Proximal ligand electron donation and reactivity of the cytochrome P450 ferric-peroxo anion.
CYP125 from Mycobacterium tuberculosis catalyzes sequential oxidation of the cholesterol side-chain terminal methyl group to the alcohol, aldehyde, and finally acid. Here, we demonstrate that CYP125 simultaneously catalyzes the formation of five other products, all of which result from deformylation of the sterol side chain. The aldehyde intermediate is shown to be the precursor of both the conventional acid metabolite and the five deformylation products. The acid arises by protonation of the ferric-peroxo anion species and formation of the ferryl-oxene species, also known as Compound I, followed by hydrogen abstraction and oxygen transfer. The deformylation products arise by addition of the same ferric-peroxo anion to the aldehyde intermediate to give a peroxyhemiacetal that leads to C-C bond cleavage. This bifurcation of the catalytic sequence has allowed us to examine the effect of electron donation by the proximal ligand on the properties of the ferric-peroxo anion. Replacement of the cysteine thiolate iron ligand by a selenocysteine results in UV-vis, EPR, and resonance Raman spectral changes indicative of an increased electron donation from the proximal selenolate ligand to the iron. Analysis of the product distribution in the reaction of the selenocysteine substituted enzyme reveals a gain in the formation of the acid (Compound I pathway) at the expense of deformylation products. These observations are consistent with an increase in the pK(a) of the ferric-peroxo anion, which favors its protonation and, therefore, Compound I formation.


Fe(III)-complexes of the tripodal trishydroxamate siderophore basidiochrome: potential biological implications.
One method of mobilization of iron by mycorrhizal organisms is through the secretion of small organic chelators called siderophores. Hydroxamate donor chelators are a common type of siderophore that is frequently used by fungal organisms. The primary siderophore that is produced by fungi from the genera Ceratobasidium and Rhizoctonia is the tripodal trishydroxamate siderophore basidiochrome. To gain some insight into the iron uptake mechanisms of these symbiotic fungi, the iron binding characteristics of basidiochrome were determined. It was found that basidiochrome exhibits a log β(110) of 27.8±0.1 and a pFe value of 25.0. These values are similar to those of another fungal trishydroxamate siderophore, ferrichrome. The similarity in iron affinity between the two siderophores suggests that the structure of the backbone has little influence in complex formation due to the length of the pendant arms, although the identity of the terminating groups of the pendant arms is likely related to complex stability. The role of basidiochrome in the biogeochemical cycling of iron is also discussed.


Stimulating myocardial regeneration with periostin Peptide in large mammals improves function post-myocardial infarction but increases myocardial fibrosis.
Mammalian myocardium has a finite but limited capacity to regenerate. Experimentally stimulating proliferation of cardiomyocytes with extracellular regeneration factors like periostin enhances cardiac repair in rodents. The aim of this study was to develop a safe method for delivering regeneration factors to the heart and to test the functional and structural effects of periostin peptide treatment in a large animal model of myocardial infarction (MI). We developed a controlled release system to deliver recombinant periostin peptide into the pericardial space. A single application of this method was performed two days after experimental MI in swine. Animals were randomly assigned to receive either saline or periostin peptide. Experimental groups were compared at baseline, day 2, 1 month and 3 months. Treatment with periostin peptide increased the EF from 31% to 41% and decreased by 22% the infarct size within 12 weeks. Periostin peptide-treated animals had newly formed myocardium strips within the infarct scar, leading to locally improved myocardial function. In addition the capillary density was increased in animals receiving periostin. However, periostin peptide treatment increased myocardial fibrosis in the remote region at one week and 12 weeks post-treatment. Our study shows that myocardial regeneration through targeted peptides is possible. However, in the case of periostin the effects on cardiac fibrosis may limit its clinical application as a viable therapeutic strategy.


Exosome mimetics: a novel class of drug delivery systems.
The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics.


Radiculopathy in the setting of lumbar nerve root compression due to an extradural intraforaminal lipoma: a report of 3 cases.
A true adult spinal lipoma is an exceedingly rare cause of lumbar compression neuropathy. Only 5 cases of true extradural intraforaminal lipomas have been documented in the medical literature. The diagnostic criteria and treatment guidelines for this specific lipoma have yet to be established. This report features 3 histologically confirmed cases of extradural intraforaminal spinal lipomas that recently presented to the authors' practice. In addition, the literature was surveyed to include the 5 previously reported cases of true adult extradural intraforaminal spinal lipomas. The consistency in presentation, response to surgical intervention, and postoperative recovery in these 8 cases supports surgical intervention at the time of diagnosis. The authors' findings support elevated clinical suspicion, efficient diagnosis based on MRI, and early surgical intervention for this rare pathological entity. All cases presented in this report were symptomatic and occurred in the absence of other significant pathologies such as general spinal epidural lipomatosis, intradural lesions, tethering, or severe degenerative stenosis or herniated discs. The clinical, neuroradiological, and histological findings characteristic of a true adult extradural intraforaminal lipoma are emphasized to differentiate this lesion from the more common etiologies for lumbar compression neuropathy. Heightened awareness and clinical suspicion for the focal, foraminal spinal lipoma as a cause of radiculopathy symptoms will enable more efficient diagnosis and treatment.


The ethics of grandfather clauses in healthcare resource allocation.
A grandfather clause is a provision whereby an old rule continues to apply to some existing situation while a new rule applies to all future cases. This paper focuses on the use of grandfather clauses in health technology appraisals (HTAs) issued by the National Institute for Health and Care Excellence (NICE) in the United Kingdom. NICE provides evidence-based guidance on healthcare technologies and public health interventions that influence resource allocation decisions in the National Health Service (NHS) and the broader public sector in England and Wales. In this context, a grandfather clause is included when NICE does not recommend treatment with a given technology. The grandfather clause provides an exemption from the general recommendation for patients who have already started treatment with the technology in question, before the publication of the NICE guidance. In this paper we first lay out the contexts in which grandfather clauses occur in NICE guidance, and then consider ethical arguments against and in support of grandfather clauses and the continuation of treatment. We argue that NICE's current practice of automatic inclusion of a grandfather clause is ethically problematic and unfair. While the inclusion of a grandfather clause may be appropriate and justified in specific cases, we argue that inclusion of such a clause should be considered as part and parcel of the decision making process on a case by case basis, rather than adopted as the default.


Immunoblotting characterization of neutrophil antigenic targets in autoimmune neutropenia.
We characterized neutrophil autoantigens using an immunoblotting technique with antibodies obtained from patients with autoimmune neutropenia. These results were correlated with serologic characterization of the antibodies, using indirect immunofluorescence and leukoagglutination. Of the 17 sera immunoblotted, 16 showed discrete bands in the molecular weight range of 30 to 112. Three patients with Felty's syndrome reacted with an antigenic target of 80 to 84 Kd molecular mass, a finding not seen in any of the other patients studied. By serologic testing, none of the autoimmune sera showed serologic specificity for any known neutrophil-specific alloantigen. Using an anti-NA-1 serum, we identified antigenic targets at 40, 50, and 101 Kd in both NA-1-positive and NA-1-negative neutrophils. Ten of 17 autoimmune sera showed reactivity in this corresponding range. These studies demonstrate that immunoblotting may be used to identify antigenic targets in autoimmune neutropenia and may suggest a specificity of these antibodies not definable by serologic techniques. Correlation of immunoblot reactivity with disease states associated with immune neutropenia may be useful in the study of the pathogenesis of the different forms of autoimmune neutropenia.


The plastic response to monocular deprivation persists in kitten visual cortex after chronic depletion of norepinephrine.
In order to clarify the role of norepinephrine (NE) in visual cortical plasticity, we monocularly deprived kittens that had received systemic injections of the neurotoxin 6-hydroxydopamine (6-OHDA) shortly after birth. We found, using high pressure liquid chromatography, that this means of drug treatment produces a permanent and substantial reduction in the level of cortical NE as compared with littermate controls. Nonetheless, single unit recording in area 17 of these kittens revealed no difference in the cortical response to monocular deprivation: both drug-treated and control kittens displayed large ocular dominance shifts to the open eye. Because local depletion of NE by intracortical 6-OHDA in kittens can prevent the expected ocular dominance shift after short-term monocular deprivation, we propose that neocortex has the capacity to compensate for chronic depletion of NE in a way which allows for the possibility of plastic changes.


A network analysis of post-traumatic stress and psychosis symptoms.
Understanding the interplay between trauma-related psychological mechanisms and psychotic symptoms may improve the effectiveness of interventions for post-traumatic stress reactions in psychosis. Network theory assumes that mental health problems persist not because of a common latent variable, but from dynamic feedback loops between symptoms, thereby addressing the heterogeneous and overlapping nature of traumagenic and psychotic diagnoses. This is a proof-of-concept study examining interactions between post-traumatic stress symptoms, which were hypothesized to reflect trauma-related psychological mechanisms, and auditory hallucinations and delusions. Baseline data from two randomised controlled trials (N = 216) of trauma-focused therapy in people with post-traumatic stress symptoms (87.5% met diagnostic criteria for PTSD) and psychotic disorder were analysed. Reexperiencing, hyperarousal, avoidance, trauma-related beliefs, auditory hallucinations and delusional beliefs were used to estimate a Gaussian graphical model along with expected node influence and predictability (proportion of explained variance). Trauma-related beliefs had the largest direct influence on the network and, together with hypervigilance, were implicated in the shortest paths from flashbacks to delusions and auditory hallucinations. These findings are in contrast to previous research suggesting a central role for re-experiencing, emotional numbing and interpersonal avoidance in psychosis. Trauma-related beliefs were the psychological mechanism most associated with psychotic symptoms, although not all relevant mechanisms were measured. This work demonstrates that investigating multiple putative mediators may clarify which processes are most relevant to trauma-related psychosis. Further research should use network modelling to investigate how the spectrum of traumatic stress reactions play a role in psychotic symptoms.


Anatomy of the lactating human breast redefined with ultrasound imaging.
The aim of this study was to use ultrasound imaging to re-investigate the anatomy of the lactating breast. The breasts of 21 fully lactating women (1-6 months post partum) were scanned using an ACUSON XP10 (5-10 MHz linear array probe). The number of main ducts was measured, ductal morphology was determined, and the distribution of glandular and adipose tissue was recorded. Milk ducts appeared as hypoechoic tubular structures with echogenic walls that often contained echoes. Ducts were easily compressed and did not display typical sinuses. All ducts branched within the areolar radius, the first branch occurring 8.0 +/- 5.5 mm from the nipple. Duct diameter was 1.9 +/- 0.6 mm, 2.0 +/- 90.7 mm and the number of main ducts was 9.6 +/- 2.9, 9.2 +/- 2.9, for left and right breast, respectively. Milk ducts are superficial, easily compressible and echoes within the duct represent fat globules in breastmilk. The low number and size of the ducts, the rapid branching under the areola and the absence of sinuses suggest that ducts transport breastmilk, rather than store it. The distribution of adipose and glandular tissue showed wide variation between women but not between breasts within women. The proportion of glandular and fat tissue and the number and size of ducts were not related to milk production. This study highlights inconsistencies in anatomical literature that impact on breast physiology, breastfeeding management and ultrasound assessment.


The high resolution structures of free and inhibitor-bound Trypanosoma rangeli sialidase and its comparison with T. cruzi trans-sialidase.
The structure of the recombinant Trypanosoma rangeli sialidase (TrSA) has been determined at 1.6A resolution, and the structures of its complexes with the transition state analog inhibitor 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid (DANA), Neu-5-Ac-thio-alpha(2,3)-galactoside (NATG) and N-acetylneuraminic acid (NANA) have been determined at 1.64A, 2.1A and 2.85A, respectively. The 3D structure of TrSA is essentially identical to that of the natural enzyme, except for the absence of covalently attached sugar at five distinct N-glycosylation sites. The protein exhibits a topologically rigid active site architecture that is unaffected by ligand binding. The overall binding of DANA to the active site cleft is similar to that observed for other viral and bacterial sialidases, dominated by the interactions of the inhibitor carboxylate with the conserved arginine triad. However, the interactions of the other pyranoside ring substituents (hydroxyl, N-acetyl and glycerol moieties) differ between trypanosomal, bacterial and viral sialidases, providing a structural basis for specific inhibitor design. Sialic acid is found to bind the enzyme with the sugar ring in a distorted (half-chair or boat) conformation and the 2-OH hydroxyl group at hydrogen bonding distance of the carboxylate of Asp60, substantiating a direct catalytic role for this residue. A detailed comparison of TrSA with the closely related structure of T.cruzi trans-sialidase (TcTS) reveals a highly conserved catalytic center, where subtle structural differences account for strikingly different enzymatic activities and inhibition properties. The structure of TrSA in complex with NATG shows the active site cleft occupied by a smaller compound which could be identified as DANA, probably the product of a hydrolytic side reaction. Indeed, TrSA (but not TcTS) was found to cleave O and S-linked sialylated substrates, further stressing the functional differences between trypanosomal sialidases and trans-sialidases.


Exploring the relationships among early maladaptive schemas, psychological mindedness and self-reported college adjustment.
The primary aim of this research was to study the statistical effects of psychological mindedness (PM) upon the relationship between early maladaptive schemas (EMS) and self-reported college adjustment. A cross-sectional design was employed to assess correlations among study variables and to assess the role of PM as moderator or mediator in the relationship between EMS and adjustment. Into this study, 264 undergraduate students were recruited in partial fulfilment of research requirements in introductory psychology class. Participants completed the Young Schema Questionnaire, the Psychological Mindedness Scale and the Student Adaptation to College Questionnaire. At the level of bivariate correlations, EMS were inversely associated with college adjustment and with PM, and PM was positively associated with adjustment. In a multiple regression equation with PM and EMS entered separately and then as an interaction term as predictors of adjustment, PM was not a significant moderator. However, in a path analysis, the indirect effect of EMS on adjustment through PM was significant, suggesting that PM is a significant mediator. These findings suggest that the assessment of EMS and PM may enhance an understanding of problems with college adjustment and that interventions to reduce the negative effects of EMS may indeed benefit from efforts to improve PM and its correlates.


Transfer learning identifies sequence determinants of cell-type specific regulatory element accessibility.
Dysfunction of regulatory elements through genetic variants is a central mechanism in the pathogenesis of disease. To better understand disease etiology, there is consequently a need to understand how DNA encodes regulatory activity. Deep learning methods show great promise for modeling of biomolecular data from DNA sequence but are limited to large input data for training. Here, we develop ChromTransfer, a transfer learning method that uses a pre-trained, cell-type agnostic model of open chromatin regions as a basis for fine-tuning on regulatory sequences. We demonstrate superior performances with ChromTransfer for learning cell-type specific chromatin accessibility from sequence compared to models not informed by a pre-trained model. Importantly, ChromTransfer enables fine-tuning on small input data with minimal decrease in accuracy. We show that ChromTransfer uses sequence features matching binding site sequences of key transcription factors for prediction. Together, these results demonstrate ChromTransfer as a promising tool for learning the regulatory code.


A Computerized Family Planning Counseling Aid: A Pilot Study Evaluation of Smart Choices.
Resource constraints may make it challenging for family planning clinics to provide comprehensive contraceptive counseling; technological tools that help providers follow recommended practices without straining resources merit evaluation. A pilot study using a two-group, posttest-only experimental design evaluated Smart Choices, a computer-based tool designed to help providers offer more patient-centered counseling and enable patients to participate proactively in the counseling session. In two North Carolina family planning clinics, 214 women received usual counseling in March-May 2013, and 126 women used Smart Choices in May-July 2013. Exit interviews provided data for the evaluation. Multivariate Poisson and multinomial logistic regression analyses were performed to examine group differences in counseling outcomes. Three of 12 hypotheses tested were supported: Compared with controls, women in the intervention group knew more contraceptive methods (adjusted mean, 11.1 vs. 10.7); discussed more topics related to sexual health during counseling (1.2 vs. 0.9 among those reporting any discussion); and rated counseling as more patient-centered, an indication of how well they felt providers understood their family planning circumstances and ideas (3.9 vs. 3.7 on a scale of 1-4). Contrary to another hypothesis, controls were more likely than women in the intervention group to choose IUDs and implants. Computerized counseling aids like Smart Choices are in an early stage of development. Future research is warranted to develop tools that lead to more productive and individualized clinic visits and, ultimately, to more effective contraceptive use and reduced levels of unintended pregnancy.


Efficacy and tolerability of potato juice in dyspeptic patients: a pilot study.
In Europe, use of potatoes (Solani tuberosi tuberecens) is a traditional remedy for stomach complaints. We performed a pilot study on the effectiveness and tolerability of freshly squeezed potato juice in patients suffering from dyspeptic symptoms. After informed written consent, 44 patients with various dyspeptic symptoms were enrolled, to drink for 1 week twice daily 100ml or more of potato juice (Biotta, if complaints persisted, a further 100ml was recommended. Validated outcome measures included the gastrointestinal symptom (GIS) profile, a disease-specific health assessment questionnaire (QOLRAD) and self-rated treatment success (efficacy, a 5-point Likert Scale). The study was completed by 42 patients. The GIS and QOLRAD scores improved significantly by 41.9+/-40.8% (p=0.001) and 50.7+/-36.1% (p<0.001), respectively (ITT); the absolute values changed from 11.5+/-5.1 to 6.3+/-5.3 (GIS) and 62.0+/-25.7 to 32.0+/-28.8 (QORAD). Sixteen, 18 and 26 patients, respectively, rated the effectiveness of the treatment as very good or good on the GIS, QOLRAD (improvements >60%) and on efficacy, respectively. Poor treatment success was achieved in 13 (GIS), 11 (QOLRAD) and 10 (Efficacy), not necessarily by the same patients. Since about two-thirds of the patients benefited to some extent from the treatment, potato juice in its present formulation may be useful for self-treatment. However, placebo-controlled studies with a longer treatment period are needed to confirm this.


B12 deficiency increases with age in hospitalized patients: a study on 14,904 samples.
Cobalamin deficiency is responsible for hematological, neurological, neurocognitive, and neuropsychiatric impairments and is a risk factor for cardiovascular diseases, particularly in the elderly people. In order to determine B12 status in old inpatients, a total number of 14,904 hospitalized patients in whom B12 measurements were performed in five hospitals in the Paris metropolitan area were included from January 1, 2011 to December 31, 2011. The aims of the study were to determine whether age had an impact on B12 and folate deficiencies and to evaluate correlations between B12 and biological parameters-folate, hemoglobin, mean cell volume, homocystein (tHcy)-and age. Patients were aged 70.3±19.5 years. Low B12 concentration (<200ng/L) was observed in 4.6% of cases, 24.2% had middle B12 concentration (200-350ng/L), 12.6% were functional B12 deficient (B12 < 350 ng/L associated to high tHcy level, tHcy > 17 µmol/L), 20.4% had low folate concentration (folate < 4 µg/L), 10.6% were functional folate deficient (folate < 4 µg/L associated to tHcy > 17 µmol/L), and 4.7% of patients were both functional B12 and folate deficient. The B12 or folate deficient patients had lower mean cell volume level than nondeficient patients. Increase in mean cell volume and tHcy concentrations with age and decrease in B12, folate, and hemoglobin levels with age were observed. Frequency of functional B12 deficiency was 9.6% in patients aged 30-60 years and 14.2% in patients over 90 years. Frequency of functional folate deficiency was 9.5% in 30-60 years and 12.1% in >90 years. In inpatients, functional B12 deficiency and functional folate deficiency increase with age and are not associated with anemia or macrocytosis. False vitamin B deficiencies are frequent.


An Infinite Restricted Boltzmann Machine.
We present a mathematical construction for the restricted Boltzmann machine (RBM) that does not require specifying the number of hidden units. In fact, the hidden layer size is adaptive and can grow during training. This is obtained by first extending the RBM to be sensitive to the ordering of its hidden units. Then, with a carefully chosen definition of the energy function, we show that the limit of infinitely many hidden units is well defined. As with RBM, approximate maximum likelihood training can be performed, resulting in an algorithm that naturally and adaptively adds trained hidden units during learning. We empirically study the behavior of this infinite RBM, showing that its performance is competitive to that of the RBM, while not requiring the tuning of a hidden layer size.


Alcohol consumption and workplace absenteeism: the moderating effect of social support.
Although it is commonly assumed that alcohol consumption has a significant impact on employee absenteeism, the nature of the alcohol-absence relationship remains poorly understood. Proposing that alcohol impairment likely serves as a key mechanism linking drinking and work absence, we posit that this relationship is likely governed less by the amount of alcohol consumed and more by the way it is consumed. Using a prospective study design and a random sample of urban transit workers, we found that the frequency of heavy episodic drinking over the previous month is positively associated with the number of days of absence recorded in the subsequent 12-month period, whereas modal consumption (a metric capturing the typical amount of alcohol consumed in a given period of time) is not. In addition, consistent with both volitional treatments of absenteeism and social exchange theory, perceived coworker support was found to attenuate, and supervisory support to amplify, the link between the frequency of heavy episodic drinking and absenteeism.


No effect of preterm birth on the risk of multiple sclerosis: a population based study.
Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear parent of origin effect has been shown in several populations, perhaps resulting from factors operating during gestation. Preterm birth (birth at less than 37 weeks gestational age) has been shown to result in long-term health problems, including impaired neurological development. Here, in a population-based cohort, we investigate whether preterm birth increases the risk to subsequently develop MS. We identified 6585 MS index cases and 2509 spousal controls with preterm birth information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Rates of individuals born preterm were compared for index cases and controls. There were no significant differences between cases and controls with respect to preterm births. 370 (5.6%) MS index cases and 130 (5.2%) spousal controls were born preterm, p = 0.41. Preterm birth does not appear to contribute to MS aetiology. Other factors involved in foetal and early development need to be explored to elucidate the mechanism of the increased risk conferred by the apparent maternal effect.


Mouse mutants from chemically mutagenized embryonic stem cells.
The drive to characterize functions of human genes on a global scale has stimulated interest in large-scale generation of mouse mutants. Conventional germ-cell mutagenesis with N-ethyl-N-nitrosourea (ENU) is compromised by an inability to monitor mutation efficiency, strain and interlocus variation in mutation induction, and extensive husbandry requirements. To overcome these obstacles and develop new methods for generating mouse mutants, we devised protocols to generate germline chimaeric mice from embryonic stem (ES) cells heavily mutagenized with ethylmethanesulphonate (EMS). Germline chimaeras were derived from cultures that underwent a mutation rate of up to 1 in 1,200 at the Hprt locus (encoding hypoxanthine guanine phosphoribosyl transferase). The spectrum of mutations induced by EMS and the frameshift mutagen ICR191 was consistent with that observed in other mammalian cells. Chimaeras derived from ES cells treated with EMS transmitted mutations affecting several processes, including limb development, hair growth, hearing and gametogenesis. This technology affords several advantages over traditional mutagenesis, including the ability to conduct shortened breeding schemes and to screen for mutant phenotypes directly in ES cells or their differentiated derivatives.


Evaluation of Oxygenation in 129 Proning Sessions in 34 Mechanically Ventilated COVID-19 Patients.
A minority of patients with Severe Acutre Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) disease-2019 (Covid-19) develop pulmonary features consistent with the Acute Respiratory Distress Syndrome (ARDS). Prone positioning (PP) is an intervention with proven survival benefits in moderate-to-severe and severe ARDS. It is advocated in international guidelines as an intervention in mechanically ventilated Covid-19 patients, despite very few published trials investigating its efficacy in Covid-19. There is an ongoing debate regarding the prevalence of reported mismatches between the severity of hypoxaemia and the preservation of pulmonary compliance in some patients, in the early stages of SARS-CoV-2 infection. This has led some to question its utility within this context. 129 proning sessions were identified in 34 consecutively prone patients admitted to the intensive care unit at a single center in the United Kingdom. Baseline characteristics of patients were consistent with previously published national and international reports and patients were ventilated in general concordance with the ARDSnet ventilation protocol. Paired analysis of the partial pressure of arterial oxygen(PaO2): fraction of inspired oxygen(FiO2) ratio (PF ratio) (n = 89) and FiO2 (n = 129) was recorded within 3 hours of both the initiation and termination of PP and differences were assessed with the paired Student's t-test and Wilcoxon Signed-Rank test. Proning improved the PF ratio by 43.5 ± 54.9 from 99.8 ± 37.5 to 151.9 ± 58.9 (43.6% increase) [p < 0.0001] and reduced FiO2 by 0.17 ± 0.2 from 0.68 ± 0.2 to 0.51 ± 0.2 (25% decrease) [p < 0.0001]. 82% of proning maneouveres resulted in an improvement in the PF ratio. In summary, PP improved arterial oxygenation and reduced oxygen requirements in most Covid-19 patients in this single- center, retrospective analysis.


Biomechanical comparison of 3 suture anchor configurations for repair of type II SLAP lesions.
Our purpose was to compare 3 commonly used suture anchor configurations for repair of type II SLAP lesions. Biomechanical testing was performed on 3 groups of 7 cadaveric shoulders by use of an optical linear strain measurement system. Standardized type II SLAP lesions were created and repaired via 3 suture anchor configurations: (1) a single simple suture anterior to the biceps; (2) two simple sutures, one anterior and one posterior to the biceps; and (3) a single mattress suture through the biceps anchor. Cyclic traction was applied to the biceps tendon, and strain failure (defined as 2 mm of permanent displacement), yield, and pullout loads were measured. The mean load to strain failure was 63 N in group 1, 70 N in group 2, and 106 N in group 3. The mean load to ultimate failure was 140 N in group 1, 194 N in group 2, and 194 N in group 3. Strain failure load was significantly higher in the mattress suture group than in either of the other two groups (P < .05). Groups 2 and 3 both had a significantly higher load to ultimate failure than group 1. When type II SLAP lesions were subjected to cyclic traction, the load to strain failure was greater with a single anchor and mattress suture than with one or two anchors with simple sutures around the labrum. Fixation with two simple sutures appears to provide intermediate load to strain failure. The results of this study suggest that a single anchor with a mattress suture may be a biomechanically advantageous construct for the repair of type II SLAP lesions.


The Hiroshima thermal-neutron discrepancy for (36)Cl at large distances. Part I: New (36)Cl measurements in granite samples exposed to A-bomb neutrons.
The long-lived radioisotope (36)Cl (half-life: 301,000 years) was measured in granite samples exposed to A-bomb neutrons at distances from 94 to 1,591 m from the hypocenter in Hiroshima, by means of accelerator mass spectrometry (AMS). Measured (36)Cl/Cl ratios decrease from 1.6 x 10(-10) close to the hypocenter to about 1-2 x 10(-13), at a distance of 1,300 m from the hypocenter. At this distance and beyond the measured (36)Cl/Cl ratios do not change significantly and scatter around values of 1-2 x 10(-13). These findings suggest that the (36)Cl had been predominantly produced by thermalized neutrons from the A-bomb via neutron capture on stable (35)Cl, at distances from the hypocenter smaller than about 1,200 m. At larger distances, however, confounding processes induced by cosmic rays or neutrons from the decay of uranium and thorium become important. This hypothesis is theoretically and experimentally supported in a consecutive paper. The results are compared to calculations that are based on the most recent dosimetry system DS02. Close to the hypocenter, measured (36)Cl/Cl ratios are lower than those calculated, while they are significantly higher at large distances from the hypocenter. If the contribution of the cosmic rays and of the neutrons from the decay of uranium and thorium in the sample was subtracted, however, no significant deviation from the DS02 calculations was observed, at those distances. Thus, the Hiroshima neutron discrepancy reported in the literature for (36)Cl for samples from large distances from the hypocenter, i.e., higher measured (36)Cl/Cl ratios than predicted by the previous dosimetry system DS86, was not confirmed.


Exercise effects on bone mineral density in older adults: a meta-analysis of randomized controlled trials.
The purpose of the study was to assess the effects of exercise interventions with different impact loading characteristics on lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) in older adults. We searched electronic databases and hand searched selected journals up to February 2011 for randomized controlled trials (RCTs) investigating the effects of impact exercise interventions on LS and FN BMD in older adults. Exercise protocols were categorized according to impact loading characteristics. Weighted mean difference (WMD) meta-analyses were undertaken. Heterogeneity amongst trials and publication bias was tested. Random-effects models were applied. Trial quality assessment was also undertaken. Nineteen RCTs, including 1577 subjects, met the inclusion criteria. Twenty-two study group comparisons reported BMD data at the LS. Meta-analysis showed a significant change in BMD at this site (WMD 0.011 g/cm(2), 95% CI 0.003 to 0.020; p = 0.007), although results were moderately inconsistent (I(2) = 52.2%). BMD data at the FN were available from 19 study group comparisons among older adults. Results were inconsistent (I(2) = 63.6%) in showing a significant positive effect of exercise on BMD at this site (WMD 0.016 g/cm(2), 95% CI 0.005 to 0.027; p = 0.004). Combined loading studies of impact activity mixed with high-magnitude joint reaction force loading through resistance training were effective at LS (WMD 0.016 g/cm(2), 95% CI 0.002 to 0.036; p = 0.028), and no inconsistency existed among these trials. Odd-impact protocols were also effective in increasing BMD at LS (WMD 0.039 g/cm(2), 95% CI 0.002 to 0.075; p = 0.038) and FN (WMD 0.036 g/cm(2), 95% CI 0.012 to 0.061; p = 0.004), although heterogeneity was evident (I(2) = 87.5% and I(2) = 83.5%, respectively). We found consistency among results for low-impact and resistance exercise studies on LS and FN, although non-significant BMD changes were evident amongst these types of protocols at any site and amongst the RCTs that provided a combined loading impact exercise at FN. Funnel plots showed no evidence of publication bias. Trial quality was moderate to high. The findings from our meta-analysis of RCTs support the efficacy of exercise for increasing LS and FN BMD in older adults.


A linkage map of mouse chromosome 12: localization of Igh and effects of sex and interference on recombination.
Inheritance of restriction fragment length polymorphisms associated with four anonymous DNA markers (D12Nyu1, 2, 3 and 4), the Fos proto-oncogene, the Mtv-9 viral integration site, and the alpha 1-antitrypsin (Aat-1) and immunoglobulin heavy chain (Igh) gene families in the mouse has been followed in a backcross experiment. A Bayesian multilocus map-building strategy yielded the map: centromere-D12Nyu2-10 cM-D12Nyu1-2 cM-D12Nyu3-15 cM-Fos-1 cM-D12Nyu4-2 cM-Mtv-9-8 cM-Aat-1-17 cM-Igh-C. A map constructed from male meiotic data was substantially shorter than one constructed from female meiotic data. Significant interference was observed for the linkage group. Two groups of markers studied in recombinant inbred strains of mice could be interpolated into the map: Es-25, D12Nyu10, D12Nyu7 and Apob form a cluster proximal to D12Nyu2, and Ly-18, Ah, and D12Nyu5 form a cluster between D12Nyu2 and D12Nyu1. These data establish an unambiguously ordered linkage group including Igh and Aat-1 that spans most of chromosome 12.


Novel lineage depletion preserves autologous blood stem cells for gene therapy of Fanconi anemia complementation group A.
A hallmark of Fanconi anemia is accelerated decline in hematopoietic stem and progenitor cells (CD34 +) leading to bone marrow failure. Long-term treatment requires hematopoietic cell transplantation from an unaffected donor but is associated with potentially severe side-effects. Gene therapy to correct the genetic defect in the patient's own CD34+ cells has been limited by low CD34+ cell numbers and viability. Here we demonstrate an altered ratio of CD34Hi to CD34Lo cells in Fanconi patients relative to healthy donors, with exclusive in vitro repopulating ability in only CD34Hi cells, underscoring a need for novel strategies to preserve limited CD34+ cells. To address this need, we developed a clinical protocol to deplete lineage+(CD3+, CD14+, CD16+ and CD19+) cells from blood and marrow products. This process depletes >90% of lineage+cells while retaining ≥60% of the initial CD34+cell fraction, reduces total nucleated cells by 1-2 logs, and maintains transduction efficiency and cell viability following gene transfer. Importantly, transduced lineage- cell products engrafted equivalently to that of purified CD34+ cells from the same donor when xenotransplanted at matched CD34+ cell doses. This novel selection strategy has been approved by the regulatory agencies in a gene therapy study for Fanconi anemia patients (NCI Clinical Trial Reporting Program Registry ID NCI-2011-00202; clinicaltrials.gov identifier: 01331018).


The Brn-2 transcription factor links activated BRAF to melanoma proliferation.
Malignant melanoma, an aggressive and increasingly common cancer, is characterized by a strikingly high rate (70%) of mutations in BRAF, a key component of the mitogen-activated protein (MAP) kinase signaling pathway. How signaling events downstream from BRAF affect the underlying program of gene expression is poorly understood. We show that the Brn-2 POU domain transcription factor is highly expressed in melanoma cell lines but not in melanocytes or melanoblasts and that overexpression of Brn-2 in melanocytes results in increased proliferation. Expression of Brn-2 is strongly upregulated by Ras and MAP kinase signaling. Importantly, the Brn-2 promoter is stimulated by kinase-activating BRAF mutants and endogenous Brn-2 expression is inhibited by RNA interference-mediated downregulation of BRAF. Moreover, silent interfering RNA-mediated depletion of Brn-2 in melanoma cells expressing activated BRAF leads to decreased proliferation. The results suggest that the high levels of Brn-2 expression observed in melanomas link BRAF signaling to increased proliferation.


The health of homeless people in high-income countries: descriptive epidemiology, health consequences, and clinical and policy recommendations.
In the European Union, more than 400,000 individuals are homeless on any one night and more than 600,000 are homeless in the USA. The causes of homelessness are an interaction between individual and structural factors. Individual factors include poverty, family problems, and mental health and substance misuse problems. The availability of low-cost housing is thought to be the most important structural determinant for homelessness. Homeless people have higher rates of premature mortality than the rest of the population, especially from suicide and unintentional injuries, and an increased prevalence of a range of infectious diseases, mental disorders, and substance misuse. High rates of non-communicable diseases have also been described with evidence of accelerated ageing. Although engagement with health services and adherence to treatments is often compromised, homeless people typically attend the emergency department more often than non-homeless people. We discuss several recommendations to improve the surveillance of morbidity and mortality in homeless people. Programmes focused on high-risk groups, such as individuals leaving prisons, psychiatric hospitals, and the child welfare system, and the introduction of national and state-wide plans that target homeless people are likely to improve outcomes.


Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization.
In the insulin-secreting beta-cell line beta TC3, stimulation with 11.2 mmol/l glucose caused a rise in the intracellular free Ca2+ concentration ([Ca2+]i) in only 18% of the tested cells. The number of glucose-responsive cells increased after pretreatment of the cells with glucagon-like peptide I (GLP-I)(7-36)amide and at 10(-11) mol/l; 84% of the cells responded to glucose with a rise in [Ca2+]i. GLP-I(7-36)amide induces a rapid increase in [Ca2+]i only in cells exposed to elevated glucose concentrations (> or = 5.6 mmol/l). The action of GLP-I(7-36)amide and forskolin involved a 10-fold increase in cytoplasmic cAMP concentration and was mediated by activation of protein kinase A. It was not associated with an effect on the membrane potential but required some (small) initial entry of Ca2+ through voltage-dependent L-type Ca2+ channels, which then produced a further increase in [Ca2+]i by mobilization from intracellular stores. The latter effect reflected Ca(2+)-induced Ca2+ release and was blocked by ryanodine. Similar increases in [Ca2+]i were also observed in voltage-clamped cells, although there was neither activation of a background (Ca(2+)-permeable) inward current nor enhancement of the voltage-dependent L-type Ca2+ current. These observations are consistent with GLP-I(7-36) amide inducing glucose sensitivity by promoting mobilization of Ca2+ from intracellular stores. We propose that this novel action of GLP-I(7-36)amide represents an important factor contributing to its insulinotropic action.


Herbal drug quality and phytochemical composition of Hypericum perforatum L. affected by ash yellows phytoplasma infection.
Qualitative/quantitative phytochemical variations were observed in dried flowering tops of cultivated Hypericum perforatum L. cv. Zorzi infected by phytoplasmas of the "ash yellows" class, identified by direct and nested polymerase chain reaction (PCR); this is the first report of ribosomial group 16SrVII phytoplasmas in St. John's Wort. Methanolic extracts of healthy and infected plants were separated by reversed phase high-performance liquid chromatography to quantify naphthodianthrones and flavonoids, while essential oils were analyzed by means of gas chromatography (GC)-GC/MS. The affected plants exhibited decreased amounts of rutin (1.96 +/- 0.23 vs 4.96 +/- 0.02 mg/g), hyperoside (2.38 +/- 0.21 vs 3.04 +/- 0.05 mg/g), isoquercitrin (1.47 +/- 0.04 vs 3.50 +/- 0.08 mg/g), amentoflavone (0.12 +/- 0.01 vs 0.39 +/- 0.02 mg/g), and pseudohypericin (1.41 +/- 0.23 vs 2.29 +/- 0.07 mg/g), whereas the chlorogenic acid content was doubled (1.56 +/- 0.11 vs 0.77 +/- 0.02 mg/g). Hypericin, quercitrin, and quercetin contents were not severely affected. The essential oil yield was drastically reduced in infected material (0.11 vs 0.75% in healthy material) and revealed an increased abundance of sesquiterpenes (beta-caryophyllene, delta-elemene, and germacrene D, in particular) and a matching decrease in monoterpene hydrocarbons and aliphatics. The consequences that the phytopathological condition of cultivated H. perforatum plants has on the commercial quality, market value, and therapeutic efficacy are outlined.


The prediction of suicide in severe mental illness: development and validation of a clinical prediction rule (OxMIS).
Assessment of suicide risk in individuals with severe mental illness is currently inconsistent, and based on clinical decision-making with or without tools developed for other purposes. We aimed to develop and validate a predictive model for suicide using data from linked population-based registers in individuals with severe mental illness. A national cohort of 75,158 Swedish individuals aged 15-65 with a diagnosis of severe mental illness (schizophrenia-spectrum disorders, and bipolar disorder) with 574,018 clinical patient episodes between 2001 and 2008, split into development (58,771 patients, 494 suicides) and external validation (16,387 patients, 139 suicides) samples. A multivariable derivation model was developed to determine the strength of pre-specified routinely collected socio-demographic and clinical risk factors, and then tested in external validation. We measured discrimination and calibration for prediction of suicide at 1 year using specified risk cut-offs. A 17-item clinical risk prediction model for suicide was developed and showed moderately good measures of discrimination (c-index 0.71) and calibration. For risk of suicide at 1 year, using a pre-specified 1% cut-off, sensitivity was 55% (95% confidence interval [CI] 47-63%) and specificity was 75% (95% CI 74-75%). Positive and negative predictive values were 2% and 99%, respectively. The model was used to generate a simple freely available web-based probability-based risk calculator (Oxford Mental Illness and Suicide tool or OxMIS) without categorical cut-offs. A scalable prediction score for suicide in individuals with severe mental illness is feasible. If validated in other samples and linked to effective interventions, using a probability score may assist clinical decision-making.


Children with chronic suppurative lung disease have a reduced capacity to synthesize interferon-gamma in vitro in response to non-typeable Haemophilus influenzae.
Chronic suppurative lung disease (CSLD) is characterized by the presence of a chronic wet or productive cough and recurrent lower respiratory infections. The aim of this study was to identify features of innate, cell-mediated and humoral immunity that may increase susceptibility to respiratory infections in children with CSLD. Because non-typeable Haemophilus influenzae (NTHi) is commonly isolated from the airways in CSLD, we examined immune responses to this organism in 80 age-stratified children with CSLD and compared their responses with 51 healthy control children. Cytokines involved in the generation and control of inflammation (IFN-γ, IL-13, IL-5, IL-10 at 72 hours and TNFα, IL-6, IL-10 at 24 hours) were measured in peripheral blood mononuclear cells challenged in vitro with live NTHi. We also measured circulating IgG subclass antibodies (IgG1 and IgG4) to two H. influenzae outer membrane proteins, P4 and P6. The most notable finding was that PBMC from children with CSLD produced significantly less IFN-γ in response to NTHi than healthy control children whereas mitogen-induced IFN-γ production was similar in both groups. Overall there were minor differences in innate and humoral immune responses between CSLD and control children. This study demonstrates that children with chronic suppurative lung disease have an altered systemic cell-mediated immune response to NTHi in vitro. This deficient IFN-γ response may contribute to increased susceptibility to NTHi infections and the pathogenesis of CSLD in children.


Associations between health-related quality of life and financial barriers to care among women veterans and women non-veterans.
The authors of this study examined the association between health-related quality of life and financial barriers to care, defined as not getting the needed care due to cost considerations. To better understand health-related quality of life among women veterans, the authors compared women veterans to women non-veterans. The authors conducted cross-sectional analyses using data from the 2009 Behavioral Risk Factor Surveillance System survey. The authors assessed four health-related quality of life measures: (1) general health; (2) physical health; (3) mental health; and (4) functional status. The authors performed multinomial logistic regressions to examine the relationship between financial barriers to receiving healthcare and health-related quality of life measures after controlling for other independent variables. The authors included women veterans not in active military duty (N = 3,747) and a matched sample of women non-veterans (N = 3,747), selected using a propensity score method so that they would have distributions of demographic and socioeconomic characteristics similar to those of the veterans. Overall, 14% of women reported financial barriers. Women who reported financial barriers to receiving healthcare were more likely to have poor health-related quality of life in all four dimensions than those who did not report such barriers. Compared to women non-veterans, women veterans did not differ in reported financial barriers but were more likely to report poor health-related quality of life. Reporting financial barriers to receiving needed healthcare was significantly associated with poor health-related quality of life among women. Veteran status was also significantly associated with poor health-related quality of life. These findings suggest the need for healthcare policy makers and practitioners to align emerging new models of healthcare delivery to improve health-related quality of life for women veterans.


Graphite, graphene on SiC, and graphene nanoribbons: Calculated images with a numerical FM-AFM.
Characterization at the atomic scale is becoming an achievable task for FM-AFM users equipped, for example, with a qPlus sensor. Nevertheless, calculations are necessary to fully interpret experimental images in some specific cases. In this context, we developed a numerical AFM (n-AFM) able to be used in different modes and under different usage conditions. Here, we tackled FM-AFM image calculations of three types of graphitic structures, namely a graphite surface, a graphene sheet on a silicon carbide substrate with a Si-terminated surface, and finally, a graphene nanoribbon. We compared static structures, meaning that all the tip and sample atoms are kept frozen in their equilibrium position, with dynamic systems, obtained with a molecular dynamics module allowing all the atoms to move freely during the probe oscillations. We found a very good agreement with experimental graphite and graphene images. The imaging process for the deposited nanoribbon demonstrates the stability of our n-AFM to image a non-perfectly planar substrate exhibiting a geometrical step as well as a material step.


Guide Me in Analysis: A Framework for Guidance Designers.
Guidance is an emerging topic in the field of visual analytics. Guidance can support users in pursuing their analytical goals more efficiently and help in making the analysis successful. However, it is not clear how guidance approaches should be designed and what specific factors should be considered for effective support. In this paper, we approach this problem from the perspective of guidance designers. We present a framework comprising requirements and a set of specific phases designers should go through when designing guidance for visual analytics. We relate this process with a set of quality criteria we aim to support with our framework, that are necessary for obtaining a suitable and effective guidance solution. To demonstrate the practical usability of our methodology, we apply our framework to the design of guidance in three analysis scenarios and a design walk-through session. Moreover, we list the emerging challenges and report how the framework can be used to design guidance solutions that mitigate these issues.


Responses of bark beetle-associated bacteria to host monoterpenes and their relationship to insect life histories.
Bark beetles that colonize living conifers and their microbial associates encounter constitutive and induced chemical defenses of their host. Monoterpene hydrocarbons comprise a major component of these allelochemicals, and many are antibiotic to insects, fungi, and bacteria. Some bark beetle species exhaust these defenses by killing their host through mass attacks mediated by aggregation pheromones. Others lack adult aggregation pheromones and do not engage in pheromone-mediated mass attacks, but rather have the ability to complete development within live hosts. In the former species, the larvae develop in tissue largely depleted of host terpenes, whereas in the latter exposure to these compounds persists throughout development. A substantial literature exists on how monoterpenes affect bark beetles and their associated fungi, but little is known of how they affect bacteria, which in turn can influence beetle performance in various manners. We tested several bacteria from two bark beetle species for their ability to grow in the presence of a diversity of host monoterpenes. Bacteria were isolated from the mountain pine beetle, Dendroctonus ponderosae Hopkins, which typically kills trees during colonization, and the red turpentine beetle, Dendroctonus valens LeConte, which often lives in their host without causing mortality. Bacteria from D. ponderosae were gram-positive Actinobacteria and Bacilli; one yeast also was tested. Bacteria from D. valens were Actinobacteria, Bacilli, and γ-Proteobacteria. Bacteria from D. valens were more tolerant of monoterpenes than were those from D. ponderosae. Bacteria from D. ponderosae did not grow in the presence of α-pinene and 3-carene, and grew in, but were inhibited by, β-pinene and β-phellandrene. Limonene and myrcene had little inhibitory effect on bacteria from either beetle species. Tolerance to these antibiotic compounds appears to have resulted from adaptation to living in a terpene-rich environment.


Longevity-related molecular pathways are subject to midlife "switch" in humans.
Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear "signature" was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF-1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the "pro-longevity" direction. Quantitative network modeling demonstrated that age-regulated ncRNA equaled the contribution of protein-coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with "neuron apoptotic processes" in protein-protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age-related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome-wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.


Interchromosomal duplication of major histocompatibility complex class I regions in rainbow trout (Oncorhynchus mykiss), a species with a presumably recent tetraploid ancestry.
Salmonid fishes are among the few animal taxa with a probable recent tetraploid ancestor. The present study is the first to compare large (>100 kb) duplicated genomic sequence fragments in such species. Two contiguous stretches with major histocompatibility complex (MHC) class I genes were detected in a rainbow trout BAC library, mapped and sequenced. The MHC class I duplicated regions, mapped by fluorescence in situ hybridization (FISH), were shown to be located on different metaphase chromosomes, Chr 14 and 18. Gene organization in both duplications is similar to that in other fishes, in that the class I loci are tightly linked with the PSMB8, PSMB9, PSMB10 and ABCB3 genes. Whereas one region, Onmy-IA, has a classical MHC class I locus (UBA), Onmy-IB encodes only non-classical class Ib proteins. The nucleotide diversity between the Onmy-IA and Onmy-IB noncoding regions is about 14%. This suggests that the MHC class I duplication event has occurred about 60 mya close to the time of an hypothesized ancestral tetraploid event. The present article is the first convincing report on the co-existence of two closely related MHC class I core regions on two different chromosomes. The interchromosomal duplication and the homology levels are supportive of the tetraploid model.


Update on oral appliance therapy.
Oral appliances are increasingly recommended for selected patients with obstructive sleep apnoea (OSA) and those who do not tolerate nor prefer continuous positive airway pressure. The most commonly used oral appliance advances the lower jaw during sleep, the so-called mandibular advancement device (MAD). Patients seek treatment because of disturbing snoring, daytime symptoms, apnoeas that disturb sleep and the longer term consequences with regard to cardiovascular risks. MADs reduce the apnoea-hypopnoea index, although to various degrees among patients. Effects on daytime sleepiness have been observed mainly among the more severe OSA patients. Blood pressure may be reduced in MAD-treated OSA patients. There is, however, uncertainty about which patients will respond to this therapy in terms of apnoea reductions, decreased sleepiness and other symptoms, and reduced risk for future impaired health. The occurrence of side-effects also remains difficult to predict at present. The majority of sleep apnoea patients suffer from various comorbidities in terms of cardiovascular diseases, type 2 diabetes and depression. The most recent findings indicate that phenotyping of patients, considering various aspects of this multifaceted disease, will shed more light on the indications for MADs in patients with nightly sleep breathing disturbances. This review summarises the most recent knowledge about MAD treatment.


Employing an extended Theory of Planned Behaviour to predict breastfeeding intention, initiation, and maintenance in White British and South-Asian mothers living in Bradford.
Despite reported differences in breastfeeding rates amongst women of different ethnic groups, little research has investigated whether the thoughts and feelings (social cognitions) of women from these different groups during pregnancy influence their later breastfeeding behaviour. This study investigates the extent to which social cognitions (based on the Theory of Planned Behaviour; TPB) predict differences in breastfeeding intentions, initiation, and maintenance between White British (WB) and South Asian (SA) women. Two hundred and fifty women (predominantly WB or SA) in the last trimester of pregnancy completed a questionnaire based on the TPB. The women were followed up 6 months later and their breastfeeding during the previous 6 months was recorded. The TPB predicted significant variance in breastfeeding across the sample and was able to account for differences between SA and WB women. Affective attitudes (emotional reactions to breastfeeding) and moral norms (reactions about whether breastfeeding is right or wrong) were the strongest predictors of intentions. Intentions and affective attitudes were predictive of breastfeeding initiation, whilst only affective attitudes were predictive of breastfeeding maintenance. Stronger intentions to breastfeed led to higher rates of breastfeeding amongst SA women. In turn, intentions were predicted by emotional and moral beliefs about breastfeeding, beliefs that were less positive amongst a WB sample. This suggests that those tasked with encouraging breastfeeding may need to have a different conversation with women about breastfeeding that goes beyond a focus on costs and benefits.


The Utility of Nanocomposites in Fire Retardancy.
Nanocomposites have been shown to significantly reduce the peak heat release rate, as measured by cone calorimetry, for many polymers but they typically have no effect on the oxygen index or the UL-94 classification. In this review, we will cover what is known about the processes by which nanocomposite formation may bring this about. Montmorillonite will be the focus in this paper but attention will also be devoted to other materials, including carbon nanotubes and layered double hydroxides. A second section will be devoted to combinations of nanocomposite formation with conventional (and unconventional) fire retardants. The paper will conclude with a section attempting to forecast the future.


Programmatic effects of a large-scale multiple-micronutrient supplementation trial in Indonesia: using community facilitators as intermediaries for behavior change.
Clinical trials can serve as an opportunity gateway for enhanced health benefits to the target population, above and beyond the specific intervention being tested. The Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a randomized, controlled clinical trial in Lombok, Indonesia, found that supplementation during pregnancy with multiple micronutrients reduced 90-day infant mortality by nearly 20% as compared with iron-folic acid. This trial was designed as both a program and research trial and used community facilitators to serve as liaisons between the study and the pregnant women. This analysis documents the programmatic impacts of SUMMIT on health-seeking and early infant mortality resulting from community facilitators' field activities. Data on compliance, human resource practices, health-seeking, and health outcomes from the 31,290 SUMMIT enrollees were analyzed. Overall compliance with either iron-folic acid or multiple micronutrients was high in the program, at 85.0%. Early prenatal care visits increased significantly. Sixty-three percent of primiparous women used a skilled birth attendant (SBA); among multiparous women, the rate of use of a SBA rose from 35% for the last birth to 53%. Use of a SBA resulted in a 30% reduction in early infant mortality (RR, 0.70; 95% CI, 0.59 to 0.83; p < .0001), independently of any reductions due to multiple micronutrients. The community facilitators played a central role in improving health-seeking; however, the quality of the community facilitators' performance was associated with the impact of the micronutrient supplement on infant health. In a subsample of community facilitators, better-performing facilitators were found to markedly improve the overall impact of the multiple micronutrients on early infant mortality (RR, 0.67; 95% CI, 0.49 to 0.92; p = .0117). In contrast, infants of women with poorly performing community facilitators were found to derive no additional benefit from the multiple micronutrients (RR, 1.04; 95% CI, 0.64 to 1.72; p = .8568). Systematic enhancements to the quality of implementation of SUMMIT led to significant increases in use of SBAs at delivery, resulting in a 30% reduction in early infant mortality independent of the impact of micronutrient supplementation. Therefore, if women were to consume multiple micronutrients on a regular basis and were to use a SBA at delivery, the risk of early infant mortality could be reduced by nearly 50%. The impacts of community facilitators in effecting changes in women's health behaviors are notable and are applicable to other health programs. Enhancements to program implementation should be driven by evidence, be accountable to the communities the program serves, and be evaluated on the basis of measurable gains in health for women and children.


Nursing Diagnoses Panorama in a Swedish Forensic Psychiatric Setting Using NANDA-International Taxonomy.
More than 1,000 Swedish hospital beds are occupied by patients in forensic psychiatric settings; their average length of hospitalization is 3-7 years. In this context, nursing diagnoses could be extremely useful to make nursing care structured, measurable, and internationally comparable. The study aimed to describe nursing diagnoses in a Swedish forensic psychiatric setting. Data were collected from electronic patient records of 55 patients in a medium-secure forensic psychiatric setting in Sweden. Anonymized data were entered into a database where entries were transformed into figures. Descriptive statistics were used, and frequencies, means, and percentages were calculated. The variables employed were characteristics and related factors, according to NANDA-International (NANDA-I) and International Statistical Classification of Dieseases and Related Heatlh Problems, 10th Revision (ICD-10), diagnoses. The patients had between 1 and 13 NANDA-I diagnoses each. Forty-one of the 55 patients had psychosis as the primary ICD-10 code. The identified nursing diagnoses described the patients' status upon arrival in the forensic psychiatric setting. Of the 55 patients, entries in the patient records describing 300 signs and symptoms (i.e., characteristics and related factors) were found. From these signs and symptoms, 371 entries that fit NANDA-I diagnoses were identified, representing 20 different NANDA-I diagnoses. NANDA-I diagnoses individualize patient care, making care person centered. NANDA-I is used all over the world and has the potential to make nursing care structured, measurable, and internationally comparable.


Measuring outcome from vestibular rehabilitation, part II: refinement and validation of a new self-report measure.
A prototype self-report measure of vestibular rehabilitation outcome is described in a previous paper. The objectives of the present work were to identify the most useful items and assess their psychometric properties. Stage 1: One hundred fifty-five participants completed a prototype 36-item Vestibular Rehabilitation Benefit Questionnaire (VRBQ). Statistical analysis demonstrated its subscale structure and identified redundant items. Stage 2: One hundred twenty-four participants completed a refined 22-item VRBQ and three established questionnaires (Dizziness Handicap Inventory, DHI; Vertigo Symptom Scale short form, VSS-sf; Medical Outcomes Study short form 36, SF-36) in a longitudinal study. Statistical analysis revealed four internally consistent subscales of the VRBQ: Dizziness, Anxiety, Motion-Provoked Dizziness, and Quality of Life. Correlations with the DHI, VSS-sf, and SF-36 support the validity of the VRBQ, and effect size estimates suggest that the VRBQ is more responsive than comparable questionnaires. Twenty participants completed the VRBQ twice in a 24-hour period, indicating excellent test-retest reliability. The VRBQ appears to be a concise and psychometrically robust questionnaire that addresses the main aspects of dizziness impact.


A Receptor's Tale: An Eon in the Life of a Trypanosome Receptor.
African trypanosomes have complex life cycles comprising at least ten developmental forms, variously adapted to different niches in their tsetse fly vector and their mammalian hosts. Unlike many other protozoan pathogens, they are always extracellular and have evolved intricate surface coats that allow them to obtain nutrients while also protecting them from the immune defenses of either insects or mammals. The acquisition of macromolecular nutrients requires receptors that function within the context of these surface coats. The best understood of these is the haptoglobin-hemoglobin receptor (HpHbR) of Trypanosoma brucei, which is used by the mammalian bloodstream form of the parasite, allowing heme acquisition. However, in some primates it also provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. Recent studies have shown that during the evolution of African trypanosome species the receptor has diversified in function from a hemoglobin receptor predominantly expressed in the tsetse fly to a haptoglobin-hemoglobin receptor predominantly expressed in the mammalian bloodstream. Structural and functional studies of homologous receptors from different trypanosome species have allowed us to propose an evolutionary history for how one receptor has adapted to different roles in different trypanosome species. They also highlight the challenges that a receptor faces in operating on the complex trypanosome surface and show how these challenges can be met.


Study on KAL1 Gene Mutations in Idiopathic Hypogonadotropic Hypogonadism Patients with X-Linked Recessive Inheritance.
Idiopathic hypogonadotropic hypogonadism (IHH) is a condition caused by low doses of hypothalamic gonadotropin-releasing hormone (GnRH) leading to absence or incomplete sexual maturation. One of the disorders leading to IHH is Kallmann syndrome which is characterized by GnRH deficiency with anosmia or hyposmia. This disorder generally occurs as a hereditary syndrome with X-linked recessive inheritance pattern. However, autosomal dominant or recessive and sporadic cases have also been reported. KAL1 is the most common mutated gene among these patients. The aim of this study was to determine the mutation spectrum of KAL1 gene in twenty patients. KAL1 exons were amplified by PCR method and the products were assessed by high resolution melting (HRM) technique. In addition, for one of the patients, all coding exons of the KAL1 gene were sequenced. Deletion of exons 4, 5 and 6 were evident in 5%, 10%, and 10% of patients, respectively. Furthermore, HRM results showed hemizygous mutation of exon 12 with more than 95% probability in 25% of patients. Finding these mutations could be helpful in the early diagnosis and presymptomic treatment of Kallman syndrome.


Comparison of fluorouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group.
Standard adjuvant chemotherapy for colorectal cancer consists of fluorouracil with folinic acid or levamisole. The large QUASAR randomised trial aimed to investigate (in a two x two design) whether use of a higher dose of folinic acid or addition of levamisole to fluorouracil and folinic acid improved survival. Patients with colorectal cancer, without evident residual disease, were randomly assigned fluorouracil (370 mg/m2) with high-dose (175 mg) or low-dose (25 mg) L-folinic acid and either active or placebo levamisole. The fluorouracil and folinic acid could be given either as six 5-day courses with 4 weeks between the start of the courses or as 30 once-weekly doses. Levamisole (50 mg) or placebo was given three times daily for 3 days repeated every 2 weeks for 12 courses. The primary endpoint was mortality from any cause. Analyses were by intention to treat. Between 1994 and 1997, 4,927 patients were enrolled. 1,776 had recurrences and 1,576 died. Survival was similar with high-dose and low-dose folinic acid (70.1% vs 71.0% at 3 years; p=0-43), as were 3-year recurrence rates (36.0% vs 35.8%; p=0.94). Survival was worse with levamisole than with placebo (69.4% vs 71.5% at 3 years; p=0.06), and there were more recurrences with the active drug (37.0% vs 34.9% at 3 years; p=0.16). The inclusion of levamisole in chemotherapy regimens for colorectal cancer does not delay recurrence or improve survival. Higher-dose folinic acid produced no extra benefit in these regimens over that from low-dose folinic acid. Trials of chemotherapy versus no chemotherapy will show whether these four treatments are equally effective or equally ineffective.


Invasive American bullfrogs and African Clawed Frogs in South America: High Suitability of Occurrence in Biodiversity Hotspots.
Fabiana G. Barbosa, Camila Both, and Miguel B. Araújo (2017) Invasion of protected areas by non-native species is currently one of the main threats to global biodiversity. Using an ensemble of bioclimatic envelope models we quantify the degree of exposure of South American protected areas to invasion by two invasive amphibian species. We focus on protected areas that coincide with global biodiversity hotspots. The species modeled, Lithobates catesbeianus and Xenopus laevis, have been reported to threaten local faunas in several non-native areas that they invaded, including areas in Asia, Europe, North America, and South America. We show that 87.5% of the protected areas within the Atlantic Forest may be most at risk of invasion by L. catesbeianus and X. laevis under current climate conditions, followed by areas in the Cerrado (51.7), Tropical Andes (37.6%), Tumbes-Choco-Magdalena (22.5%), and Chilean Winter Rainfall and Valdivian Forests (20.5%). Conservation plans for these regions should, therefore, consider latent threats from multiple sources including invasion by highly competitive non-native species such as the ones modeled in our study.


The role of epidemiology in the detection of harmful effects of radiation.
Data relating to acute injuries of atomic bomb survivors show that the life span study cohort is biased in favor of exceptionally low levels of radiosensitivity. These data also show that factors influencing the death rates of this cohort include irreversible damage to the immune system. These impressions are still awaiting confirmation. Meanwhile, the Oxford Survey of Childhood Cancers and surveys of nuclear workers show that at low dose levels the cancer risk is much greater than estimates based on atomic bomb survivors; the special association between leukemia and radiation is an exclusively high dose effect, and levels of radiosensitivity are much lower in the middle of the life span than at either extreme.


A selective phenelzine analogue inhibitor of histone demethylase LSD1.
Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. This study describes the design and synthesis of analogues of a monoamine oxidase antidepressant, phenelzine, and their LSD1 inhibitory properties. A novel phenelzine analogue (bizine) containing a phenyl-butyrylamide appendage was shown to be a potent LSD1 inhibitor in vitro and was selective versus monoamine oxidases A/B and the LSD1 homologue, LSD2. Bizine was found to be effective at modulating bulk histone methylation in cancer cells, and ChIP-seq experiments revealed a statistically significant overlap in the H3K4 methylation pattern of genes affected by bizine and those altered in LSD1-/- cells. Treatment of two cancer cell lines, LNCaP and H460, with bizine conferred a reduction in proliferation rate, and bizine showed additive to synergistic effects on cell growth when used in combination with two out of five HDAC inhibitors tested. Moreover, neurons exposed to oxidative stress were protected by the presence of bizine, suggesting potential applications in neurodegenerative disease.


Lymph node metastasis in maxillary sinus carcinoma.
To evaluate the incidence and prognostic significance of lymph node metastasis in maxillary sinus carcinoma. We reviewed the records of 97 patients treated for maxillary sinus carcinoma with radiotherapy at Stanford University and at the University of California, San Francisco between 1959 and 1996. Fifty-eight patients had squamous cell carcinoma (SCC), 4 had adenocarcinoma (ADE), 16 had undifferentiated carcinoma (UC), and 19 had adenoid cystic carcinoma (AC). Eight patients had T2, 36 had T3, and 53 had T4 tumors according to the 1997 AJCC staging system. Eleven patients had nodal involvement at diagnosis: 9 with SCC, 1 with UC, and 1 with AC. The most common sites of nodal involvement were ipsilateral level 1 and 2 lymph nodes. Thirty-six patients were treated with definitive radiotherapy alone, and 61 received a combination of surgical and radiation treatment. Thirty-six patients had neck irradiation, 25 of whom received elective neck irradiation (ENI) for N0 necks. The median follow-up for alive patients was 78 months. The median survival for all patients was 22 months (range: 2.4-356 months). The 5- and 10-year actuarial survivals were 34% and 31%, respectively. Ten patients relapsed in the neck, with a 5-year actuarial risk of nodal relapse of 12%. The 5-year risk of neck relapse was 14% for SCC, 25% for ADE, and 7% for both UC and ACC. The overall risk of nodal involvement at either diagnosis or on follow-up was 28% for SCC, 25% for ADE, 12% for UC, and 10% for AC. All patients with nodal involvement had T3-4, and none had T2 tumors. ENI effectively prevented nodal relapse in patients with SCC and N0 neck; the 5-year actuarial risk of nodal relapse was 20% for patients without ENI and 0% for those with elective neck therapy. There was no correlation between neck relapse and primary tumor control or tumor extension into areas containing a rich lymphatic network. The most common sites of nodal relapse were in the ipsilateral level 1-2 nodal regions (11/13). Patients with nodal relapse had a significantly higher risk of distant metastasis on both univariate (p = 0.02) and multivariate analysis (hazard ratio = 4.5, p = 0.006). The 5-year actuarial risk of distant relapse was 29% for patients with neck control versus 81% for patients with neck failure. There was also a trend for decreased survival with nodal relapse. The 5-year actuarial survival was 37% for patients with neck control and 0% for patients with neck relapse. The overall incidence of lymph node involvement at diagnosis in patients with maxillary sinus carcinoma was 9%. Following treatment, the 5-year risk of nodal relapse was 12%. SCC histology was associated with a high incidence of initial nodal involvement and nodal relapse. None of the patients presenting with SCC histology and N0 necks had nodal relapse after elective neck irradiation. Patients who had nodal relapse had a higher risk of distant metastasis and poorer survival. Therefore, our present policy is to consider elective neck irradiation in patients with T3-4 SCC of the maxillary sinus.


Characterization of Desulfitobacterium chlororespirans sp. nov., which grows by coupling the oxidation of lactate to the reductive dechlorination of 3-chloro-4-hydroxybenzoate.
Strain Co23, an anaerobic spore-forming microorganism, was enriched and isolated from a compost soil on the basis of its ability to grow with 2,3-dichlorophenol (DCP) as its electron acceptor, ortho chlorines were removed from polysubstituted phenols but not from monohalophenols. Growth by chlororespiration was indicated by a growth yield of 3.24 g of cells per mol of reducing equivalents (as 2[H]) from lactate oxidation to acetate in the presence of 3-chloro-4-hydroxybenzoate but no growth in the absence of the halogenated electron acceptor. Other indicators of chlororespiration were the fraction of electrons from the electron donor used for dechlorination (0.67) and the H2 threshold concentration of < 1.0 ppm. Additional electron donors utilized for reductive dehalogenation were pyruvate, formate, butyrate, crotonate, and H2. Pyruvate supported homoacetogenic growth in the absence of an electron acceptor. Strain Co23 also used sulfite, thiosulfate, and sulfur as electron acceptors for growth, but it did not use sulfate, nitrate or fumarate. The temperature optimum for growth was 37 degrees C; however, the rates of dechlorination were optimum at 45 degrees C and activity persisted to temperatures as high as 55 degrees C. The 16S rRNA sequence was determined, and strain Co23 was found to be related to Desulfitobacterium dehalogenans JW/IU DC1 and Desulfitobacterium strain PCE1, with sequence similarities of 97.2 and 96.8%, respectively. The phylogenetic and physiological properties exhibited by strain Co23 place it into a new species designated Desulfitobacterium chlororespirans.


DNA synthesis enzymes and proliferating cell nuclear antigen in normal and neoplastic nerve cells.
The activity of nuclear DNA polymerases alpha, beta and delta/epsilon, uracil-DNA glycosylase, thymidine kinase and the presence of Proliferating Cell Nuclear Antigen (PCNA) have been examined in developing rat glial cells, in rat and human glioma, in human neuroblastoma and in differentiated neuroblastoma cell lines in vitro. During glial development the activity of all enzymes tested, except DNA polymerase beta, markedly decreased, suggesting their coordinate regulation in respect to the proliferative state of the cells. Glioma and neuroblastoma cell lines restore the enzymatic activities that were no longer expressed in normal adult cells. Neuroblastoma cell lines induced to differentiate in vitro by retinoic acid showed a decline of the activities of DNA polymerase alpha, DNA polymerase delta/epsilon, uracil-DNA glycosylase and thymidine kinase similar to that observed during in vivo differentiation. We also demonstrate that PCNA is not detectable in glial and neuronal cells at all developmental stages, but can be found in tumor nerve cells. A possible use of enzymatic assays or anti-PCNA antibodies to detect brain tumors is discussed.


Members of WRKY Group III transcription factors are important in TYLCV defense signaling pathway in tomato (Solanum lycopersicum).
Transmitted by the whitefly Bemisia tabaci, tomato yellow leaf curly virus (TYLCV) has posed serious threats to plant growth and development. Plant innate immune systems against various threats involve WRKY Group III transcription factors (TFs). This group participates as a major component of biological processes in plants. In this study, 6 WRKY Group III TFs (SolyWRKY41, SolyWRKY42, SolyWRKY53, SolyWRKY54, SolyWRKY80, and SolyWRKY81) were identified, and these TFs responded to TYLCV infection. Subcellular localization analysis indicated that SolyWRKY41 and SolyWRKY54 were nuclear proteins in vivo. Many elements, including W-box, were found in the promoter region of Group III TFs. Interaction network analysis revealed that Group III TFs could interact with other proteins, such as mitogen-activated protein kinase 5 (MAPK) and isochorismate synthase (ICS), to respond to biotic and abiotic stresses. Positive and negative expression patterns showed that WRKY Group III genes could also respond to TYLCV infection in tomato. The DNA content of TYLCV resistant lines after SolyWRKY41 and SolyWRKY54 were subjected to virus-induced gene silencing (VIGS) was lower than that of the control lines. In the present study, 6 WRKY Group III TFs in tomato were identified to respond to TYLCV infection. Quantitative real-time-polymerase chain reaction (RT-qPCR) and VIGS analyses demonstrated that Group III genes served as positive and negative regulators in tomato-TYLCV interaction. WRKY Group III TFs could interact with other proteins by binding to cis elements existing in the promoter regions of other genes to regulate pathogen-related gene expression.


miR-142-5p and miR-130a-3p are regulated by IL-4 and IL-13 and control profibrogenic macrophage program.
Macrophages play a pivotal role in tissue fibrogenesis, which underlies the pathogenesis of many end-stage chronic inflammatory diseases. MicroRNAs are key regulators of immune cell functions, but their roles in macrophage's fibrogenesis have not been characterized. Here we show that IL-4 and IL-13 induce miR-142-5p and downregulate miR-130a-3p in macrophages; these changes sustain the profibrogenic effect of macrophages. In vitro, miR-142-5p mimic prolongs STAT6 phosphorylation by targeting its negative regulator, SOCS1. Blocking miR-130a relieves its inhibition of PPARγ, which coordinates STAT6 signalling. In vivo, inhibiting miR-142-5p and increasing miR-130a-3p expression with locked nucleic acid-modified oligonucleotides inhibits CCL4-induced liver fibrosis and bleomycin-induced lung fibrosis in mice. Furthermore, macrophages from the tissue samples of patients with liver cirrhosis and idiopathic pulmonary fibrosis display increased miR-142-5p and decreased miR-130a-3p expression. Therefore, miR-142-5p and miR-130a-3p regulate macrophage profibrogenic gene expression in chronic inflammation.


[The Good Samaritan Donor Experience].
The need for patients with a chronic kidney failure and on dialysis to embark on a kidney transplant process, poses the challenge to identify alternative and effective surgical strategies to overcome the insufficient number of deceased donors. The purpose is to allow the considerable number of patients on the kidney transplant waiting lists to receive appropriate treatment in time and under the most favorable clinical conditions. Living donation from a significant other is becoming increasingly widespread, on a national and international level. Furthermore, in the last years clinical experience is showing a special kind of kidney living donation : the Good Samaritan donation, i.e. when the donor has no emotional or blood bond with the recipient and decides to become a donor as a mere act of generosity, with no remuneration or reward in return. This article, after a brief analysis of the phenomenon through data obtained from recent international studies, shares the direct experience of the Clinical Psychology Service at IRCCS - ISMETT with regard to the psychological assessment and support throughout the clinical process of a Good Samaritan kidney donor. Sharing our experience and starting a discussion on this issue is the result of the need to define shared guidelines on the psychological approach to be used with potential Good Samaritan donors.


Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial.
Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer-BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8-12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.


Diurnal variations of performance and information processing.
The aim of the study was to establish whether performance of a task in which controlled search is required fluctuates during the day or, on the other hand, performance of a task in which the automatic detection is required does not fluctuate during the day. The material and the procedure for setting the subject with an automatic detection set and for controlled search were determined as experimental paradigms and based on the results of the studies published by Shiffrin and Schneider. Eighteen volunteers from first and second year students of Psychology (9 boys and 9 girls) took part in the study. The study was done in January and February 1985 in the Laboratory of experimental psychology of Tours (France) on Tuesdays, Thursdays and Fridays. Each subject individually participated in 4 sessions on the same day, at 08(30); 11(45); 13(45) and 17(00). The results indicate that the performances (number of the targets correctly detected and the reaction time) only fluctuate in the course of the day when the controlled search is required. We suggest that the independence or the dependence of performance variation may be linked to the use of one or another of the two information processes described by Shiffrin and Schneider: controlled search and automatic detection.


Construction of a porcine adrenal medullary cDNA library and nucleotide sequence analysis of two clones encoding a galanin precursor.
The presence of the 29-amino acid peptide galanin and galanin-like immunoreactivity in the peripheral and central nervous system have been established. We describe below the construction of a 1.1-million-recombinant cDNA library derived from poly(A)+ RNA from pig adrenal medulla, rich in galanin-like immunoreactivity, and the isolation and characterization of clones encoding preprogalanin. Mixtures of synthetic oligodeoxyribonucleotides corresponding to galanin-(7-19) and galanin-(22-29) were synthesized and used as hybridization probes to screen the cDNA library. Sequencing of two recombinant plasmids shows that pig galanin mRNA in the adrenal medulla encodes a precursor protein of 123 amino acids that is comprised of a leader sequence, a single galanin sequence, and a 59-amino acid sequence (galanin message-associated peptide) of as yet unknown function. The single galanin sequence, followed by a glycine (the amide donor), is flanked on both sides by pairs of lysine and arginine residues. RNA blot-hybridization analysis of poly(A)+ RNA from pig adrenal medulla reveals a single mRNA of approximately equal to 900-950 bases.


Biobased monoliths for adenovirus purification.
Adenoviruses are important platforms for vaccine development and vectors for gene therapy, increasing the demand for high titers of purified viral preparations. Monoliths are macroporous supports regarded as ideal for the purification of macromolecular complexes, including viral particles. Although common monoliths are based on synthetic polymers as methacrylates, we explored the potential of biopolymers processed by clean technologies to produce monoliths for adenovirus purification. Such an approach enables the development of disposable and biodegradable matrices for bioprocessing. A total of 20 monoliths were produced from different biopolymers (chitosan, agarose, and dextran), employing two distinct temperatures during the freezing process (-20 °C and -80 °C). The morphological and physical properties of the structures were thoroughly characterized. The monoliths presenting higher robustness and permeability rates were further analyzed for the nonspecific binding of Adenovirus serotype 5 (Ad5) preparations. The matrices presenting lower nonspecific Ad5 binding were further functionalized with quaternary amine anion-exchange ligand glycidyltrimethylammonium chloride hydrochloride by two distinct methods, and their performance toward Ad5 purification was assessed. The monolith composed of chitosan and poly(vinyl) alcohol (50:50) prepared at -80 °C allowed 100% recovery of Ad5 particles bound to the support. This is the first report of the successful purification of adenovirus using monoliths obtained from biopolymers processed by clean technologies.


Chemical composition and biological activities of Salvia officinalis essential oil from Tunisia.
The aim of this study is to evaluate the chemical composition, antioxidant, antimicrobial, insecticidal and allelopathic activities of Tunisia Salvia officinalis essential oil (SoEO). The SoEO was characterized by the presence of 49 components with camphor (25.14 %), α-thujone (18.83 %), 1,8-cineole (14.14 %), viridiflorol (7.98 %), β-thujone (4.46 %) and β-caryophyllene (3.30 %) as the major components, determined by gas chromatography-mass spectrometry. The level of antioxidant activity, determined by complementary tests, namely 2,2-diphenyl-1-picrylhydrazyl radical-scavenging (IC50= 6.7 mg/mL), linoleic acid peroxidation (IC50= 9.6 mg/mL) and ferric reducing assays (IC50= 28.4 mg/mL), was relatively moderate. The SoEO was also screened for its antimicrobial activity. Good to moderate inhibitions were recorded for most of tested microorganisms. It also exhibited important insecticidal activity against Spodoptera littoralis larvae and Tribolium castaneum adults with LC50 values of 55.99 and 97.43 µl/L air, respectively. The effect of the SoEO on seeds germination and growth showed different activities against radical and hypocotyl elongation of the tested species. These results suggest the potential use of the SoEO as natural antimicrobial preservative in cosmetic, pharmaceutical industry and in pest management.