasts as significantly more attractive than satiated men. Taken together, these studies provide evidence that resource security impacts upon men's attractiveness ratings based on women's breast size.


Determinants for refusal of HIV testing among women attending for antenatal care in Gambella Region, Ethiopia.
In Gambella region, inhabitants owe socio-cultural factors that might favor refusal for HIV testing service utilization among Antenatal Care attendees. To assess determinants for refusal of HIV testing service utilization among ANC attendees in Gambella Region. A comparative cross sectional study was conducted among ANC attendees from March 2008 to May 2008 in four selected health facilities of Gambella region. Sample size of 332 participants (83 who refused HIV testing and 249 who accepted HIV testing) were taken for the study. The study was supplemented with four focus group discussions. Multivariate binary logistic regression was employed to control for confounding factors. When adjusted with other factors pregnant women with 2-3 live births in the past; who claimed divorce as a perceived response of their husband following HIV positive test result; who had not sought agreement from their husband for testing; disclosure of test for husband and being from certain ethnic group (E.g. Mejenger) were independent predictors for refusal of HIV testing among ANC attendees. Based on the findings, the following recommendations were forwarded: Provision of innovative information and education on the pre-test session for those pregnant women having two or more children; community involvement to tackle stigma; women empowerment; designing couple friendly counseling service; and fighting harmful traditional practices related with decision of HIV testing.


Bi-paratopic and multivalent human VH domains neutralize SARS-CoV-2 by targeting distinct epitopes within the ACE2 binding interface of Spike.
Neutralizing agents against SARS-CoV-2 are urgently needed for treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domain binders with high affinity toward neutralizing epitopes without the need for high-resolution structural information. We constructed a VH-phage library and targeted a known neutralizing site, the angiotensin-converting enzyme 2 (ACE2) binding interface of the trimeric SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified 85 unique VH binders to two non-overlapping epitopes within the ACE2 binding site on Spike-RBD. This enabled us to systematically link these VH domains into multivalent and bi-paratopic formats. These multivalent and bi-paratopic VH constructs showed a marked increase in affinity to Spike (up to 600-fold) and neutralization potency (up to 1400-fold) on pseudotyped SARS-CoV-2 virus when compared to the standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with half-minimal inhibitory concentration (IC 50 ) of 4.0 nM (180 ng/mL). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain bound an RBD at the ACE2 binding site, explaining its increased neutralization potency and confirming our original design strategy. Our results demonstrate that targeted selection and engineering campaigns using a VH-phage library can enable rapid assembly of highly avid and potent molecules towards therapeutically important protein interfaces.


The real problem with equipoise.
The equipoise requirement in clinical research demands that, if patients are to be randomly assigned to one of two interventions in a clinical trial, there must be genuine doubt about which is better. This reflects the traditional view that physicians must never knowingly compromise the care of their patients, even for the sake of future patients. Equipoise has proven to be deeply problematic, especially in the Third World. Some recent critics have argued against equipoise on the grounds that clinical research is fundamentally distinct from clinical care, and thus should be governed by different norms. I argue against this "difference position," and instead take issue with the traditional, exclusively patient-centered account of physicians' obligations that equipoise presupposes. In place of this traditional view, I propose a Kantian test for the reasonable partiality that physicians should show their patients, focusing on its application in clinical research and medical education.


Essentiality of DevR/DosR interaction with SigA for the dormancy survival program in Mycobacterium tuberculosis.
The DevR/DosR regulator is believed to play a key role in dormancy adaptation mechanisms of Mycobacterium tuberculosis in response to a multitude of gaseous stresses, including hypoxia, which prevails within granulomas. DevR activates transcription by binding to target promoters containing a minimum of two binding sites. The proximal site overlaps with the SigA -35 element, suggesting that DevR-SigA interaction is required for activating transcription. We evaluated the roles of 14 charged residues of DevR in transcriptional activation under hypoxic stress. Seven of the 14 alanine substitution mutants were defective in regulon activation, of which K191A, R197A, and K179A+K168A (designated K179A*) mutants were significantly or completely compromised in DNA binding. Four mutants, namely, E154A, R155A, E178A, and K208A, were activation defective in spite of binding to DNA and were classified as positive-control (pc) mutants. The SigA interaction defect of the E154A and E178A proteins was established by in vitro and in vivo assays and implies that these substitutions lead to an activation defect because they disrupt an interaction(s) with SigA. The relevance of DevR interaction to the transcriptional machinery was further established by the hypoxia survival phenotype displayed by SigA interaction-defective mutants. Our findings demonstrate the role of DevR-SigA interaction in the activation mechanism and in bacterial survival under hypoxia and establish the housekeeping sigma factor SigA as a molecular target of DevR. The interaction of DevR and RNA polymerase suggests a new and novel interceptable molecular interface for future antidormancy strategies for Mycobacterium tuberculosis.


Pulmonary vascular and alveolar development in tetralogy of Fallot: a recommendation for early correction.
Using quantitative morphometric techniques, we analysed pulmonary arterial and alveolar development in the lungs of seven children aged 1.2-12 years who died during or soon after repair of tetralogy of Fallot. One child had a residual ventricular septal defect and survived for five months. One other child had had a previous Waterston-Cooley anastomosis (Waterston shunt). Postmortem lung volume in relation to body surface area was generally below normal for age, the alveoli were small, and the total alveolar number was below normal in five of the seven cases. Microscopically, airway and alveolar structure appeared normal. The preacinar arteries were larger and the intra-acinar arteries were smaller than normal for age. The preacinar elastic pulmonary arteries appeared to contain less elastin and in both preacinar and intra-acinar muscular arteries the media was thinner than normal, although muscle was normally distributed along the arterial pathway. Eccentric areas of intimal fibrosis were small and uncommon. The bronchial arteries were generally more prominent than usual both macroscopically and microscopically, but no abnormal bronchopulmonary connections were present. After corrective surgery a residual ventricular septal defect and pulmonary hypertension were associated with arterial medial hypertrophy, and this change was also found in the right lung of a normotensive patient who had had a Waterston shunt. This group probably represents the most favourable clinical picture of tetralogy in patients who usually survive but, even so, pulmonary arterial and alveolar development was abnormal. The structural findings are discussed in relation to the functional outcome in patients with tetralogy who have survived. Repair of the abnormality during the first two to three years of life is recommended.


The cage test as an easy way to screen and evaluate spontaneous activity in preclinical neuroscience studies.
Within behavioral neuroscience, subjects used to be randomly assigned to the experimental groups based on the premise that interindividual variability will be homogeneously distributed. However, the equivalence offered by randomization diminishes in small samples, which is the case for most experiments in the field. In rodents, it is well-recognized that individual differences in psychomotor reactivity, risk-assessment behaviors, and emotional responsiveness modulate the effects of different pharmacological and non-pharmacological treatments. For that reason, knowing such differences before the experiment provides highly valuable information for balancing the groups so that the interindividual variability is equally distributed within the groups without excluding subjects as far as possible. Because unconditioned anxiety tests such as the open-field (OF) and the elevated plus-maze are commonly used within experimental procedures, we developed a strategy to explore the rat's behavioral phenotype by assessing it in a very innocuous testing context: a housing cage.•We offer a very straightforward protocol for assessing spontaneous, novelty-induced reactivity in rodents.•We describe its implementation, analysis, and use, as well as some suggestions about key behavioral readouts for the group allocation procedure.•The current protocol provides an alternative strategy to assess a reasonably wide range of behavioral outcomes, most of which are of great interest in modeling different neuropsychiatric disorders.


Movement system impairment-based categories for low back pain: stage 1 validation.
Cross-sectional study of patients with mechanical low back pain (MLBP). To test the construct validity of 3 categories of a movement system impairment-based classification proposed for use with patients with MLBP. A pathoanatomic basis for directing treatment has not proven useful in a wide variety of patients with MLBP. In addition, there is a paucity of data describing the movement system impairments that characterize many of the pathoanatomically based MLBP diagnoses. Because of the mechanical nature of MLBP, a system based on groups of signs and symptoms relevant to conservative management needs to be developed. A movement system impairment-based classification was proposed that defined 5 categories of MLBP based on the findings from a standardized examination. Using the examination, 5 physical therapists examined a total of 188 patients with MLBP. A principal components analysis with an oblique rotation was conducted. Eigenvalues were plotted and a scree test was used to determine the number of factors to retain. A split-sample cross-validation procedure was conducted to verify the factor structure. Three factors were identified in both samples: 2 factors related to symptoms with lumbar rotation and lumbar extension alignments or movements, and 1 factor related to signs of lumbar rotation with different alignments and movements. Our results provide support for 3 factors related to 3 of the 5 proposed categories: lumbar rotation with extension, lumbar rotation, and lumbar extension. The existence of these 3 factors provides preliminary evidence for specific clusters of tests of alignment and movement impairments that could be used in classifying patients with MLBP into movement-system-related categories.


A PCA approach for fast retrieval of structural patterns in attributed graphs.
An attributed graph (AG) is a useful data structure for representing complex patterns in a wide range of applications such as computer vision, image database retrieval, and other knowledge representation tasks where similar or exact corresponding structural patterns must be found. Existing methods for attributed graph matching (AGM) often suffer from the combinatorial problem whereby the execution cost for finding an exact or similar match is exponentially related to the number of nodes the AG contains. The square matching error of two AGs subject to permutations is approximately relaxed to a square matching error of two AGs subject to orthogonal transformations. Hence, the principal component analysis (PCA) algorithm can be used for the fast computation of the approximate matching error, with a considerably reduced execution complexity. Experiments demonstrate that this method works well and is robust against noise and other simple types of transformations.


Historical, archaeological and linguistic evidence test the phylogenetic inference of Viking-Age plant use.
In this paper, past plant knowledge serves as a case study to highlight the promise and challenges of interdisciplinary data collection and interpretation in cultural evolution. Plants are central to human life and yet, apart from the role of major crops, people-plant relations have been marginal to the study of culture. Archaeological, linguistic, and historical evidence are often limited when it comes to studying the past role of plants. This is the case in the Nordic countries, where extensive collections of various plant use records are absent until the 1700s. Here, we test if relatively recent ethnobotanical data can be used to trace back ancient plant knowledge in the Nordic countries. Phylogenetic inferences of ancestral states are evaluated against historical, linguistic, and archaeobotanical evidence. The exercise allows us to discuss the opportunities and shortcomings of using phylogenetic comparative methods to study past botanical knowledge. We propose a 'triangulation method' that not only combines multiple lines of evidence, but also quantitative and qualitative approaches. This article is part of the theme issue 'Foundations of cultural evolution'.


Validation of the phenol red thread test in a Chinese population.
To investigate the validation of phenol red thread (PRT) test in a Chinese population by evaluating the intraobserver repeatability and interobserver reproducibility, determining correlations between the PRT test and other dry eye disease (DED) parameters including tear meniscus height (TMH) and Schirmer I test, and testing the accuracy of diagnosing DED when using the PRT test alone. A total of 108 eyes were involved in this prospective and diagnostic study, and were divided into two groups (with and without DED). Each subject underwent a series of ocular surface examinations, including Ocular Surface Disease Index (OSDI) questionnaire, non-invasive tear breakup time (NIBUT), tear meniscus height (TMH) assessment, PRT test, fluorescein tear breakup time (FBUT), corneal fluorescein staining and Schirmer I test. In the experimental group and the control group, the intra-class correlation coefficients (ICCs) of the repeatability were 0.747 and 0.723, respectively (all P < 0.05). The ICCs of the reproducibility in both groups were 0.588 and 0.610, respectively (all P < 0.05). The PRT test correlated weakly with the Schirmer I test and the tear meniscus height, with Spearman coefficients of 0.385 and 0.306, respectively (all P < 0.05). The PRT test is available to diagnose DED, with an area under the curve of 0.806 and a Youden index of 0.556 at the cutoff point of 8.83 mm. The PRT test can provide patients a comfortable, timesaving and less irritating approach to screening and diagnosing DED compared to Schirmer I test.


Snake venom Vascular Endothelial Growth Factors (VEGF-Fs) exclusively vary their structures and functions among species.
Vascular endothelial growth factor (VEGF-A) and its family proteins are crucial regulators of blood vessel formation and vascular permeability. Snake venom has recently been shown to be an exogenous source of unique VEGF (known as VEGF-F), and now, two types of VEGF-F with distinct biochemical properties have been reported. Here, we show that VEGF-Fs (venom-type VEGFs) are highly variable in structure and function among species, in contrast to endogenous tissue-type VEGFs (VEGF-As) of snakes. Although the structures of tissue-type VEGFs are highly conserved among venomous snake species and even among all vertebrates, including humans, those of venom-type VEGFs are extensively variegated, especially in the regions around receptor-binding loops and C-terminal putative coreceptor-binding regions, indicating that highly frequent variations are located around functionally key regions of the proteins. Genetic analyses suggest that venom-type VEGF gene may have developed from a tissue-type gene and that the unique sequence of its C-terminal region was generated by an alteration in the translation frame in the corresponding exons. We further verified that a novel venom-type VEGF from Bitis arietans displays unique properties distinct from already known VEGFs. Our results may provide evidence of a novel mechanism causing the generation of multiple snake toxins and also of a new model of molecular evolution.


Essential Oils as an Alternative Treatment for Migraine Headache: A Systematic Review and Meta-Analysis.
Alternative and complementary medicines are widely used to treat migraine headaches. This review aimed to determine the effectiveness of essential oils as an alternative treatment approach. A structured search was conducted to identify randomized trials comparing essential oils with a placebo for migraine headaches, using databases (MEDLINE and CENTRAL) to search for articles published between 1966 and 2021. We included trials involving adult males and females diagnosed with migraine headaches according to the International Headache Society. The outcomes included number of attacks, headache severity, associated symptoms, number of days of limited activity, headache duration, use of analgesics, and adverse effects. Seven trials were included with a total of 558 participants. No difference was observed in the number of migraine headache attacks compared to placebo (mean difference [MD], -1.34; 95% confidence interval [CI], -3.31 to 0.64; I2=94%; P=0.190; four trials, 242 participants; moderatequality evidence). There was no difference in this outcome between the essential oils treated group and the placebo (MD, -0.38; 95% CI, -1.76 to 0.99; I2 statistics=86%; P=0.580; five trials, 240 participants; moderate-quality evidence). We found no significant difference between the use of essential oils and placebo in managing migraine headaches.


Current Quality of Videos on Colorectal Cancer Screening for General Public.
One-third of American adults encompassed by current colorectal cancer screening guidelines fail to obtain recommended screening evaluations. Educational videos are a valuable medium through which to educate and encourage recommended health behaviors in patients. A cross-sectional study reviewing the quality of patient education videos addressing colorectal cancer screening. Video quality was assessed in 3 domains: accountability, content, and production. Forty-four videos met inclusion criteria. Out of 33 possible points, videos scored a median of 15.0 (interquartile range 12.9-16.6). Videos scored 1.0 (interquartile range .8-1.0) out of 4.0 for accountability, 6.0 (interquartile range 4.4-8.0) out of 20 for content, and 8.0 (interquartile range 7.4-8.0) out of 9.0 for production. Colonoscopy was the most frequently discussed method of screening (38, 86%). While 13 (34%) videos discussed the risk of colorectal cancer in the general population and 15 (32%) discussed the risk in those with a family history, few videos addressed those with other risk factors. Most (31, 70%) videos discussed the medical consequences of not receiving screening, but only 1 (2%) video discussed the social consequences. Similarly, medical benefits were discussed in 34 (77%) videos while other benefits were not discussed by any video. Only one-fifth of the videos address three or more barriers to screening. Videos on colorectal cancer screening have excellent production quality but need improvement in the domains of accountability and content. The videos included in this analysis did not adequately address the concerns of viewers nor the benefits of colorectal cancer screening.


Antidepressant prevention of postnatal depression.
Postnatal depression is a common and important complication of childbearing. Untreated depression can lead to potentially negative effects on the foetus and infant, in addition to serious morbidity for the mother. The use of antidepressants during pregnancy for prevention of postnatal depression is unclear, due to the possibility of adverse effects on the mother and developing foetus, and the difficulty of reliably identifying the women who would go on to develop postnatal depression. To evaluate the effectiveness of different antidepressant drugs in addition to standard clinical care in the prevention of postnatal depression. To compare the effectiveness of different antidepressant drugs and with any other form of intervention for postnatal depression i.e. hormonal, psychological or social support. To assess any adverse effects of antidepressant drugs in either the mother or the foetus/infant. The register of clinical trials maintained and updated by the Cochrane Depression, Anxiety and Neurosis Group and the Cochrane Pregnancy and Childbirth Group. Randomised studies of antidepressants alone or in combination with another treatment, compared with placebo or a psychosocial intervention in non-depressed pregnant women or women who had given birth in the previous six weeks (i.e. women at risk of postnatal depression) Data were extracted independently from the trial reports by the authors. Missing information was requested from investigators wherever possible. Data were sought to allow an "intention to treat" analysis. Two trials fulfilled the inclusion criteria for this review. Both looked at women with a past history of postpartum depression. Nortriptyline (n=26) (Wisner 2001) did not show any benefit over placebo (n=25). Sertraline (n=14) Wisner 2004 reduced the recurrence of postnatal depression and the time to recurrence when compared with placebo (n=8). Intention to treat analyses were not carried out in either trial. It is not possible to draw any clear conclusions about the effectiveness of antidepressants given immediately postpartum in preventing postnatal depression and, therefore, cannot be recommended for prophylaxis of postnatal depression, due to the lack of clear evidence. Larger trials are needed which also include comparisons of antidepressant drugs with other prophylactic treatments to reflect clinical practice, and examine adverse effects for the foetus and infant, as well as assess womens' attitudes to the use of antidepressants at this time.


A prostate-specific membrane antigen activated molecular rotor for real-time fluorescence imaging.
Surgery is an efficient way to treat localized prostate cancer (PCa), however, it is challenging to demarcate rapidly and accurately the tumor boundary intraoperatively, as existing tumor detection methods are seldom performed in real-time. To overcome those limitations, we develop a fluorescent molecular rotor that specifically targets the prostate-specific membrane antigen (PSMA), an established marker for PCa. The probes have picomolar affinity (IC50 = 63-118 pM) for PSMA and generate virtually instantaneous onset of robust fluorescent signal proportional to the concentration of the PSMA-probe complex. In vitro and ex vivo experiments using PCa cell lines and clinical samples, respectively, indicate the utility of the probe for biomedical applications, including real-time monitoring of endocytosis and tumor staging. Experiments performed in a PCa xenograft model reveal suitability of the probe for imaging applications in vivo.


Small dose contrast venography as venous mapping in predialysis patients.
This study was designed to evaluate radiocontrast-induced nephrotoxicity (RIN), and the image quality and findings of venography using small doses of radiocontrast as a venous mapping method in pre-dialysis patients. Twenty-eight patients with stage 4 and 5 chronic kidney disease underwent arm venography with 10-15 ml of dilute contrast medium. Image quality, venographic findings and glomerular filtration rate (GFR) before and after the procedure were evaluated. Mean GFR was 19.3+/-5.8 ml/min/1.73 m2 (7-30 ml/min/1.73 m2). Image quality of venography in the forearm and upper arm veins was good in all patients. Central veins were visualized well in 26 (92.8%) patients. Eight (28.5%) patients showed cephalic veins inadequate for creation of radiocephalic arteriovenous fistula (AVF) because of occlusion or small diameter veins. There was no significant difference in GFR between the pre- and post-study (19.3+/-5.8 vs. 19.2+/-6.2 ml/min/1.73 m2, p=0.693). RIN developed (GFR: 17 to 13 ml/min/1.73 m2) in only one patient but without sequelae, and the GFR completely recovered to baseline level 7 days after the study. Small dose venography is safe and effective for venous mapping in pre-dialysis patients.


Practice guideline for the treatment of coccidioidomycosis. Infectious Diseases Society of America.
Management of patients diagnosed with coccidioidomycosis involves defining the extent of infection and assessing host factors that predispose to disease severity. Patients with relatively localized acute pulmonary infections and no risk factors for complications often require only periodic reassessment to demonstrate resolution of their self-limited process. On the other hand, patients with extensive spread of infection or at high risk of complications because of immunosuppression or other preexisting factors require a variety of treatment strategies that may include antifungal therapy, surgical debridement, or both. Amphotericin B is often selected for treatment of patients with respiratory failure due to Coccidioides immitis or rapidly progressive coccidioidal infections. With other more chronic manifestations of coccidioidomycosis, treatment with fluconazole, itraconazole, or ketoconazole is common. Duration of therapy often ranges from many months to years, and, for some patients, chronic suppressive therapy is needed to prevent relapses.


The Blood-Brain Barrier, an Evolving Concept Based on Technological Advances and Cell-Cell Communications.
The construction of the blood-brain barrier (BBB), which is a natural barrier for maintaining brain homeostasis, is the result of a meticulous organisation in space and time of cell-cell communication processes between the endothelial cells that carry the BBB phenotype, the brain pericytes, the glial cells (mainly the astrocytes), and the neurons. The importance of these communications for the establishment, maturation and maintenance of this unique phenotype had already been suggested in the pioneering work to identify and demonstrate the BBB. As for the history of the BBB, the evolution of analytical techniques has allowed knowledge to evolve on the cell-cell communication pathways involved, as well as on the role played by the cells constituting the neurovascular unit in the maintenance of the BBB phenotype, and more particularly the brain pericytes. This review summarises the key points of the history of the BBB, from its origin to the current knowledge of its physiology, as well as the cell-cell communication pathways identified so far during its development, maintenance, and pathophysiological alteration.


Site of salicylaldoxime interaction with photosystem II.
The reversible inhibition of Photosystem II by salicylaldoxime was studied in spinach D-10 particles by fluorescence, optical absorption, and electron spin resonance spectroscopy. In the presence of 15 mM salicylaldoxime, the initial fluorescence yield was raised to the level of the maximum fluorescence, indicating efficient charge recombination between reduced pheophytin (Ph) and P680(+). In agreement with the rapid (ns) backreaction expected between Ph(-) and P680(+), the optical absorption transient at 820 mm was not observed. When the particles were washed free of salicylaldoxime, the optical absorption transient resulting from the rereduction of P680(+) was restored to the µs timescale. These results, along with the previously observed inhibition of electron transport reactions and diminution of the 515-nm absorption change in chloroplasts [Golbeck, J.H. (1980) Arch Biochem Biophys 202, 458-466], are consistent with a site of inhibition between Ph and QA in Photosystem II. ESR Signal IIf and Signal Its were abolished in the presence of 25 mM salicylaldoxime, but both signals could be recovered by washing the D-10 particles free of the inhibitor. The loss of Signal Ilf is most likely a consequence of the inhibition between Ph and QA; the rapid charge recombination between Ph(-) and P680(+) would preclude electron transfer from an electron donor on the oxidizing side of Photosystem II. The loss of Signal Its may be due to a change in the environment of the donor complex such that the semiquinone radical giving rise to Signal Its interacts with a nearby reductant.


Decoupling Resource-Coupled Gene Expression in Living Cells.
Synthetic biology aspires to develop frameworks that enable the construction of complex and reliable gene networks with predictable functionalities. A key limitation is that increasing network complexity increases the demand for cellular resources, potentially causing resource-associated interference among noninteracting circuits. Although recent studies have shown the effects of resource competition on circuit behaviors, mechanisms that decouple such interference remain unclear. Here, we constructed three systems in Escherichia coli, each consisting of two independent circuit modules where the complexity of one module (Circuit 2) was systematically increased while the other (Circuit 1) remained identical. By varying the expression level of Circuit 1 and measuring its effect on the expression level of Circuit 2, we demonstrated computationally and experimentally that indirect coupling between these seemingly unconnected genetic circuits can occur in three different regulatory topologies. More importantly, we experimentally verified the computational prediction that negative feedback can significantly reduce resource-coupled interference in regulatory circuits. Our results reveal a design principle that enables cells to reliably multitask while tightly controlling cellular resources.


Cancer risk is not increased after conventional hip arthroplasty.
Wear debris from conventional total hip arthroplasty (THA) induces chromosomal aberrations and DNA damage, which may promote cancerogenesis. A long latent period is required for solid tumors. We therefore re-analyzed a large THA cohort for cancer. We updated a cohort of 24,636 patients with primary osteoarthritis and metal-on-polyethylene THA who had been entered in the Finnish Arthroplasty Register between 1980 and 1995, and linked it to the Finnish Cancer Registry for cancer risk assessment up to 2005. The mean follow-up time was 13 years. The numbers of cancer cases observed were compared with expected rates based on incidence in the general population. The standardized incidence ratio (SIR) for the whole follow-up period was 0.95 (95% confidence interval (CI): 0.92-0.97). After 10 years of follow-up, the SIR was equal to that in the normal population (SIR = 0.98, 95% CI: 0.94-1.03). Incidence of lung cancer was low throughout the follow-up time and that of prostate cancer was slightly elevated. The incidence rates for all other forms of cancer did not deviate significantly from those in the normal population. We found no increased cancer risk in patients with conventional THA after an average of 13 years and up to 25 years of follow-up.


Pathogenesis of dialysis encephalopathy.
Among patients with renal failure, there have been impressive modifications of both the duration and quality of life as a result of dialysis, renal transplantation, and improved medical management. However, patients who have renal failure continue to manifest a variety of neurologic disorders. Patients with chronic renal failure who have not yet received dialytic therapy may develop a symptom complex progressing from mild sensorial clouding to delirium and coma, with tremor, asterixis, multifocal myoclonus, and seizures. Even after the institution of otherwise adequate maintenance dialysis therapy, patients may continue to be afflicted with more subtle nervous system dysfunction, including impaired mentation, generalized weakness, and peripheral neuropathy. The central nervous system disorders of both untreated renal failure and that persisting despite dialysis are referred to as uremic encephalopathy. The dialytic treatment of end stage renal disease has itself been associated with the emergence of two distinct, new disorders of the central nervous system: Dialysis dysequilibrium and dialysis dementia. The dialysis disequilibrium syndrome consists of headache, nausea, muscle cramps, obtundation and seizures, and is a consequence of the initiation of dialysis therapy in some patients. Dialysis dementia is a progressive, generally fatal encephalopathy which affects patients on chronic hemodialysis. This disease also appears to be a complication of the therapy for renal failure.


Synchronizing the transcranial magnetic pulse with electroencephalographic recordings effectively reduces inter-trial variability of the pulse artefact.
Electroencephalography (EEG) can capture the cortical response evoked by transcranial magnetic stimulation (TMS). The TMS pulse provokes a large artefact, which obscures the cortical response in the first milliseconds after TMS. Removing this artefact remains a challenge. We delivered monophasic and biphasic TMS to a melon as head phantom and to four healthy participants and recorded the pulse artefact at 5 kHz with a TMS-compatible EEG system. Pulse delivery was either synchronized or non-synchronized to the clock of the EEG recording system. The effects of synchronization were tested at 10 and 20 kHz using the head phantom. We also tested the effect of a soft sheet placed between the stimulation coil and recording electrodes in both human and melon. Synchronizing TMS and data acquisition markedly reduced trial-to-trial variability of the pulse artefact in recordings from the phantom or from the scalp. Reduced trial-to-trial variability was also observed at high sampling frequencies. The use of a soft sheet reduced the variability in recordings on the head phantom, but not in human participants. Effective reduction of the trial-to-trial variability renders it possible to create an artefact template for off-line filtering. Template-based subtraction of the artefact from the EEG signals is a prerequisite to effectively recover the immediate physiological response in the stimulated cortex and inter-connected areas.


Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia.
Hypertriglyceridemia and impaired fibrinolytic function are linked to coronary heart disease and other atherothrombotic disorders. Triglyceride-rich lipoproteins may attenuate fibrinolysis by increasing the plasma levels of plasminogen activator inhibitor-1 (PAI-1). Furthermore, a common 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene has been indicated to influence plasma PAI-1 activity and to be involved in an allele-specific response to triglycerides. Herein we show by transfection assays that VLDLs induce transcription of the human PAI-1 promoter in endothelial cells. A VLDL response element (VLDLRE) is located to residues -672 to -657 in the promoter region by electromobility shift assay, methylation interference, and DNase I footprinting, and its activity is shown to be influenced by the common 4G/5G polymorphism located adjacent to and upstream of the binding site of a VLDL-inducible transcription factor. These findings may provide a molecular explanation to the link between VLDL and PAI-1 activity elevation in plasma and to the interaction between the 4G/5G polymorphism and plasma triglycerides.


Effects of diet on population growth of psocids Lepinotus reticulatus and Liposcelis entomophila.
We investigated the suitability of 11 diets as culture media for the psocids Lepinotus reticulatus Enderlein (Psocoptera: Trogiidae) and Liposcelis entomophila (Enderlein) (Psocoptera: Liposcelididae). The culture media comprised six diets made of plain cereals, namely, wheat (Triticum aestivum L.), corn (Zea mays L.), milo Sorghum bicolor (L.), barley (Hordeum vulgare L.), oats (Avena sativa L.), and rice (Oryza sativa L.), and five artificial diets. We found that, with the exception of corn, L. reticulatus population increase was greater on plain cereal diets than on artificial diets, and the greatest population growth was on oats. There was an inverse relationship between L. reticulatus population growth and diet compactness. L. entomophila populations grew fastest on wheat, barley, and a mixture of cracked wheat, rice krispies, and brewer's yeast (97:2:1, wt:wt). The proportion of females was greater in diets that were less suitable for L. entomophila population growth compared with that in the more suitable diets. Diet compactness had a weak effect on L. entomophila population growth. This study also has established the relative level of suitability of damaged wheat, corn, milo, barley, oats, and rice to L. reticulatus and L. entomophila.


Plasmid pSM19035, a model to study stable maintenance in Firmicutes.
pSM19035 is a low-copy-number theta-replicating plasmid, which belongs to the Inc18 family. Plasmids of this family, which show a modular organization, are functional in evolutionarily diverse bacterial species of the Firmicutes Phylum. This review summarizes our understanding, accumulated during the last 20 years, on the genetics, biochemistry, cytology and physiology of the five pSM19035 segregation (seg) loci, which map outside of the minimal replicon. The segA locus plays a role both in maximizing plasmid random segregation, and in avoiding replication fork collapses in those plasmids with long inverted repeated regions. The segB1 locus, which acts as the ultimate determinant of plasmid maintenance, encodes a short-lived epsilon(2) antitoxin protein and a long-lived zeta toxin protein, which form a complex that neutralizes zeta toxicity. The cells that do not receive a copy of the plasmid halt their proliferation upon decay of the epsilon(2) antitoxin. The segB2 locus, which encodes two trans-acting, ParA- and ParB-like proteins and six cis-acting parS centromeres, actively ensures equal or roughly equal distribution of plasmid copies to daughter cells. The segC locus includes functions that promote the shift from the use of DNA polymerase I to the replicase (PolC-PolE DNA polymerases). The segD locus, which encodes a trans-acting transcriptional repressor, omega(2), and six cis-acting cognate sites, coordinates the expression of genes that control copy number, better-than-random segregation and partition, and assures the proper balance of these different functions. Working in concert the five different loci achieve almost absolute plasmid maintenance with a minimal growth penalty.


Ontogenetic expression of thyroid hormone signaling genes: An in vitro and in vivo species comparison.
Thyroid hormone (TH) is essential for brain development. While disruption of TH signaling by environmental chemicals has been discussed as a mechanism of developmental neurotoxicity (DNT) for more than a decade, there remains a paucity of information linking specific TH disrupting chemicals to adverse neurodevelopmental outcomes. This data gap reflects, in part, the fact that the molecular machinery of TH signaling is complex and varies according to cell type and developmental time. Thus, establishing a baseline of the ontogenetic profile of expression of TH signaling molecules in relevant cell types is critical for developing in vitro and alternative systems-based models for screening TH disrupting chemicals for DNT. Here, we characterize the transcriptomic profile of molecules critical to TH signaling across three species-human, rat, and zebrafish-in vitro and in vivo across different stages of neurodevelopment. Our data indicate that while cultured human and rat neural progenitor cells, primary cultures of rat cortical cells, and larval zebrafish all express a fairly comprehensive transcriptome of TH signaling molecules, the spatiotemporal expression profiles as well as the responses to TH vary across species and developmental stages. The data presented here provides a roadmap for identifying appropriate in vitro and in simpler systems-based models for mechanistic studies and screening of chemicals that alter neurodevelopment via interference with TH action.


Conv-ViT: A Convolution and Vision Transformer-Based Hybrid Feature Extraction Method for Retinal Disease Detection.
The current advancement towards retinal disease detection mainly focused on distinct feature extraction using either a convolutional neural network (CNN) or a transformer-based end-to-end deep learning (DL) model. The individual end-to-end DL models are capable of only processing texture or shape-based information for performing detection tasks. However, extraction of only texture- or shape-based features does not provide the model robustness needed to classify different types of retinal diseases. Therefore, concerning these two features, this paper developed a fusion model called 'Conv-ViT' to detect retinal diseases from foveal cut optical coherence tomography (OCT) images. The transfer learning-based CNN models, such as Inception-V3 and ResNet-50, are utilized to process texture information by calculating the correlation of the nearby pixel. Additionally, the vision transformer model is fused to process shape-based features by determining the correlation between long-distance pixels. The hybridization of these three models results in shape-based texture feature learning during the classification of retinal diseases into its four classes, including choroidal neovascularization (CNV), diabetic macular edema (DME), DRUSEN, and NORMAL. The weighted average classification accuracy, precision, recall, and F1 score of the model are found to be approximately 94%. The results indicate that the fusion of both texture and shape features assisted the proposed Conv-ViT model to outperform the state-of-the-art retinal disease classification models.


Cholesterol flux between lipid vesicles and apolipoprotein AI discs of variable size and composition.
Reconstituted discoidal high-density lipoproteins (rHDLs) of apolipoprotein AI are able to induce leakage of the internal aqueous space of lipid vesicles (A. Tricerri et al., 1998, Biochim. Biophys. Acta 1391, 67-78) and such interaction depends on the cholesterol content of vesicles and rHDL as well as the rHDL size. With the aim of knowing if this rHDL/vesicle interaction plays some role in the cholesterol exchange, the time course for bidirectional radiolabeled cholesterol transfer between 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) vesicles and different sized rHDLs was measured. The results show that size increase in the rHDL decreases the rate constant for cholesterol transfer from POPC/cholesterol vesicles and that the initial presence of cholesterol in the vesicles results in an increased rate constant for cholesterol transfer from the rHDLs. This cannot be explained by a simple aqueous diffusion mechanism. The existing correlation between rHDL/vesicle interaction and cholesterol transfer rate suggests that besides the aqueous diffusion, another mechanism involving the binding or interaction between donor and acceptor may occur. This fact may be of physiological relevance since the relative high affinity of small cholesterol-poor discs for cell membranes could facilitate the cholesterol efflux, while the decreased membrane affinity as a consequence of cholesterol enrichment and increase in size would decrease the rate of transfer in the opposite direction.


[Circadian and seasonal changes of the inducer:suppressor ratio (OKT4+:OKT8+) in venous blood of healthy adults].
Circadian and seasonal variations in the T helper: T suppressor-cytotoxic ratio were investigated in peripheral blood from five healthy young men. Mononuclear cells were isolated on Ficoll-Paque gradient, then incubated with OKT4 and OKT8 monoclonal antibodies. Plasma cortisol was determined in four of these seven time series. Large interindividual differences were documented and statistically validated for the 24-hr.-means of total lymphocytes, OKT4+:OKT8+ ratio, and of plasma cortisol (both total and free). For a pooled data, a circadian rhythm was demonstrated by cosinor (p less than 0.001) for total lymphocytes (acrophase at 1.00 hr.), total plasma cortisol (acrophase at 10.30 hrs.) and free plasma cortisol (acrophase at 9.50 hrs.), but not for OKT4+:OKT8+ ratio. This index however exhibited a statistically significant circadian rhythm in April and August, but not in November. Its double-amplitude exceeded 80% of the 24-hour-mean and its acrophase was localized at 6.40 hrs. in April and at 22.30 hrs. in August. Its 24-hr-mean was higher in August as compared to April and November. The circadian rhythm in the OKT4+:OKT8+ ratio did not seem to be related to that of plasma cortisol. Both circadian and seasonal variations need to be taken into account when investigating the regulations of immune variables such as T helper: T suppressor-cytotoxic ratio.


Histology of the fascial-periosteal interface in lower limb chronic deep posterior compartment syndrome.
To describe the histological features of the fascial-periosteal interface at the medial tibial border of patients surgically treated for chronic deep posterior compartment syndrome and to make statistical comparisons with control tissue. Nineteen subjects and 11 controls were recruited. Subject tissue was obtained at operation, and control tissue from autopsy cases. Tissue samples underwent histological preparation and then examination by an independent pathologist. Samples were analysed with regard to six histological variables: fibroblastic activity, chronic inflammatory cells, vascularity, collagen regularity, mononuclear cells, and ground substance. Collagen regularity was measured with respect to collagen density, fibre arrangement, orientation, and spacing. The observed changes were graded from 1 to 4 in terms of abnormality. Mann-Whitney U test, Spearman correlation coefficients, and intraobserver reliability scores were used. With regard to collagen arrangement, control tissue showed greater degrees of irregularity than subject tissue (p = 0.01). Subjects with a symptom duration of greater than 12 months (as opposed to less than 12 months) showed greater degrees of collagen irregularity (p = 0.043). Vascular changes approached significance (p = 0.077). With regard to the amount of fibrocyte activity, chronic inflammatory cell activity, mononuclear cells, or ground substance, there were no significant differences between controls and subjects. Good correlation was seen in scores measuring chronic inflammatory cell activity and mononuclear cells (r = 0.649), and moderate correlation was seen between fibrocyte activity and vascular changes (r = 0.574). Intraobserver reliability scores were good for chronic inflammatory cell activity and moderate for vascular changes, but were poor for collagen and fibrocyte variables. Individual cases showed varying degrees of fibrocyte activity, chronic inflammatory cellular infiltration, vascular abnormalities, and collagen fibre disruption. Statistical analysis showed no histological differences at the fascial-periosteal interface in cases of chronic deep posterior compartment syndrome, except for collagen, which showed less irregularity in subject samples. The latter may indicate a remodelling process, and this is supported by greater collagen irregularity in subjects with longer duration of symptoms.


Irreversible Electroporation in Liver Cancers and Whole Organ Engineering.
Liver cancers contribute significantly to cancer-related mortality worldwide and liver transplants remain the cornerstone of curative treatment for select, early-stage patients. Unfortunately, because of a mismatch between demand and supply of donor organs, liver cancer patients must often wait extended periods of time prior to transplant. A variety of local therapies including surgical resection, transarterial chemoembolization, and thermal ablative methods exist in order to bridge to transplant. In recent years, a number of studies have examined the role of irreversible electroporation (IRE) as a non-thermal local ablative method for liver tumors, particularly for those adjacent to critical structures such as the vasculature, gall bladder, or bile duct. In addition to proving its utility as a local treatment modality, IRE has also demonstrated promise as a technique for donor organ decellularization in the context of whole-organ engineering. Through complete non-thermal removal of living cells, IRE allows for the creation of an acellular extra cellular matrix (ECM) scaffold that could theoretically be recellularized and implanted into a living host. Here, we comprehensively review studies investigating IRE, its role in liver cancer treatment, and its utility in whole organ engineering.


Treatment monitoring of 5-fluorouracil 0.5%/salicylic acid 10% lesion-directed therapy for actinic keratosis using dermoscopy and in-vivo reflectance confocal microscopy.
Recently, 5-fluorouracil 0.5%/salicylic acid 10% (5-FU/SA) topical solution has been included in the National Italian portfolio for lesion-directed treatment of grade I/II actinic keratosis (AKs) located on the face or scalp. To describe the utility of dermoscopy and RCM in treatment response monitoring of a series of AKs treated with 5-FU/SA as lesion-directed therapy. Consecutive patients were prospectively treated for a maximum of 12 weeks with 5-FU/SA for AKs located on the face or scalp. Clinical, dermoscopic, and confocal images of one index AK were acquired at each visit and pre-specified criteria were evaluated. Clinical, dermoscopic, and confocal responses were evaluated at last follow-up visit. Fourteen patients were enrolled, of which five were treated for 12 weeks, seven for 8, and two for 4 weeks. At a median follow up of 30 weeks, 64.3% (9/14) index AKs achieved complete clinical, 50% (7/14) complete dermoscopic and 42.9% (6/14) complete confocal clearance. Local skin reaction was mild and significantly decreased during therapy administration. Although the small number of cases, our study underlines the utility of both dermoscopy and in-vivo RCM in 5-FU/SA treatment response monitoring for AKs located on the face or scalp.


Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R.
Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor. This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle. A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome. IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.


Profiling cancer-associated genetic alterations and molecular classification of cancer in Korean gastric cancer patients.
Recently, the Cancer Genome Atlas (TCGA) Research Network and Asian Cancer Research Group provided a new classification of gastric cancer (GC) to aid the development of biomarkers for targeted therapy and predict prognosis. We studied associations between genetically aberrant profiles of cancer-related genes, environmental factors, and histopathological features in 107 paired gastric tumor-non-tumor tissue GC samples. 6.5% of our GC cases were classified as the EBV subtype, 17.8% as the MSI subtype, 43.0% as the CIN subtype, and 32.7% as the GS subtype. The distribution of four GC subgroups based on the TCGA and our dataset were similar. The MSI subtype showed a hyper-mutated status and the best prognosis among molecular subtype. However, molecular classification based on the four GC subtypes showed no significant survival differences in terms of overall survival (p= 0.548) or relapse-free survival (RFS, p=0.518). The P619fs*43 in ZBTB20 was limited to MSI group (n= 5/19, 26.3%), showing similar trends observed in TCGA dataset. Genetic alterations of the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways were detected in 34.6% of GC cases (37 individual cases). We also found two cases with likely pathogenic variants (NM_004360.4: c. 2494 G>A, p.V832M) in the CDH1 gene. Here, we classified molecular subtypes of GC according to the TCGA system and provide a critical starting point for the design of more appropriate clinical trials based on a comprehensive analysis of genetic alterations in Korean GC patients.


A multi-country analysis of COVID-19 hospitalizations by vaccination status.
Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes. Here, we use data from an international consortium to study this question and assess whether differences between these groups are context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed. While typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed. These findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history. This work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill & Melinda Gates Foundation (OPP1209135); and the philanthropic support of the donors to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the "acknowledgments" section.


The role of isovalency in the reactions of the cyano (CN), boron monoxide (BO), silicon nitride (SiN), and ethynyl (C2H) radicals with unsaturated hydrocarbons acetylene (C2H2) and ethylene (C2H4).
The classification of chemical reactions based on shared characteristics is at the heart of the chemical sciences, and is well exemplified by Langmuir's concept of isovalency, in which 'two molecular entities with the same number of valence electrons have similar chemistries'. Within this account we further investigate the ramifications of the isovalency of four radicals with the same X(2)Σ(+) electronic structure - cyano (CN), boron monoxide (BO), silicon nitride (SiN), and ethynyl (C2H), and their reactions with simple prototype hydrocarbons acetylene (C2H2) and ethylene (C2H4). The fact that these four reactants own the same X(2)Σ(+) electronic ground state should dictate the outcome of their reactions with prototypical hydrocarbons holding a carbon-carbon triple and double bond. However, we find that other factors come into play, namely, atomic radii, bonding orbital overlaps, and preferential location of the radical site. These doublet radical reactions with simple hydrocarbons play significant roles in extreme environments such as the interstellar medium and planetary atmospheres (CN, SiN and C2H), and combustion flames (C2H, BO).


Frustrated demand for sterilization among low-income Latinas in El Paso, Texas.
Sterilization is the most commonly used contraceptive in the United States, yet access to this method is limited for some. A 2006-2008 prospective study of low-income pill users in El Paso, Texas, assessed unmet demand for sterilization among 801 women with at least one child. Multivariable logistic regression analysis identified characteristics associated with wanting sterilization. In 2010, at an 18-month follow-up, women who had wanted sterilization were recontacted; 120 semistructured and seven in-depth interviews were conducted to assess motivations for undergoing the procedure and the barriers faced in trying to obtain it. At baseline, 56% of women wanted no more children; at nine months, 65% wanted no more children, and of these, 72% wanted sterilization. Only five of the women interviewed at 18 months had undergone sterilization; two said their partners had obtained a vasectomy. Women who had not undergone sterilization were still strongly motivated to do so, mainly because they wanted no more children and were concerned about long-term pill use. Among women's reasons for not having undergone sterilization after their last pregnancy were not having signed the Medicaid consent form in time and having been told that they were too young or there was no funding for the procedure. Because access to a full range of contraceptive methods is limited for low-income women, researchers and providers should not assume a woman's current method is her method of choice.


SOD2, a Potential Transcriptional Target Underpinning CD44-Promoted Breast Cancer Progression.
CD44, a cell-adhesion molecule has a dual role in tumor growth and progression; it acts as a tumor suppressor as well as a tumor promoter. In our previous work, we developed a tetracycline-off regulated expression of CD44's gene in the breast cancer (BC) cell line MCF-7 (B5 clone). Using cDNA oligo gene expression microarray, we identified SOD2 (superoxide dismutase 2) as a potential CD44-downstream transcriptional target involved in BC metastasis. SOD2 gene belongs to the family of iron/manganese superoxide dismutase family and encodes a mitochondrial protein. SOD2 plays a role in cell proliferation and cell invasion via activation of different signaling pathways regulating angiogenic abilities of breast tumor cells. This review will focus on the findings supporting the underlying mechanisms associated with the oncogenic potential of SOD2 in the onset and progression of cancer, especially in BC and the potential clinical relevance of its various inhibitors.


Sudden unresponsive patient with normal vital signs: what is going on?
To summarize the differential diagnosis and diagnostic approach of sudden unresponsiveness with normal vital signs in various settings, including the ICU. Sudden unresponsiveness may be either transient or persistent, and may result from primary brain diseases or nonstructural systemic conditions. Life-threatening causes should always be discriminated from those more benign. Regional epidemiology, for example regarding intoxications, and evolving therapeutic management, for example for ischemic stroke, should always be taken into account for optimal opportunity for rapid diagnosis and best management. Sudden unresponsiveness with normal vital signs should trigger immediate and focused diagnostic evaluation to find or exclude those conditions requiring urgent, and possibly life-saving, management.


DEPRESSION AND MEDICATION ADHERENCE AMONG ALDER ADULTS WITH SELECTED CHRONIC MEDICAL CONDITIONS IN MAIDUGURI, NIGERIA.
Older adults constitute a rapidly growing population whose healthcare needs are unique, with a higher prevalence of physical and psychiatric morbidities. A knowledge gap exists regarding the association of chronic medical conditions with Depression and how they affect medication adherence. This may be linked to their chronic nature and impacts on the mood of older adults. This study assessed Depression among older adults with Hypertension, Diabetes Mellitus, and Arthritis; and compared its relationship with medication adherence in the speciality clinics of UMTH, Maiduguri. A comparative cross-sectional analytic study was employed to recruit 327 older adults aged≥60years for six months. They were proportionally distributed into groups of Hypertension only (140), Diabetes only (85), Arthritis only (43), hypertension and diabetes (59). The socio- clinical proforma, Geriatric Depression Scale (GDS-30), and Morisky Medication Adherence Scale (MMAS-8) were administered. Data were analysed using SPSS version 26.0. The mean adherence scores for those with depression were compared with the mean scores of those without depression using a t-test. The study found that the mean medication adherence score was lower in those with depression than those without depression. The difference is significant among the group with arthritis only (t = 1.943 and p-value = 0.049) where those with depression had an adherence score (2.299 ± 0.500) while those without depression scored (3.177 ± 1.267); and also, among the group with HTN + DM (t = 2.769, p-value = 0.006) where those with depression had an adherence score (2.000 ± 0.001) while those without depression scored (4.299 ±2.026). Depression is associated with low medication adherence in older adults with chronic medical conditions. This underscores the need for consultation-liaison practice and proactivity in assessing for depression in older adults with chronic conditions to improve their adherence.


Radiation inactivation studies of renal brush border water and urea transport.
Radiation inactivation was used to determine the nature and molecular weight of water and urea transport pathways in brush border membrane vesicles (BBMV) isolated from rabbit renal cortex. BBMV were frozen to -50 degrees C, irradiated with 1.5 MeV electrons, thawed, and assayed for transport or enzyme activity. The freezing process had no effect on enzyme or transport kinetics. BBMV alkaline phosphatase activity gave linear ln(activity) vs. radiation dose plots with a target size of 68 +/- 3 kDa, similar to previously reported values. Water and solute transport were measured using the stopped-flow light-scattering technique. The rates of acetamide and osmotic water transport did not depend on radiation dose (0-7 Mrad), suggesting that transport of these substances does not require a protein carrier. In contrast, urea and thiourea transport gave linear ln(activity) vs. dose curves with a target size of 125-150 kDa; 400 mM urea inhibited thiourea flux by -50% at 0 and 4.7 Mrad, showing that radiation does not affect inhibitor binding to surviving transporters. These studies suggest that BBMV urea transport requires a membrane protein, whereas osmotic water transport does not.


Mineralocorticoid receptor antagonists for heart failure.
Although mineralocorticoid receptor (MR) antagonists are indicated in systolic heart failure, they are underprescribed in patients with appropriate indications for their prescription and often used in those in whom the evidence for probable benefit is scant. The rate of adverse events in practice has exceeded that foreshadowed by randomized controlled trials (RCTs). With the recent publication of the landmark therapeutic trial (EMPHASIS), it is timely to review the appropriate use of these agents in heart failure. This review addresses the pathophysiological importance of MR activation in heart failure and summarizes pivotal RCTs of MR antagonists in heart failure. MR antagonism reduces mortality and morbidity in heart failure with reduced systolic function in severe chronic disease, in heart failure complicating myocardial infarction and also in those with impaired systolic function (but only mild symptoms). Evidence for benefits in a significant proportion of 'real-life' patients with heart failure, including those with preserved left ventricular ejection fraction, is lacking. MR antagonism is an important part of the pharmaceutical armamentarium in managing heart failure but must be prescribed with careful case selection, taking note of the evidence of where risks are acceptable and benefits are likely.


Hypotony and aqueous humor dynamics in myotonic dystrophy.
A group of 26 subjects with myotonic dystrophy were studied with fluorophotometry to evaluate the relationship between aqueous humor dynamics and the hypotony found in this disorder. All 26 received topical fluorescein to determine the anterior chamber elimination coefficient; five received systemic fluorescein to evaluate the integrity of the blood-aqueous barrier. The group has a mean intraocular pressure of 7.1 mm Hg. The rate of clearance of fluorescein from the anterior chamber and the cornea-to-anterior chamber transfer coefficient for fluorescein were normal. An abnormally high level of fluorescence, three times normal, was observed in the anterior chambers of the myotonic subjects after oral administration of fluorescein. This finding could not be attributed to abnormal absorption and elimination of fluorescein or to abnormal plasma binding. This finding indicates that there is a defect in the blood-ocular barrier to fluorescein in myotonic subjects. Thus conclusions regarding aqueous humor flow cannot be made from the rate of clearance of topically applied fluorescein in myotonic subjects, since the clearance due to diffusion may represent a significantly large fraction of the total clearance.


Anabolic Effect of Insulin Therapy on the Bone: Osteoprotegerin and Osteocalcin Up-Regulation in Streptozotocin-Induced Diabetic Rats.
Type 1 diabetes mellitus (T1DM) is associated with several skeletal alterations, particularly in conditions of poor glycaemic control. Insulin therapy is the major conservative treatment for T1DM; however, the effects of this hormone on bone markers of T1DM rats are limited, and the regulatory mechanisms remain elusive. Therefore, the evaluation of molecular and non-molecular parameters in a chronic animal model of T1DM-induced bone loss, treated with and without insulin, may help in elucidating the insulin mechanisms. Male Wistar rats were assigned into three groups: control, T1DM (T1DM rats induced with streptozotocin [STZ] at 40 mg/kg intravenously) and T1DM plus insulin therapy (T1DMI). After 8 weeks, we evaluated the serum biochemical, tibia histomorphometric and biomechanical parameters, as well as the gene expression of the receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and osteocalcin (OC) of femur mRNA. Compared with T1DM, the T1DMI group showed less bone loss, which was revealed by the increased trabecular width (TbWi, p < 0.001) and trabecular bone area (BAr, p < 0.01), reduced trabecular separation (TbSp, p < 0.01) and increased Young's modulus (p < 0.05). Moreover, molecular analyses indicated that the expression of OPG and OC was up-regulated (p < 0.001 and p < 0.05, respectively). In summary, the up-regulation of OPG and OC in the T1DMI group supports an anabolic effect of insulin, which was demonstrated by the maintenance of bone architecture and flexibility. These results suggest that insulin therapy may prevent T1DM-induced bone loss via the effects on the bone formation.


Risk assessment of cancer of the female reproductive system.
To create an information resource concerning multifactorial oncological diseases of the female reproductive system. A comprehensive search of the literature in the PubMed and Ukrainian scientific sources published from 1995 to 2014 and the results of researches performed in R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine. Development environment of information resource "Multifactorial oncological disease" was Borland Delphi. The information content of web page concerning cancers of the female reproductive system was posted in the information resource "Multifactorial oncological disease". The assessment algorithm of genetic contribution to cancers of the female reproductive system and recurrent risk of cancer development in families have been described. These algorithms can be used in assessment of contribution of genetic and environmental factors in the development of malignant tumors.


Compounded percutaneous testosterone gel: use and effects in hypogonadal men.
Current methods of testosterone replacement therapy are limited to fixed-dosage patches and depot injections. Neither of these methods provides ideal therapy because of the inflexibility of dosing and other nuisance problems associated with the patches and nonphysiologic hormone levels when depot injections are used. Testosterone gels offer the potential for convenience and ease of administration, as well as flexible dosing regimens, by means of a simple topical application. Ten hypogonadal men were selected from the author's general practice, ranging in age from 44 to 77 years. Four of these men had newly diagnosed and 6 had preexisting hypogonadism. Patients were withdrawn from their previous hormone therapy (where applicable), and baseline laboratory studies were obtained for total testosterone, free testosterone, dihydrotestosterone, estradiol, luteinizing hormone, follicle-stimulating hormone, complete blood counts, lipid panels, and chemistry panels. The patients then started taking increasing dosages of the testosterone gel until physiologic levels of testosterone were realized or until the study period (6 weeks) was concluded. There was no blinding, and each patient served as his own control. Testosterone and free testosterone levels were monitored weekly, and estradiol and dihydrotestosterone less frequently. At the conclusion of the study, all the baseline laboratory tests were repeated. A questionnaire evaluating the psychosexual well-being of the patients was administered before and after the treatment period. The average total testosterone level rose from 136 ng/dL to 442.9 ng/dL (P < .001). Average free testosterone levels rose from 34.2 pg/mL to 120.3 pg/mL (P < .001). Average dihydrotestosterone levels rose from 20.5 to 199.2 ng/dL (P = .006). Average estradiol levels rose only slightly from 34.1 pg/mL to 40.0 pg/mL P = .191). Average total androgens (testosterone plus dihydrotestosterone) rose in all patients to therapeutic levels, from 149.3 ng/dL to 642.1 ng/dL (P = .001). The ratio of total androgen to estradiol rose from 5.1 to 17.1 (P < .002). Luteinizing hormone was suppressed in the 6 patients for whom meaningful data were available, and decreased on average from 5.66 to 1.10 mIU/mL (P = .005) Lipid effects were measured, and a 15% drop in all cholesterol fractions was noted (P < .005). Evaluation of the questionnaire showed considerable improvements in sexual function and overall well-being in all but 1 patient. No adverse effects or nuisance-problems were detected during the duration of the study. Topically applied testosterone gels are an effective and convenient means of hormone replacement in hypogonadal men.


Effect of vagal cooling on the counterregulatory response to hypoglycemia induced by a low dose of insulin in the conscious dog.
We previously demonstrated, using a nerve-cooling technique, that the vagus nerves are not essential for the counterregulatory response to hypoglycemia caused by high levels of insulin. Because high insulin levels per se augment the central nervous system response to hypoglycemia, the question arises whether afferent nerve fibers traveling along the vagus nerves would play a role in the defense of hypoglycemia in the presence of a more moderate insulin level. To address this issue, we studied two groups of conscious 18-h-fasted dogs with cooling coils previously placed on both vagus nerves. Each study consisted of a 100-min equilibration period, a 40-min basal period, and a 150-min hypoglycemic period. Glucose was lowered using a glycogen phosphorylase inhibitor and a low dose of insulin infused into the portal vein (0.7 mU.kg(-1) min(-1)). The arterial plasma insulin level increased to 15 +/- 2 microU/ml and the plasma glucose level fell to a plateau of 57 +/- 3 mg/dl in both groups. The vagal cooling coils were perfused with a 37 degrees C (SHAM COOL; n = 7) or a -20 degrees C (COOL; n = 7) ethanol solution for the last 90 min of the study to block parasympathetic afferent fibers. Vagal cooling caused a marked increase in the heart rate and blocked the hypoglycemia-induced increase in the arterial pancreatic polypeptide level. The average increments in glucagon (pg/ml), epinephrine (pg/ml), norepinephrine (pg/ml), cortisol (microg/dl), glucose production (mg.kg(-1). min(-1)), and glycerol (micromol/l) in the SHAM COOL group were 53 +/- 9, 625 +/- 186, 131 +/- 48, 4.63 +/- 1.05, -0.79 +/- 0.24, and 101 +/- 18, respectively, and in the COOL group, the increments were 39 +/- 7, 837 +/- 235, 93 +/- 39, 6.28 +/- 1.03 (P < 0.05), -0.80 +/- 0.20, and 73 +/- 29, respectively. Based on these data, we conclude that, even in the absence of high insulin concentrations, afferent signaling via the vagus nerves is not required for a normal counterregulatory response to hypoglycemia.


Two different methods result in the selection of peptides that induce a protective antibody response to Neisseria meningitidis serogroup C.
Neisseria meningitidis is a leading cause of morbidity and mortality worldwide. The presently available capsular polysaccharide vaccine is poorly immunogenic in children under the age of 2 due to its T-independent (TI) nature. Efforts to overcome the TI response elicited by the polysaccharide vaccine have led to the development of polysaccharide-protein conjugate vaccines. Although a T-dependent (TD) response can be achieved in young children, the response to the polysaccharide still retains characteristics of a TI antibody response. An alternative method of potentially inducing a TD response to a carbohydrate antigen is through peptides that mimic the capsular polysaccharide. Our laboratory, through the production of an anti-idiotypic (anti-id) monoclonal antibody, designated 6F9, has previously identified a peptide mimic of the meningococcal serogroup C polysaccharide (MCPS). Using the same selecting monoclonal antibody (mAb), 1E4, we have screened a phage display library and identified 13 unique peptides that bound specifically to mAb1E4. Two peptides, Pep1C and Pep2C, that demonstrated the highest binding to mAb1E4, were selected, complexed to proteosomes, and used to immunize Balb/c mice. Of the 13 peptide motifs, only one peptide motif, that of Pep2C, was found to resemble the immunogenic peptide sequence of the anti-id selected with the same mAb, although many contained several similar amino acid residues. Immunization with Pep2C, but not Pep1C, induced a significant and functional anti-MCPS antibody response that conferred protection from a lethal challenge with meningococci. Our results indicate that immunization with a peptide of N. meningitidis serogroup C, screened with the same mAb that selected an anti-id of MCPS, induces a functional and protective anti-MCPS immune response similar to that of the anti-id. This study demonstrates that two different selection methods, production of an anti-id and biopanning using a phage display library, can be used to select functional and protective peptides of MCPS with similar moieties.


Ferroelasticity, anelasticity and magnetoelastic relaxation in Co-doped iron pnictide: Ba(Fe0.957Co0.043)2As2.
The hypothesis that strain has a permeating influence on ferroelastic, magnetic and superconducting transitions in 122 iron pnictides has been tested by investigating variations of the elastic and anelastic properties of a single crystal of Ba(Fe0.957Co0.043)2As2 by resonant ultrasound spectroscopy as a function of temperature and externally applied magnetic field. Non-linear softening and stiffening of C 66 in the stability fields of both the tetragonal and orthorhombic structures has been found to conform quantitatively to the Landau expansion for a pseudoproper ferroelastic transition which is second order in character. The only exception is that the transition occurs at a temperature (T S ≈ 69 K) ~10 K above the temperature at which C 66 would extrapolate to zero ([Formula: see text] ≈ 59 K). An absence of anomalies associated with antiferromagnetic ordering below T N ≈ 60 K implies that coupling of the magnetic order parameter with shear strain is weak. It is concluded that linear-quadratic coupling between the structural/electronic and antiferromagnetic order parameters is suppressed due to the effects of local heterogeneous strain fields arising from the substitution of Fe by Co. An acoustic loss peak at ~50-55 K is attributed to the influence of mobile ferroelastic twin walls that become pinned by a thermally activated process involving polaronic defects. Softening of C 66 by up to ~6% below the normal-superconducting transition at T c ≈ 13 K demonstrates an effective coupling of the shear strain with the order parameter for the superconducting transition which arises indirectly as a consequence of unfavourable coupling of the superconducting order parameter with the ferroelastic order parameter. Ba(Fe0.957Co0.043)2As2 is representative of 122 pnictides as forming a class of multiferroic superconductors in which elastic strain relaxations underpin almost all aspects of coupling between the structural, magnetic and superconducting order parameters and of dynamic properties of the transformation microstructures they contain.


Condition dependence of nestling mouth colour and the effect of supplementing carotenoids on parental behaviour in the hihi (Notiomystis cincta).
Carotenoids are integument pigments that often reflect foraging efficiency, disease resistance and body condition. In contrast to the widespread attention this relationship has received in adult birds, the condition dependence of nestling colouration remains an understudied component of animal communication. Here we assess the condition dependence of carotenoid pigmentation in nestling hihi (Notiomystis cincta, an endangered New Zealand bird) and examine the influence of carotenoid supplementation on nestling quality and parental visitation rates. Our results show that carotenoids provided to breeding adult hihi were transferred to their offspring and resulted in an intensified orange-yellow flange colour. After accounting for carotenoid supplementation the parameter that most consistently explained variation in nestling flange colour was nestling tarsus length at 23 days, indicating condition dependence of this trait. We did not, however, detect direct effects of carotenoid supplementation on nestling mass or immune response (or any other fitness parameter measured). Carotenoid supplementation did, however, result in an increased paternal provisioning rate.


Patient perceptions regarding the likelihood of cure after surgical resection of lung and colorectal cancer.
The objective of the current study was to characterize the prevalence of the expectation that surgical resection of lung or colorectal cancer might be curative. The authors sought to assess patient-level, tumor-level, and communication-level factors associated with the perception of cure. Between 2003 and 2005, a total of 3954 patients who underwent cancer-directed surgery for lung (30.3%) or colorectal (69.7%) cancer were identified from a population-based and health system-based survey of participants from multiple US regions. Approximately 80.0% of patients with lung cancer and 89.7% of those with colorectal cancer responded that surgery would cure their cancer. Even 57.4% and 79.8% of patients with stage IV lung and colorectal cancer, respectively, believed surgery was likely to be curative. On multivariable analyses, the odds ratio (OR) of the perception of curative intent was found to be higher among patients with colorectal versus lung cancer (OR, 2.27). Patients who were female, with an advanced tumor stage, unmarried, and having a higher number of comorbidities were less likely to believe that surgery would cure their cancer; educational level, physical function, and insurance status were not found to be associated with perception of cure. Patients who reported optimal physician communication scores (reference score, 0-80; score of 80-100 [OR, 1.40] and score of 100 [OR, 1.89]) and a shared role in decision-making with their physician (OR, 1.16) or family (OR, 1.17) had a higher odds of perceiving surgery would be curative, whereas patients who reported physician-controlled (OR, 0.56) or family-controlled (OR, 0.72) decision-making were less likely to believe surgery would provide a cure. Greater focus on patient-physician engagement, communication, and barriers to discussing goals of care with patients who are diagnosed with cancer is needed.


Catchment-scale quantification of hyporheic denitrification using an isotopic and solute flux approach.
A dual-isotope and solute flux mass-balance was used to elucidate the processes that lead to attenuation of nitrogen contamination in an agriculturally impacted river. The River Wensum drains a lowland catchment with an area of 570 km² in East Anglia, eastern England. Analysis of nitrate concentration, δ¹⁵N(NO₃) and δ¹⁸O(NO₃) of samples from the River Wensum collected from upstream locations to the catchment outlet through all seasons and flow conditions showed a consistent pattern of increasing isotope values with decreasing nitrate concentrations downstream. δ¹⁵N(NO₃) and δ¹⁸O(NO₃) of catchment surface water and groundwater samples revealed a dominant influence from microbially cycled and nitrified source-nitrogen, which results in high nitrate concentrations in Chalk groundwater and upstream in the River Wensum. Denitrification of Chalk groundwater-baseflow in the hyporheic zone results in the downstream trend observed in the river. Hyporheic denitrification is estimated to remove 931 kg/day of nitrate-nitrogen by the catchment outlet, representing 31% of the potential riverine nitrate load. The use of dual-isotope and solute flux modeling at the catchment scale is a novel application to quantify denitrification within the river valley, demonstrating the importance of hyporheic zone processes in attenuating the impacts of anthropogenic contamination of hydrologic systems.


Dynamic 3D MR angiography of intra- and extracranial vascular malformations at 3T: a technical note.
Time-resolved, contrast-enhanced 3D MR angiography combined with parallel imaging at 3T was applied to an intracranial arteriovenous malformation, a dural arteriovenous fistula, and an extracranial facial arteriovenous malformation. The temporal resolution was one image every 1.5 seconds. Arterial feeders were depicted in all three cases. Early venous drainage was observed in the intracerebral arteriovenous malformation and the dural arteriovenous fistula, but not in the facial arteriovenous malformation. All findings were concordant with conventional angiography.


Design and test of a system for tracking referrals.
Many health and welfare programs are based on a model in which services needed by consumers are identified by one agency with referral to others for provision of services. The referring agency often does not know whether the services recommended are received, yet it is assumed that receipt of those services by their clients is essential to achievement of program goals. A procedure was devised for tracking families evaluated by North Carolina's State-supported developmental evaluation centers (DECs), agencies that reflect this model. The multidisciplinary evaluation teams of these centers serve children and their families of all income levels. The developmental evaluation family tracking system is a method for determining if recommended services are received, the reasons why they are not, and whether the family desires additional help from the center or othersources. The system was piloted in the Greensboro DEC with a selected group of 67 families. Parents were contacted, mostly by telephone, at 6 months and 18 months following evaluation. Tracking forms were completed for 61 families. Professional staff spent only 2.7% of their working hours during a 3-month period on direct tracking activities and other tasks in behalf of the consumers contacted. The cost was $7.15 per case for immediate tracking and $14.49 if additional activities generated by the tracking contact were included. The system, which provides the information necessary for achieving program goals, was implemented for all 11 DECs in North Carolina in 1976.


CYP2B6*6 allele and age substantially reduce steady-state ketamine clearance in chronic pain patients: impact on adverse effects.
Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients. CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k ) and norketamine (Css,nk ) were determined using HPLC. The median plasma clearance of ketamine after 100 mg 24 h(-1) dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h(-1) ) and CYP2B6*1/*6 (40.6 l h(-1) ) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h(-1) , P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h(-1) ) than those who did not (52.6 l h(-1) , P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k , respectively. Similar results were observed after higher doses. The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects.


Transcriptional enhancer related DNA sequences: anomalous 1H NMR NOE crosspeaks.
A dynamic heterogeneity which correlates with the function of the operator DNA in the lactose operon of E. coli. was previously observed (1) as a local minimum in the thymine imino proton T1 centered at a GTG/C-CAC sequence. Since this triplet occurs frequently in DNA regulatory regions, it was proposed that these sequences may be part of a structural element for specific protein interaction. We examine here three additional biologically significant 17 base pair duplexes containing GTG/CAC triplets: (1) a sequence from the mouse heavy chain immunoglobulin enhancer, (2) a sequence from the critical core of the Simian Virus 40 (SV40) enhancer, and (3) a sequence from pBR322 plasmid used as control for experiments with the SV40 DNA sequences. The 1H NMR resonance assignment for nearly all the nonexchangeable protons for both eukaryotic enhancer duplexes with the exception of the H5'/H5" protons was accomplished to use for structural analysis of these duplexes. The data presented show several NOE's associated with the GTG/CAC triplets which suggest structural variation from uniform B-DNA. In addition, anomalous broad crosspeaks for the fixed thymine methyl to its own H6 proton in combination with the imino proton kinetics associated with these triplets reinforces the original observation of a sequence dependent dynamic variation.


Fatal epistaxis caused by rupture of an intratumoral aneurysm enclosed by a large prolactinoma--case report.
A 72-year-old female presented with episodes of epistaxis. Neuroimaging demonstrated a large prolactinoma totally enclosing a large intracavernous aneurysm of the internal carotid artery. Adjacent bony structures were eroded and destroyed by tumor invasion and extension. Rupture of the intratumoral aneurysm caused fatal epistaxis rather than subarachnoid hemorrhage before surgery. Intratumoral aneurysm is rare and epistaxis caused by rupture of it is extremely rare. Lack of bony protection apparently have contributed to the aneurysmal growth and rupture.


Solid-Phase Synthesis of Caged Luminescent Peptides via Side Chain Anchoring.
The synthesis of caged luminescent peptide substrates remains challenging, especially when libraries of the substrates are required. Most currently available synthetic methods rely on a solution-phase approach, which is less suited for parallel synthesis purposes. We herein present a solid-phase peptide synthesis (SPPS) method for the synthesis of caged aminoluciferin peptides via side chain anchoring of the P1 residue. After the synthesis of a preliminary test library consisting of 40 compounds, the synthetic method was validated and optimized for up to >100 g of resin. Subsequently, two separate larger peptide libraries were synthesized either having a P1 = lysine or arginine residue containing in total 719 novel peptide substrates. The use of a more stable caged nitrile precursor instead of caged aminoluciferin rendered our parallel synthetic approach completely suitable for SPPS and serine protease profiling was demonstrated using late-stage aminoluciferin generation.


Adaptation of the Texas Christian University Organisational Readiness for Change Short Form (TCU-ORC-SF) for use in primary health facilities in South Africa.
The Texas Christian University Organisational Readiness for Change Scale (TCU-ORC) assesses factors influencing adoption of evidence-based practices. It has not been validated in low-income and middle-income countries (LMIC). This study assessed its psychometric properties in a South African setting with the aim of adapting it into a shorter measure. This study was conducted in 24 South African primary healthcare clinics in the Western Cape Province. The TCU-ORC and two other measures, the Organisational Readiness to Change Assessment (ORCA) and the Checklist for Assessing Readiness for Implementation (CARI) were administered. The questionnaire was readministered after 2 weeks to obtain data on test-retest reliability. Three hundred and ninety-five surveys were completed: 281 participants completed the first survey, and 118 recompleted the assessments. We used exploratory factor analysis (EFA) to identify latent dimensions represented in the data. Cronbach's alpha for each subscale was assessed and we examined the extent to which the subscales and total scale scores for the first and retest surveys correlated. Convergent validity was assessed by the correlation coefficient between the TCU-ORC, ORCA and CARI total scale scores. EFA resulted in a three-factor solution. The three subscales proposed are Clinic Organisational Climate (8 items), Motivational Readiness for Change (13 items) and Individual Change Efficacy (5 items) (26 items total). Cronbach's alpha for each subscale was >0.80. The overall shortened scale had a test-retest correlation of r=0.80, p<0.01, acceptable convergent validity with the ORCA scale (r=0.56, p<0.05), moderate convergence with the CARI (r=39, p<0.05) and strong correlation with the original scale (r=0.79, p<0.05). This study presents the first psychometric data on the TCU-ORC from an LMIC. The proposed shortened tool may be more feasible for use in LMICs. Results stage. Project MIND trial. Pan-African Clinical Trials Registry. PACTR201610001825405.