The challenge and impact of engaging hard-to-reach populations in regular physical activity and health behaviours: an examination of an English Premier League 'Football in the Community' men's health programme.
To investigate the challenges that men from hard-to-reach (HTR) populations encounter when attempting to commit to regular participation in physical activity and health behaviours, and to explore the psychological and social effects of participation in a twelve week football-led health improvement intervention. A twelve week football specific physical activity intervention targeting men from HTR populations was delivered by Everton Football Clubs' Football in the Community (FitC) scheme as part of a national programme of men's health delivered in/by English Premier League (EPL) football clubs. Men living in homeless shelters and/or recovering from substance misuse were recruited over a period of three months. The programme consisted of a two hour football session, twice weekly, alongside the dissemination of healthy living messages. Football sessions were conducted by a qualified FitC coach. This research was conducted during a twelve week period of immersed practitioner-research. Ethnographic and observational methodologies were adopted. Psychosocial issues were discussed with participants through informal client-researcher interactions and data were logged via field notes. Records of attendance were logged. Participants who failed to attend a session were contacted and their reason(s) for non-attendance were recorded. Data were analysed using deductive and inductive reasoning. Despite the apparent ambition of the participants to regularly participate in the FitC programme, adherence to the programme was poor. Economic, environmental and social barriers to engagement in the programme were apparent. Engagement in the programme resulted in positive psychosocial developments; the development of structure, social interaction and social capital. Community based football-led health improvement programmes endorsed by professional football clubs appear well positioned to connect with, and attract, men from HTR populations. The evidence suggests that such programmes can improve psychosocial health amongst these populations. However, a bottom-up programme design and management strategy is required in order to reduce the challenges facing HTR participants when attempting to regularly engage in physical activity and health behaviours.


Safety and immune response of a live-attenuated herpes zoster vaccine in patients with systemic lupus erythematosus: a randomised placebo-controlled trial.
To study the safety and immunogenicity of a live-attenuated herpes zoster (HZ) vaccine in patients with systemic lupus erythematosus (SLE). Adult SLE patients having a SLEDAI <6 and stable immunosuppressive treatment for ≥6 months were recruited. Participants were randomly assigned to receive HZ vaccine (Zostavax) or placebo injection. Anti-varicella zoster virus (VZV) IgG reactivity (baseline and week 6) was measured by an enzyme-linked fluorescence assay. Cell-mediated response was assessed by a VZV-stimulated interferon-gamma (IFN-γ) enzyme-linked ELISPOT assay. Adverse events and immune responses of the two groups were compared. 90 SLE patients were recruited (age 45.6±14.1 years; 93% women) and assigned to Zostavax or placebo (in 1:1 ratio). Baseline clinical parameters were similar between the two groups. The change in anti-VZV IgG from week 0 to 6 was +59.8% in the vaccine and -2.1% in the placebo group. Week 6 anti-VZV IgG was significantly higher in vaccinated than placebo-treated patients, after adjustment for baseline (4.16±1.26 vs 3.32±1.01; p<0.001). The number of IFN-γ secreting T-cell spots decreased in the placebo-treated patients (-17%) but increased in vaccinated patients (+42%). The T-cell spots number at week 6 was significantly higher in vaccine-than placebo-treated patients after adjustment for baseline (38.1±78.2 vs 23.1±47.9; p=0.02). Significantly more vaccinated patients reported self-limiting injection site reaction than controls (31% vs 7%; p<0.01). Two vaccinated patients (4.4%) and one (2.2%) placebo-treated patient had mild/moderate SLE flares but no patients developed HZ eruption within 6 weeks postvaccination. In patients with stable SLE not receiving intensive immunosuppression, Zostavax was well-tolerated and provoked an immune response. US ClinicalTrials.gov registry (NCT02477150).


Output factor measurements with multiple detectors in CyberKnife® Robotic Radiosurgery System.
The aim of this study was to measure and compare the output factor (OF) of a CyberKnife Robotic Radiosurgery System with eight different small field detectors and validate with Technical Report Series (TRS) report 483. Accurate dosimetry of CyberKnife system is limited due to the challenges in small field dosimetry. OF is a vital dosimetric parameter used in the photon beam modeling and any error would affect the dose calculation accuracy. In this study, the OF was measured with eight different small-field detectors for the 12 IRIS collimators at 800 mm SAD setup at 15 mm depth. The detectors used were PTW 31016 PinPoint 3D, IBA PFD shielded diode, IBA EFD unshielded diode, IBA SFD unshielded diode (stereotactic), PTW 60008 shielded diode, PTW 60012 unshielded diode, PTW 60018 unshielded diode (stereotactic), and PTW 60019 CVD diamond detector. OF was obtained after correcting for field output correction factors from IAEA TRS No. 483. The field OFs in CyberKnife are derived from the measured data by applying the correction factors from Table 23 in TRS 483 for the eight small field detectors. These field OFs matched within 2% of peer-reviewed published values. The range and standard deviation showed a decreasing trend with collimator diameter. The field OF obtained after applying the appropriate correction factor from TRS 483 matched well with the peer-reviewed published OFs. The inter-detector variation showed a decreasing trend with increasing collimator field size. This study gives physicists confidence in measuring field OFs while using small field detectors mentioned in this work.


Supramolecular systems chemistry.
The field of supramolecular chemistry focuses on the non-covalent interactions between molecules that give rise to molecular recognition and self-assembly processes. Since most non-covalent interactions are relatively weak and form and break without significant activation barriers, many supramolecular systems are under thermodynamic control. Hence, traditionally, supramolecular chemistry has focused predominantly on systems at equilibrium. However, more recently, self-assembly processes that are governed by kinetics, where the outcome of the assembly process is dictated by the assembly pathway rather than the free energy of the final assembled state, are becoming topical. Within the kinetic regime it is possible to distinguish between systems that reside in a kinetic trap and systems that are far from equilibrium and require a continuous supply of energy to maintain a stationary state. In particular, the latter systems have vast functional potential, as they allow, in principle, for more elaborate structural and functional diversity of self-assembled systems - indeed, life is a prime example of a far-from-equilibrium system. In this Review, we compare the different thermodynamic regimes using some selected examples and discuss some of the challenges that need to be addressed when developing new functional supramolecular systems.


A blood-resistant surgical glue for minimally invasive repair of vessels and heart defects.
Currently, there are no clinically approved surgical glues that are nontoxic, bind strongly to tissue, and work well within wet and highly dynamic environments within the body. This is especially relevant to minimally invasive surgery that is increasingly performed to reduce postoperative complications, recovery times, and patient discomfort. We describe the engineering of a bioinspired elastic and biocompatible hydrophobic light-activated adhesive (HLAA) that achieves a strong level of adhesion to wet tissue and is not compromised by preexposure to blood. The HLAA provided an on-demand hemostatic seal, within seconds of light application, when applied to high-pressure large blood vessels and cardiac wall defects in pigs. HLAA-coated patches attached to the interventricular septum in a beating porcine heart and resisted supraphysiologic pressures by remaining attached for 24 hours, which is relevant to intracardiac interventions in humans. The HLAA could be used for many cardiovascular and surgical applications, with immediate application in repair of vascular defects and surgical hemostasis.


Bidirectional crosstalk between eosinophils and esophageal epithelial cells regulates inflammatory and remodeling processes.
Eosinophils accumulate adjacent to epithelial cells in the mucosa of patients with eosinophilic esophagitis (EoE), yet the bidirectional communication between these cells is not well understood. Herein, we investigated the crosstalk between human eosinophils and esophageal epithelial cells. We report that blood-derived eosinophils have prolonged survival when cocultured with epithelial cells; 96 ± 1% and 30 ± 6% viability was observed after 7 and 14 days of coculture, respectively, compared with 1 ± 0% and 0 ± 0% of monoculture. In the presence of IL-13 and epithelial cells, eosinophils had greater survival (68 ± 1%) at 14 days compared with cocultures lacking IL-13. Prolonged eosinophil viability did not require cellular contact and was observed when eosinophils were cultured in conditioned media from esophageal epithelial cells; neutralizing GM-CSF attenuated eosinophil survival. The majority of eosinophil transcripts (58%) were dysregulated in cocultured eosinophils compared with freshly isolated cells. Analysis of epithelial cell transcripts indicated that exposure to eosinophils induced differential expression of a subset of genes that were part of the EoE esophageal transcriptome. Collectively, these results uncover a network of crosstalk between eosinophils and esophageal epithelial cells involving epithelial mediated eosinophil survival and reciprocal changes in cellular transcripts, events likely to occur in EoE.


Brain Natriuretic Peptide and Troponin T in Patients With Acute Pulmonary Embolism and Grade 3 Obesity: A Retrospective Analysis.
Introduction The interpretation of brain natriuretic peptide (BNP) and Troponin T (TnT) in patients with obesity is very challenging. The applicability of these biomarkers as prognostic indicators of increased mortality in pulmonary embolism (PE) in patients with Grade 3 obesity has yet to be determined. Methods To investigate whether the combination of BNP and TnT may help to identify patients at low risk for short-term mortality, we assessed 92 patients admitted with the diagnosis of PE and Grade 3 obesity. The study endpoint was all-cause mortality at 30 days. Results The negative predictive value (NPV) of these tests combined is 98.8%; however, we were not able to detect a statistically significant difference between the patients who had a BNP < 100 pg/mL and TnT < 0.03 ng/mL and the other individuals who had either BNP ≥ 100 pg/mL or TnT ≥ 0.03 or both. The mortality rate was 5.43% within 30 days of the diagnosis. The logistic regression analysis using BNP and troponin as continuous variables identified BNP (p < 0.005) as an independent predictor for 30 days mortality. Receiver operating characteristic (ROC) analysis determined that a BNP level of 684 pg/mL was the cutoff level to predict mortality in the population studied. Conclusions Our results support that BNP and TnT levels retain an excellent NPV among patients with PE and Grade 3 obesity. BNP testing could be an independent predictor of high-risk patients in this population. The low incidence of all-cause mortality in this study (5.43%) is primarily explained by the more frequent use (9.75%) of systemic or catheter-based thrombolysis associated with a lower rate of major bleeding compared to the general population.


[Emotional regulation and motivation in children with ADHD].
Impaired cognitive control functions have long been regarded as the main problem in the development of Attention-Deficit/Hyperactivity Disorder (ADHD). A more recent model emphasizes the importance of emotional and motivational problems. We have reviewed the evidence for this model, which may have important implications for clinical practice. The article is based on literature identified through a non-systematic search in PubMed. Although limited research was carried out in this topic earlier, studies are currently emerging. Persons with ADHD react differently than controls on tasks that include rewards and on tasks that stress their capacity to regulate emotions. Abnormal signals during examination with electroencephalography (EEG) and anatomical and functional magnetic resonance imaging (fMRI) reflect problems with emotional regulation in patients with ADHD. Neurobiological research supports a model that includes emotional and motivational problems in the development of ADHD. Increased knowledge about emotional and motivational problems may improve treatment of these patients through development of more individually adapted therapy.


Reflection and Phase Matching in Plasmonic Gold Tapers.
We investigate different dynamic mechanisms, reflection and phase matching, of surface plasmons in a three-dimensional single-crystalline gold taper excited by relativistic electrons. Plasmonic modes of gold tapers with various opening angles from 5° to 47° are studied both experimentally and theoretically, by means of electron energy-loss spectroscopy and finite-difference time-domain numerical calculations, respectively. Distinct resonances along the taper shaft are observed in tapers independent of opening angles. We show that, despite their similarity, the origin of these resonances is different at different opening angles and results from a competition between two coexisting mechanisms. For gold tapers with large opening angles (above ∼20°), phase matching between the electron field and that of higher-order angular momentum modes of the taper is the dominant contribution to the electron energy-loss because of the increasing interaction length between electron and the taper near-field. In contrast, reflection from the taper apex dominates the EELS contrast in gold tapers with small opening angles (below ∼10°). For intermediate opening angles, a gradual transition of these two mechanisms was observed.


Percutaneous nephrolithotomy and the flyer.
Percutaneous nephrolithotomy (PN) is a relatively new procedure that is coming in vogue for the removal of upper urinary tract stones. Although there are possible complications from the procedure--bleeding being the most common one--its advantages make it a desirable treatment modality vis-a-vis conventional surgery. This article describes the case of a pilot who underwent PN, but remained disqualified from flying status for 6 months because of an unfortunate complication.


Combined modality therapy for Stage IIIMO non-small cell lung cancer. A five-year experience.
Between 1975 and 1980, 101 patients with inoperable Stage IIIMO non-small cell lung carcinoma were entered into combined radiotherapy and chemotherapy trials at Michael Reese Hospital and University of Chicago Hospital. Sixty-four percent of the patients responded. Median survival for all patients was 8.8 months. Responders survived 13.7 months and nonresponders 4.6 months (P = 0.002). Patients treated with 4200 rad had a higher response rate than those treated with 3000 rad (74% versus 54%, P = 0.04) but there was no difference in survival. Although all patients with squamous cell carcinoma died by 30 months, 18% of patients with adenocarcinoma and 20% of patients with large cell carcinoma are long-term survivors. Brain metastases occurred more frequently in patients with large cell or adenocarcinoma than in patients with squamous cell carcinoma (P = 0.02). The prognostic effect of age, initial performance status, sex, histology, and tumor extent are examined. Toxicity was substantial with a 13% treatment-related mortality. Combined modality therapy may benefit selected patients with non-squamous cell types, but more effective chemotherapeutic agents are needed. Prophylactic cranial irradiation in patients with large cell carcinoma or adenocarcinoma may decrease the incidence of subsequent brain metastases.


The fission yeast TFIIB-related factor limits RNA polymerase III to a TATA-dependent pathway of TBP recruitment.
The RNA polymerase (pol) III-transcribed (e.g. tRNA and 5S rRNA) genes of traditionally studied organisms rely on gene-internal promoters that precisely position the initiation factor, TFIIIB, on the upstream promoter-less DNA. This is accomplished by the ability of the TFIIIB subunit, TFIIB-related factor (Brf1), to make stable protein-protein interactions with TATA-binding protein (TBP) and place it on the promoter-less upstream DNA. Unlike traditional model organisms, Schizosaccharomyces pombe tRNA and 5S rRNA genes contain upstream TATA promoters that are required to program functional pol III initiation complexes. In this study we demonstrate that S.pombe (Sp)Brf does not form stable interactions with TBP in the absence of DNA using approaches that do reveal stable association of TBP and S.cerevisiae (Sc)Brf1. Gel mobility analyses demonstrate that a TBP-TATA DNA complex can recruit SpBrf to a Pol III promoter. Consistent with this, overproduction of SpBrf in S.pombe increases the expression of a TATA-dependent, but not a TATA-less, suppressor tRNA gene. Since previous whole genome analysis also revealed TATA elements upstream of tRNA genes in Arabidopsis, this pathway may be more widespread than appreciated previously.


The effects of chronic hypoxia on renal function in the rat.
1. Studies were performed on rats that had been made chronically hypoxic (CH rats) in a normoxic chamber at 12% O2 for 3-5 weeks. Under Saffan anaesthesia, respiratory and cardiovascular variables, renal haemodynamics and renal function were recorded while the rats spontaneously breathed 12% O2 followed by a switch to air breathing for 20 min. Plasma renin activity was assessed by radioimmunoassay of angiotensin I. Plasma atrial natiruetic peptide (ANP) was indirectly assessed by measurement of cyclic GMP in urine. 2. When breathing 12% O2, CH rats showed hyperventilation and raised haematocrit (52%) relative to normoxic (N) rats. But arterial pressure (ABP), renal blood flow (RBF), renal vascular conductance (RVC), mean right atrial pressure (mRAtP), urine flow, glomerular filtration rate (GFR) and absolute sodium excretion (UNaV) were comparable to those recorded in N rats breathing air. Urinary cGMP was 40% greater than in N rats, but plasma renin activity was not significantly greater in CH than in N rats. 3. Air breathing in CH rats induced hypoventilation, a 12% increase in ABP, no change in mRAtP, RBF or GFR, but increases of 75 and 100% in urine flow and UNaV, respectively. Neither urinary cGMP nor plasma renin activity changed. Such increases in urine flow and UNaV were absent when renal perfusion pressure (RPP) was prevented from rising during air breathing by using an occluder on the dorsal aorta. 4. We propose that by 3-5 weeks of chronic hypoxia renal function was normalized, principally because arterial O2 content was normalized by the increase in haematocrit and because ABP and renal haemodynamics were normalized: acute hypoxia in N rats produces a fall in ABP. We suggest that plasma ANP was raised by the actions of hypoxia or erythropoietin on the atrium, rather than by atrial distension, but suggest that ANP had little direct influence on renal function and tended to limit the influence of the renin-angiotensin system. We further propose that the diuresis and natriuresis seen during air breathing were mediated by the increase in RPP; neither plasma ANP nor renin activity change in the immediate short term.


Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: the importance of the F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation.
In this study, we tested the hypothesis that a CB(1) TMH3-4-5-6 aromatic microdomain, which includes F3.25(190), F3.36(201), W5.43(280), and W6.48(357), is centrally involved in CB(1) receptor activation, with the F3.36(201)/W6.48(357) interaction key to the maintenance of the CB(1)-inactive state. We have shown previously that when F3.36(201), W5.43(280), and W6.48(357) are individually mutated to alanine, a significant reduction in ligand binding affinity is observed in the presence of WIN 55,212-2 and SR141716A but not CP55,940 and anandamide. In the work presented here, we report a detailed functional analysis of the F3.36(201)A, F3.25(190)A, W5.43(280)A, and W6.48(357)A mutant receptors in stable cell lines created in HEK cells for agonist-stimulated guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding and GIRK1/4 channel current effects in Xenopus oocytes where the mutant proteins were expressed transiently. The F3.36(201)A mutation showed statistically significant increases in ligand-independent stimulation of GTPgammaS binding versus wild type CB(1), although basal levels for the W6.48(357)A mutant were not statistically different from wild type CB(1). F3.36(201)A demonstrated a limited activation profile in the presence of multiple agonists. In contrast, enhanced agonist activation was produced by W6.48(357)A. These results suggest that a F3.36(201)/W6.48(357)-specific contact is an important constraint for the CB(1)-inactive state that may need to break during activation. Modeling studies suggest that the F3.36(201)/W6.48(357) contact can exist in the inactive state of CB(1) and be broken in the activated state via a chi(1) rotamer switch (F3.36(201) trans, W6.48(357) g+) --> (F3.36(201) g+, W6.48(357) trans). The F3.36(201)/W6.48(357) interaction therefore may represent a "toggle switch" for activation of CB(1).


Molecularly imprinted polymer films grafted from porous or nonporous silica: novel affinity stationary phases in capillary electrochromatography.
Molecularly imprinted composite materials were evaluated as chiral stationary phases in capillary electrochromatography (CEC). These consisted of spherical silica particles of different sizes and of different porosities, containing a surface-immobilized layer of molecularly imprinted polymer (MIP) targeted to bind L-phenylalanine anilide. Fused silica capillaries were packed over a length of 8.5 cm, using a pneumate amplification pump, and the stationary phase thus obtained was tested with respect to its electrochromatographic performance. The electroendosmotic flow (EOF) mobility was evaluated with respect to the content of grafted polymer, as well as the ionic strength and the acetonitrile content of the electrolyte. Moreover, the influence of the layer thickness and of the stationary phase porosity on the performance and on the sample load capacity was investigated. The packings exhibited different relative efficiencies for the two enantiomers. The results were discussed in terms of differencies in accessibility to the binding sites of the packings and of the mechanism of EOF generation. In the wide context of the different approaches so far proposed for MIP stationary phases in CEC, these materials can be a good alternative, worthy of further development and application, not restricted to chiral separations.


The genesis of an exceptionally lethal venom in the timber rattlesnake (Crotalus horridus) revealed through comparative venom-gland transcriptomics.
Snake venoms generally show sequence and quantitative variation within and between species, but some rattlesnakes have undergone exceptionally rapid, dramatic shifts in the composition, lethality, and pharmacological effects of their venoms. Such shifts have occurred within species, most notably in Mojave (Crotalus scutulatus), South American (C. durissus), and timber (C. horridus) rattlesnakes, resulting in some populations with extremely potent, neurotoxic venoms without the hemorrhagic effects typical of rattlesnake bites. To better understand the evolutionary changes that resulted in the potent venom of a population of C. horridus from northern Florida, we sequenced the venom-gland transcriptome of an animal from this population for comparison with the previously described transcriptome of the eastern diamondback rattlesnake (C. adamanteus), a congener with a more typical rattlesnake venom. Relative to the toxin transcription of C. adamanteus, which consisted primarily of snake-venom metalloproteinases, C-type lectins, snake-venom serine proteinases, and myotoxin-A, the toxin transcription of C. horridus was far simpler in composition and consisted almost entirely of snake-venom serine proteinases, phospholipases A2, and bradykinin-potentiating and C-type natriuretic peptides. Crotalus horridus lacked significant expression of the hemorrhagic snake-venom metalloproteinases and C-type lectins. Evolution of shared toxin families involved differential expansion and loss of toxin clades within each species and pronounced differences in the highly expressed toxin paralogs. Toxin genes showed significantly higher rates of nonsynonymous substitution than nontoxin genes. The expression patterns of nontoxin genes were conserved between species, despite the vast differences in toxin expression. Our results represent the first complete, sequence-based comparison between the venoms of closely related snake species and reveal in unprecedented detail the rapid evolution of snake venoms. We found that the difference in venom properties resulted from major changes in expression levels of toxin gene families, differential gene-family expansion and loss, changes in which paralogs within gene families were expressed at high levels, and higher nonsynonymous substitution rates in the toxin genes relative to nontoxins. These massive alterations in the genetics of the venom phenotype emphasize the evolutionary lability and flexibility of this ecologically critical trait.


Incidence and Prevalence of Drug-Resistant Epilepsy: A Systematic Review and Meta-analysis.
To evaluate the incidence and prevalence of drug-resistant epilepsy (DRE) as well as its predictors and correlates, we conducted a systematic review and meta-analysis of observational studies. Our protocol was registered with PROSPERO, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology reporting standards were followed. We searched MEDLINE, Embase, and Web of Science. We used a double arcsine transformation and random-effects models to perform our meta-analyses. We performed random-effects meta-regressions using study-level data. Our search strategy identified 10,794 abstracts. Of these, 103 articles met our eligibility criteria. There was high interstudy heterogeneity and risk of bias. The cumulative incidence of DRE was 25.0% (95% confidence interval [CI]: 16.8-34.3) in child studies but 14.6% (95% CI: 8.8-21.6) in adult/mixed age studies. The prevalence of DRE was 13.7% (95% CI: 9.2-19.0) in population/community-based populations but 36.3% (95% CI: 30.4-42.4) in clinic-based cohorts. Meta-regression confirmed that the prevalence of DRE was higher in clinic-based populations and in focal epilepsy. Multiple predictors and correlates of DRE were identified. The most reported of these were having a neurologic deficit, an abnormal EEG, and symptomatic epilepsy. The most reported genetic predictors of DRE were polymorphisms of the ABCB1 gene. Our observations provide a basis for estimating the incidence and prevalence of DRE, which vary between populations. We identified numerous putative DRE predictors and correlates. These findings are important to plan epilepsy services, including epilepsy surgery, a crucial treatment option for people with disabling seizures and DRE.


Age-related decline in the microstructural integrity of white matter in children with early- and continuously-treated PKU: a DTI study of the corpus callosum.
Structural, volumetric, and microstructural abnormalities have been reported in the white matter of the brain in individuals with phenylketonuria (PKU). Very little research, however, has been conducted to investigate the development of white matter in children with PKU, and the developmental trajectory of their white matter microstructure is unknown. In the current study, diffusion tensor imaging (DTI) was used to examine the development of the microstructural integrity of white matter across six regions of the corpus callosum in 34 children (7-18 years of age) with early- and continuously-treated PKU. Comparison was made with 61 demographically-matched healthy control children. Two DTI variables were examined: mean diffusivity (MD) and relative anisotropy (RA). RA was comparable to that of controls across all six regions of the corpus callosum. In contrast, MD was restricted for children with PKU in anterior (i.e., genu, rostral body, anterior midbody) but not posterior (posterior midbody, isthmus, splenium) regions of the corpus callosum. In addition, MD restriction became more pronounced with increasing age in children with PKU in the two most anterior regions of the corpus callosum (i.e., genu, rostral body). These findings point to an age-related decrement in the microstructural integrity of the anterior white matter of the corpus callosum in children with PKU.


Intravenous omeprazole rapidly raises intragastric pH.
Twenty four hour intragastric acidity was measured in five duodenal ulcer patients studied at least three times. The effects of different dosage regimens of intravenous omeprazole was compared with placebo. Mean intragastric acidity from 1000 to 0800 was 34.3 +/- 4.3 mmol/l on placebo. After omeprazole 80 mg at 0900 and 40 mg at 1700 mean acidity was 2.1 +/- 0.9 mmol/l and after omeprazole 80 mg at 0900 and 80 mg at 1700 it was 0.7 +/- 0.2 mmol/l. pH remained above 4.0 for about 80% of recordings with these regimens and for only 5% with placebo. Three of the five patients also received omeprazole 80 mg at 0900, 40 mg at 1700 and 40 mg at 0100 when pH remained above 4.0 for 90% of recordings with 99% inhibition of acidity. Omeprazole rapidly raised intragastric pH in all patients and maintained a gastric pH of greater than 4.0 for most of the time. Large doses of IV omeprazole were required compared with studies using the oral compound.


Exocrine pancreatic insufficiency in adults: a shared position statement of the Italian Association for the Study of the Pancreas.
This is a medical position statement developed by the Exocrine Pancreatic Insufficiency collaborative group which is a part of the Italian Association for the Study of the Pancreas (AISP). We covered the main diseases associated with exocrine pancreatic insufficiency (EPI) which are of common interest to internists/gastroenterologists, oncologists and surgeons, fully aware that EPI may also occur together with many other diseases, but less frequently. A preliminary manuscript based on an extended literature search (Medline/PubMed, Cochrane Library and Google Scholar) of published reports was prepared, and key recommendations were proposed. The evidence was discussed at a dedicated meeting in Bologna during the National Meeting of the Association in October 2012. Each of the proposed recommendations and algorithms was discussed and an initial consensus was reached. The final draft of the manuscript was then sent to the AISP Council for approval and/or modification. All concerned parties approved the final version of the manuscript in June 2013.


Comparing higher and lower weekly treatment intensity for chronic aphasia: A systematic review and meta-analysis.
Optimizing intensity for aphasia treatment is a high priority research issue for people with aphasia, their families and clinicians, and could result in healthcare cost savings. An important aspect of intensity is the frequency of intervention, or how regularly treatment should be provided each week. While principles of neuroplasticity endorse massed practice, cognitive psychology has established superiority of distributed practice within normal learning. Neither concept has been conclusively tested in aphasia. There have been many literature reviews of intensity in aphasia intervention, but most have not investigated treatment intensity whilst also ensuring that therapy dose and treatment type are identical between study groups. Some have also combined studies across acute, subacute and chronic aphasia. We searched systematically for studies directly comparing higher and lower weekly treatment frequency in chronic aphasia. Eight studies were retrieved and rated for methodological quality. Meta-analysis was completed for group and single case experimental designs. Results showed that there are few studies investigating treatment frequency in chronic aphasia and their quality is low-moderate. Meta-analyses were inconclusive due to limited data, but there was no indication of either schedule being superior. Further research directly comparing treatment schedules is needed.


Risk of HIV-1 transmission for parenteral exposure and blood transfusion: a systematic review and meta-analysis.
The role of iatrogenic transmission within the HIV/AIDS pandemic remains contentious. Estimates of the risk of HIV transmission from injections and blood transfusions are required to inform appropriate prevention policy. Systematic review and meta-analysis of the literature on HIV-1 infectivity for parenteral transmission and blood transfusion. All identified studies with relevant transmission probability estimates up to May 2005 were included. When appropriate, summary estimates for accidental percutaneous and blood product exposures were derived. Infectivity estimates following a needlestick exposure ranged from 0.00 to 2.38% [weighted mean, 0.23%; 95% confidence interval (CI), 0.00-0.46%; n = 21]. Three estimates of infectivity per intravenous drug injection ranged from 0.63 to 2.4% (median, 0.8%); a summary estimate could not be calculated. The quality of the only estimate of infectivity per contaminated medical injection (1.9-6.9%) was assessed. Instead we propose a range of 0.24-0.65%. Infectivity estimates for confirmed contaminated blood transfusions range from 88.3 to 100.0% (weighted mean, 92.5%; 95% CI, 89.0-96.1%; n = 6). Infectivity estimates for infected blood transfusions are larger than for other modes of HIV transmission. Few studies on transmission risk per contaminated injection were found. However, transmission risk per needlestick injury, where needles are more likely to be rinsed or disinfected between recipients (especially for medical injections), may be representative of non-intravenous medical injections and lower than the risk from intravenous injections, which are likely to be deeper and to involve more fluids. Further work is needed to better estimate transmission probability related to contaminated injections and its likely contribution to overall HIV transmission.


miR-15/16 Restrain Memory T Cell Differentiation, Cell Cycle, and Survival.
Coordinate control of T cell proliferation, survival, and differentiation are essential for host protection from pathogens and cancer. Long-lived memory cells, whose precursors are formed during the initial immunological insult, provide protection from future encounters, and their generation is the goal of many vaccination strategies. microRNAs (miRNAs) are key nodes in regulatory networks that shape effective T cell responses through the fine-tuning of thousands of genes. Here, using compound conditional mutant mice to eliminate miR-15/16 family miRNAs in T cells, we show that miR-15/16 restrict T cell cycle, survival, and memory T cell differentiation. High throughput sequencing of RNA isolated by cross-linking immunoprecipitation of AGO2 combined with gene expression analysis in miR-15/16-deficient T cells indicates that these effects are mediated through the direct inhibition of an extensive network of target genes within pathways critical to cell cycle, survival, and memory.


A chromosome-level reference genome for the common octopus, Octopus vulgaris (Cuvier, 1797).
Cephalopods are emerging animal models and include iconic species for studying the link between genomic innovations and physiological and behavioral complexities. Coleoid cephalopods possess the largest nervous system among invertebrates, both for cell counts and brain-to-body ratio. Octopus vulgaris has been at the center of a long-standing tradition of research into diverse aspects of cephalopod biology, including behavioral and neural plasticity, learning and memory recall, regeneration, and sophisticated cognition. However, no chromosome-scale genome assembly was available for O. vulgaris to aid in functional studies. To fill this gap, we sequenced and assembled a chromosome-scale genome of the common octopus, O. vulgaris. The final assembly spans 2.8 billion basepairs, 99.34% of which are in 30 chromosome-scale scaffolds. Hi-C heatmaps support a karyotype of 1n = 30 chromosomes. Comparisons with other octopus species' genomes show a conserved octopus karyotype and a pattern of local genome rearrangements between species. This new chromosome-scale genome of O. vulgaris will further facilitate research in all aspects of cephalopod biology, including various forms of plasticity and the neural machinery underlying sophisticated cognition, as well as an understanding of cephalopod evolution.


Controlled synthesis and Li-electroactivity of rutile TiO2 nanostructure with walnut-like morphology.
Herein, we report on the synthesis of phase-pure rutile walnut-like TiO(2) (W-TiO(2)) spheres composed of single-crystalline nanorod-building blocks using a surfactant-free non-aqueous acidic modified "benzyl alcohol route". Based on the various HCl concentration- and reaction time-dependent experiments, an effect of hydrochloric acid on the phase formation mechanism in a non-aqueous system is suggested. As anodes for Li-ion batteries, the W-TiO(2) sphere electrodes exhibited superior cycling performance at a rate of 0.2 C without any conducting layers coated onto the anodes; this result is attributed to their high crystallinity and large surface area.


A cluster of cuticle protein genes of Drosophila melanogaster at 65A: sequence, structure and evolution.
A 36-kb genomic DNA segment of the Drosophila melanogaster genome containing 12 clustered cuticle genes has been mapped and partially sequenced. The cluster maps at 65A 5-6 on the left arm of the third chromosome, in agreement with the previously determined location of a putative cluster encompassing the genes for the third instar larval cuticle proteins LCP5, LCP6 and LCP8. This cluster is the largest cuticle gene cluster discovered to date and shows a number of surprising features that explain in part the genetic complexity of the LCP5, LCP6 and LCP8 loci. The genes encoding LCP5 and LCP8 are multiple copy genes and the presence of extensive similarity in their coding regions gives the first evidence for gene conversion in cuticle genes. In addition, five genes in the cluster are intronless. Four of these five have arisen by retroposition. The other genes in the cluster have a single intron located at an unusual location for insect cuticle genes.


MALDI-TOF MS analysis of Burkholderia pseudomallei and closely related species isolated from soils and water in Khon Kaen, Thailand.
Melioidosis is caused by Burkholderia pseudomallei (Bp) acquired from the environment. Conventional identification methods for environmental Bp are challenging due to the presence of closely related species. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is accurate for bacterial identification, but has been little used to identify Bp from environmental samples. This study aims to evaluate MALDI-TOF MS for the identification of Bp and closely related species isolated from environmental samples in Thailand using whole-genome sequencing (WGS) as the gold standard, including determining the best sample preparation method for this purpose. We identified Bp (n = 22), Burkholderia spp. (n = 28), and other bacterial species (n = 32) using WGS. MALDI-TOF analysis of all Bp isolates yielded results consistent with WGS. A decision-tree algorithm identified 16 important variable peaks, using the protein extraction method (PEM), demonstrating distinct MALDI-TOF profiles for the three categories (Bp, Burkholderia spp. and "other bacterial species"). Three biomarker peaks (4060, 5196, and 6553 Da) could discriminate Bp from other Burkholderia and closely related species with 100% sensitivity and specificity. Hence, the MALDI-TOF technique has shown its potential as a species discriminatory tool, providing results comparable to WGS for classification and surveillance of environmental Bp.


Summary of the 2022 report on cardiovascular health and diseases in China.
Recent decades have seen the remarkable development of China in medical accessibility and quality index, and the application of a number of new advanced cardiovascular technologies benefits more patients. However, according to the Annual Report on Cardiovascular Health and Diseases in China published in this article, which was organized and summarized by National Center for Cardiovascular Diseases, there is still a huge population living with risk factors of cardiovascular diseases (CVD), and the morbidity and mortality of CVD are increasing. It is estimated that there are around 330 million patients suffering from CVD currently, including 245 million of hypertension, 13 million of stroke, 45.3 million of peripheral artery disease, 11.39 million of coronary heart disease (CHD), 8.9 million of heart failure, 5 million of pulmonary heart disease, 4.87 million of atrial fibrillation, 2.5 million of rheumatic heart disease, and 2 million of congenital heart disease. Tobacco use, diet and nutrition factors, physical activity, overweight and obesity, and psychological factors are what affect cardiovascular health, while hypertension, dyslipidemia, diabetes, chronic kidney disease, metabolic syndrome, and air pollution are the risk factors for CVD. In this article, in addition to risk factors for CVD, we also report the epidemiological trends of CVD, including CHD, cerebrovascular disease, arrhythmias, valvular heart disease, congenital heart disease, cardiomyopathy, heart failure, pulmonary vascular disease and venous thromboembolism, and aortic and peripheral artery diseases, as well as the basic research and medical device development in CVD. In a word, China has entered a new stage of transforming from high-speed development focusing on scale growth to high-quality development emphasizing on strategic and key technological development to curb the trend of increasing incidence and mortality of CVD.


Buprenorphine transdermal system in adults with chronic low back pain: a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase.
Buprenorphine is a mixed-activity, partial mu-opioid agonist. Its lipid solubility makes it well suited for transdermal administration. This study assessed the efficacy and safety profile of a 7-day buprenorphine transdermal system (BTDS) in adult (age >18 years) patients with moderate to severe chronic low back pain previously treated with > or =1 tablet daily of an opioid analgesic. This was a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. After a 2- to 7-day washout of previous opioid therapy, eligible patients were randomized to receive BTDS 10 microg/h or matching placebo patches. The dose was titrated weekly using 10- and 20-microg/h patches (maximum, 40 microg/h) based on efficacy and tolerability. After 4 weeks, patients crossed over to the alternative treatment for another 4 weeks. Patients who completed the double-blind study were eligible to enter the 6-month open-label phase. Rescue analgesia was provided as acetaminophen 325 mg to be taken as 1 or 2 tablets every 4 to 6 hours as needed. The primary outcome assessments were daily pain intensity, measured on a 100-mm visual analog scale (VAS), from no pain to excruciating pain, and a 5-point ordinal scale, from 0 = none to 4 = excruciating. Secondary outcome assessments included the Pain and Sleep Questionnaire (100-mm VAS, from never to always), Pain Disability Index (ordinal scale, from 0 = no disability to 11 = total disability), Quebec Back Pain Disability Scale (categorical scale, from 0 = no difficulty to 5 = unable to do), and the 36-item Short Form Health Survey (SF-36). Patients and investigators assessed overall treatment effectiveness at the end of each phase; they assessed treatment preference at the end of double-blind treatment. After implementation of a precautionary amendment, the QTc interval was measured 3 to 4 days after randomization and after any dose adjustment. All assessments performed during the double-blind phase were also performed every 2 months during the open-label extension. Adverse events were collected by non-directed questioning throughout the study. Of 78 randomized patients, 52 (66.7%) completed at least 2 consecutive weeks of treatment in each study phase without major protocol violations (per-protocol [PP] population: 32 women, 20 men; mean [SD] age, 51.3 [11.4] years; mean weight, 85.5 [19.5] kg; 94% white, 4% black, 2% other). The mean (SD) dose of study medication during the last week of treatment was 29.8 (12.1) microg/h for BTDS and 32.9 (10.7) microg/h for placebo (P = NS). During the last week of treatment, BTDS was associated with significantly lower mean (SD) pain intensity scores compared with placebo on both the VAS (45.3 [21.3] vs 53.1 [24.3] mm, respectively; P = 0.022) and the 5-point ordinal scale (1.9 [0.7] vs 2.2 [0.8]; P = 0.044). The overall Pain and Sleep score was significantly lower with BTDS than with placebo (177.6 [125.5] vs 232.9 [131.9]; P = 0.027). There were no treatment differences on the Pain Disability Index, Quebec Back Pain Disability Scale, or SF-36; however, BTDS was associated with significant improvements compared with placebo on 2 individual Quebec Back Pain Disability Scale items (get out of bed: P = 0.042; sit in a chair for several hours: P = 0.022). Of the 48 patients/physicians in the PP population who rated the effectiveness of treatment, 64.6% of patients (n = 31) rated BTDS moderately or highly effective, as did 62.5% of investigators (n = 30). Among the 50 patients in the PP population who answered the preference question, 66.0% of patients (n = 33) preferred the phase in which they received BTDS and 24.0% (n = 12) preferred the phase in which they received placebo (P = 0.001), with the remainder having no preference; among investigators, 60.0% (n = 30) and 28.0% (n = 14) preferred the BTDS and placebo phases, respectively (P = 0.008), with the remainder having no preference. The mean placebo-adjusted change from baseline in the QTc interval ranged from -0.8 to +3.8 milliseconds (P = NS). BTDS treatment was associated with a significantly higher frequency of nausea (P < 0.001), dizziness (P < 0.001), vomiting (P = 0.008), somnolence (P = 0.020), and dry mouth (P = 0.003), but not constipation. Of the 49 patients completing 8 weeks of double-blind treatment, 40 (81.6%) entered the 6-month, open-label extension study and 27 completed it. Improvements in pain scores achieved during the double-blind phase were maintained in these patients. In the 8-week, double-blind portion of this study, BTDS 10 to 40 microg/h was effective compared with placebo in the management of chronic, moderate to severe low back pain in patients who had previously received opioids. The improvements in pain scores were sustained throughout the 6-month, open-label extension. (Current Controlled Trials identification number: ISRCTN 06013881).


Empirical descriptors of unelevated MMPI profiles among chronic pain patients: a typological approach.
The task of the clinician in evaluating the possible role of psychological factors in patients' pain disability is a most difficult one. This task becomes even more arduous when confronted with unelevated MMPI profiles from patients in whom physical findings are minimal or absent. The current study employs a multivariate, quantitative taxonomic procedure to delineate homogeneous subgroupings of chronic pain patients who meet this criterion. Subsequent analysis of base rate data for subgroups across a broad range of pain-related variables provide an actuarial basis of assessment of psychological factors within this population. Results indicate that of five subtypes identified, only one group of patients, who comprise 9% of the total sample, are likely to be free of significant psychological components in their pain behavior. Implications for clinical interpretation and future research are discussed.


Radioimmunoassay for dog myoglobin.
A radioimmunoassay specific for dog myoglobin (MGB) has been developed. Antibody (Ab) to purified dog heart MGB was prepared in rabbits and the Ab was labelled with 125I using the chloramine-T procedure. The assay is conducted at room temperature with addition of second Ab at 24 hr, the forward reaction being 95% complete at this point and irreversible. The assay is free of matrix affects. The working range is 20 to 360 ng/ml. Coefficients of variation for within run replicates are 10.5% (low) and 4.4% (high), and for between run replicates are 13.8% (low) and 7.6% (high). Serial measurement of serum MGB in dogs undergoing experimental myocardial infarction indicates that appearance time, peak time, and disappearance rate are respectively, 1.1 hr, 7.7 hr and 0.0025 min-1 for MGB and 2.6 hr, 13.35 hr, and 0.0018 min-1 for CK.


Does Chronic Kidney Disease Predict Stroke Risk Independent of Blood Pressure?: A Systematic Review and Meta-Regression.
Background and Purpose- Chronic kidney disease is strongly associated with stroke with various purported mechanisms proposed. Low glomerular filtration rate appears to be a risk factor for stroke independent of cardiovascular risk factors in epidemiological studies, but there has been no systematic assessment of the impact of more complete adjustment for blood pressure on the association. Methods- We did a systematic review to February 2018 (MEDLINE/EMBASE) for cohort studies or randomized controlled trials that reported stroke incidence in adults according to baseline estimated glomerular filtration rate. Study and participant characteristics and relative risks (RR) were extracted. Estimates were combined using a random-effects model. Heterogeneity was assessed by x2 statistics and I2 and by subgroup strata and meta-regression. Results- We identified 168 studies reporting data on 5 611 939 participants with 115 770 stroke outcomes. Eighty-five studies (3 417 098 participants; 72 996 strokes) provided adequate data for meta-analysis of estimated glomerular filtration rate and stroke risk. Incident stroke risk was increased among participants with estimated glomerular filtration rate <60 mL/min per 1.73 m2 (RR=1.73; 95% CI, 1.57-1.90; P<0.001), but there was substantial heterogeneity between studies (P<0.0001; I2, 78.5%). Moreover, the association was reduced after adjustment for cardiovascular risk factors, with progressive attenuation on more thorough adjustment for hypertension: single baseline blood pressure measure (RR=1.63; CI, 1.34-1.99; P<0.001); history or treated hypertension (RR=1.35; CI, 1.24-1.46; P<0.001); multiple blood pressure measurements over months to years (RR=1.10; CI, 1.02-1.18; P=0.01). Conclusions- The association between chronic kidney disease and stroke appears to be highly dependent on the method of adjustment for hypertension. The apparently independent relationship between chronic kidney disease and stroke may be confounded by their shared association with long-term prior blood pressure.


Dissection of a complex phenotype by functional genomics reveals roles for the yeast cyclin-dependent protein kinase Pho85 in stress adaptation and cell integrity.
Cyclin-dependent kinases (Cdks) are key regulators of the cell division cycle. Pho85 is a multifunctional Cdk in budding yeast involved in aspects of metabolism, the cell cycle, cell polarity, and gene expression. Consistent with a broad spectrum of functions, Pho85 associates with a family of 10 cyclins and deletion of PHO85 causes a pleiotropic phenotype. Discovering the physiological substrates of protein kinases is a major challenge, and we have pursued a number of genomics approaches to reveal the processes regulated by Pho85 and to understand the root cause of reduced cellular fitness in pho85Delta mutant strains. We used a functional-genomics approach called synthetic genetic array (SGA) analysis to systematically identify strain backgrounds in which PHO85 is required for viability. In parallel, we used DNA microarrays to examine the genome-wide transcriptional consequences of deleting PHO85 or members of the Pho85 cyclin family. Using this pairwise approach coupled with phenotypic tests, we uncovered clear roles for Pho85 in cell integrity and the response to adverse growth conditions. Importantly, our combined approach allowed us to ascribe new aspects of the complex pho85 phenotype to particular cyclins; our data highlight a cell integrity function for the Pcl1,2 subgroup of Pho85 Cdks that is independent of a role for the Pho80-Pho85 kinase in the response to stress. Using a modification of the SGA technique to screen for suppressors of pho85Delta strain growth defects, we found that deletion of putative vacuole protein gene VTC4 suppressed the sensitivity of the pho85Delta strain to elevated CaCl(2) and many other stress conditions. Expression of VTC4 is regulated by Pho4, a transcription factor that is inhibited by the Pho80-Pho85 kinase. Genetic tests and electron microscopy experiments suggest that VTC4 is a key target of Pho4 and that Pho80-Pho85-mediated regulation of VTC4 expression is required for proper vacuole function and for yeast cell survival under a variety of suboptimal conditions. The integration of multiple genomics approaches is likely to be a generally useful strategy for extracting functional information from pleiotropic mutant phenotypes.


Analysis of the bond between encephalomyocarditis virus and its human erythrocyte receptor by affinity chromatography on virus-sepharose columns.
Affinity chromatography was used to analyse the bond between encephalomyocarditis (EMC) virus and glycophorin, the receptor for EMC virus on human erythrocytes. Between 60 and 80% of glycophorin added to virus-Sepharose columns was retained compared with 10 to 20% retention on glycine-Sepharose columns. Elution with 0.2 M-NaCl released about 80 to 90% of the retained glycophorin from virus-Sepharose columns but little from glycine-Sepharose. Glycophorin remaining on either the virus or glycine columns after 0.2 M-NaCl treatment was released with Triton X-100, suggesting that this material was aggregated and trapped non-specifically. The sensitivity of the EMC virus-glycophorin bond to 0.2 M-NaCl was confirmed by showing that the radiolabelled EMC virus that bound to human erythrocyte membranes in 0.02 M-phosphate buffer was released when washed with this buffer containing 0.2 M-NaCl. It was concluded that weak ionic interactions were involved in this virus-receptor bond. Treatment of glycophorin with neuraminidase prevented it binding to EMC virus-Sepharose indicating the requirement for sialic acid for receptor activity. However, other sialylated molecules did not bind. Only one chymotryptic peptide of glycophorin (CH0) bound to EMC virus-Sepharose, confirming that this peptide contains the virus-binding site as had been previously suggested using other techniques. The effects of two non-ionic detergents and two anionic detergents on the virus-glycophorin bond were examined. In each case a very low concentration of detergent disrupted the bond and the concentration required was in parallel with that which dissolved erythrocyte membranes. It appears that multivalent glycophorin aggregates are required for stable bond formation.


Signal transduction growth factors: the effective governance of transcription and cellular adhesion in cancer invasion.
Giulio Bizzozero classified the tissues concerning their capacity to self-renew during the adult life in labile, stable and permanent tissues. In 1940 Viktor Hamburger and Rita Levi Montalcini exposed the possibility to induce the growth of permanent cells thanks to a specific ligand Nerve Growth Factor (NGF). Stanley Cohen purified a protein the Epidermal Growth Factor (EGF), able to induce epidermis proliferation and to elicit precocious eye disclosure and teeth eruption, establishing the "inverse" relationships between the proliferation and differentiation. These two biological effects induced by EGF were according to EGFR signaling is involved in a large array of cellular functions such as proliferation, survival, adhesion, migration and differentiation. This review is focused on the key role of growth factors signaling and their downstream effectors in physiological and in pathological phenomena, the authors highlight the governance of Growth factors during the EMT in cancer invasion.


Small-Molecule Antiviral β-d-N4-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance.
Coronaviruses (CoVs) have emerged from animal reservoirs to cause severe and lethal disease in humans, but there are currently no FDA-approved antivirals to treat the infections. One class of antiviral compounds, nucleoside analogues, mimics naturally occurring nucleosides to inhibit viral replication. While these compounds have been successful therapeutics for several viral infections, mutagenic nucleoside analogues, such as ribavirin and 5-fluorouracil, have been ineffective at inhibiting CoVs. This has been attributed to the proofreading activity of the viral 3'-5' exoribonuclease (ExoN). β-d-N4-Hydroxycytidine (NHC) (EIDD-1931; Emory Institute for Drug Development) has recently been reported to inhibit multiple viruses. Here, we demonstrate that NHC inhibits both murine hepatitis virus (MHV) (50% effective concentration [EC50] = 0.17 μM) and Middle East respiratory syndrome CoV (MERS-CoV) (EC50 = 0.56 μM) with minimal cytotoxicity. NHC inhibited MHV lacking ExoN proofreading activity similarly to wild-type (WT) MHV, suggesting an ability to evade or overcome ExoN activity. NHC inhibited MHV only when added early during infection, decreased viral specific infectivity, and increased the number and proportion of G:A and C:U transition mutations present after a single infection. Low-level NHC resistance was difficult to achieve and was associated with multiple transition mutations across the genome in both MHV and MERS-CoV. These results point to a virus-mutagenic mechanism of NHC inhibition in CoVs and indicate a high genetic barrier to NHC resistance. Together, the data support further development of NHC for treatment of CoVs and suggest a novel mechanism of NHC interaction with the CoV replication complex that may shed light on critical aspects of replication.IMPORTANCE The emergence of coronaviruses (CoVs) into human populations from animal reservoirs has demonstrated their epidemic capability, pandemic potential, and ability to cause severe disease. However, no antivirals have been approved to treat these infections. Here, we demonstrate the potent antiviral activity of a broad-spectrum ribonucleoside analogue, β-d-N4-hydroxycytidine (NHC), against two divergent CoVs. Viral proofreading activity does not markedly impact sensitivity to NHC inhibition, suggesting a novel interaction between a nucleoside analogue inhibitor and the CoV replicase. Further, passage in the presence of NHC generates only low-level resistance, likely due to the accumulation of multiple potentially deleterious transition mutations. Together, these data support a mutagenic mechanism of inhibition by NHC and further support the development of NHC for treatment of CoV infections.


A possible cause of multiple intramuscular masses: Mazabraud's syndrome (2007: 11b).
Mazabraud's syndrome is the association of fibrous bone dysplasia and myxomas in soft tissues. We present a new case of this condition in a 52-year-old female patient who presented with pain in the epigastric region. As an incidental finding an abdominal CT showed multiple hypodense intramuscular masses in the upper third of her left thigh associated with a bone lesion in the left femur and left ischiopubic ramus. A plain X-ray showed bone damage in those two bones with a ground-glass pattern and gross trabeculation, consistent with fibrous bone dysplasia. The MRI showed multiple intramuscular masses hypointense in T1-weighted images and hyperintense in T2-weighted images with contrast peripheral enhancement after administering an intravenous contrast agent, with the exception of one of the masses, which showed central enhancement, suggesting multiple myxomas. Very few conditions exist that present as multiple intramuscular masses. The association of multiple intramuscular myxomas and fibrous bone dysplasia should raise suspicion of the presence of this syndrome, and allows for the follow-up of lesions, preventing unnecessary biopsies. The objective of this report is to describe a new case.


Combining Docking Pose Rank and Structure with Deep Learning Improves Protein-Ligand Binding Mode Prediction over a Baseline Docking Approach.
We present a simple, modular graph-based convolutional neural network that takes structural information from protein-ligand complexes as input to generate models for activity and binding mode prediction. Complex structures are generated by a standard docking procedure and fed into a dual-graph architecture that includes separate subnetworks for the ligand bonded topology and the ligand-protein contact map. Recent work has indicated that data set bias drives many past promising results derived from combining deep learning and docking. Our dual-graph network allows contributions from ligand identity that give rise to such biases to be distinguished from effects of protein-ligand interactions on classification. We show that our neural network is capable of learning from protein structural information when, as in the case of binding mode prediction, an unbiased data set is constructed. We next develop a deep learning model for binding mode prediction that uses docking ranking as input in combination with docking structures. This strategy mirrors past consensus models and outperforms a baseline docking program (AutoDock Vina) in a variety of tests, including on cross-docking data sets that mimic real-world docking use cases. Furthermore, the magnitudes of network predictions serve as reliable measures of model confidence.


Cannabis and tobacco use: where are the boundaries? A qualitative study on cannabis consumption modes among adolescents.
The purpose of this article is to identify tobacco and cannabis co-consumptions and consumers' perceptions of each substance. A qualitative research including 22 youths (14 males) aged 15-21 years in seven individual interviews and five focus groups. Discussions were recorded, transcribed verbatim and transferred to Atlas.ti software for narrative analysis. The main consumption mode is cannabis cigarettes which always mix cannabis and tobacco. Participants perceive cannabis much more positively than tobacco, which is considered unnatural, harmful and addictive. Future consumption forecasts thus more often exclude tobacco smoking than cannabis consumption. A substitution phenomenon often takes place between both substances. Given the co-consumption of tobacco and cannabis, in helping youths quit or decrease their consumptions, both substances should be taken into account in a global approach. Cannabis consumers should be made aware of their tobacco use while consuming cannabis and the risk of inducing nicotine addiction through cannabis use, despite the perceived disconnect between the two substances. Prevention programs should correct made-up ideas about cannabis consumption and convey a clear message about its harmful consequences. Our findings support the growing evidence which suggests that nicotine dependence and cigarette smoking may be induced by cannabis consumption.


Inverse associations of outdoor activity and vitamin D intake with the risk of Parkinson's disease.
Early studies had suggested that vitamin D intake was inversely associated with neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. However, the associations of vitamin D intake and outdoor activities with Parkinson's disease (PD) are still unclear, so this study is to evaluate these relationships from a case-control study in elderly Chinese. The study population involved 209 cases with new onsets of PD and 210 controls without neurodegenerative diseases. The data on dietary vitamin D and outdoor activities were collected using a food-frequency questionnaire and self-report questionnaire. Multivariable logistic regressions were used to examine the associations between dietary outdoor activities, vitamin D intake and PD. Adjustment was made for sex, age, smoking, alcohol use, education, and body mass index (BMI). Adjusted odds ratios (ORs) for PD in quartiles for outdoor physical activity were 1 (reference), 0.739 (0.413, 1.321), 0.501 (0.282, 0.891), and 0.437 (0.241, 0.795), respectively (P=0.002 for trend). Adjusted ORs for PD in quartiles for total vitamin D intake were 1 (reference), 0.647 (0.357, 1.170), 0.571 (0.318, 1.022), and 0.538 (0.301, 0.960), respectively (P=0.011 for trend). Our study suggested that outdoor activity and total vitamin D intake were inversely associated with PD, and outdoor activity seems to be more significantly associated with decreased risk for PD.


NEW METHOD FOR PURIFYING COXIELLA BURNETII BY DEXTRAN SULFATE PRECIPITATION FOLLOWED BY CENTRIFUGATION.
This paper describes a simple method for purifying Coxiella burnetii cultivated in the chick embryo. The procedure is based upon the preliminary clarification of infected whole-egg suspensions by precipitating the low-density lipoproteins and other extraneous solids with dextran sulfate, calcium chloride, and sodium chloride solutions, and then concentrating the rickettsiae by centrifugation.


Does sustained lung inflation at resuscitation reduce lung injury in the preterm infant?
Bronchopulmonary dysplasia (BPD) is a common outcome of preterm birth. Experimental animal work has shown that initial ventilation strategies injure the immature lung and may lead to BPD. Studies with asphyxiated babies have shown that, if tidal ventilation at birth is preceded by sustained lung inflation, larger inflation volumes can be achieved, which is thought to lead to clearance of lung fluid and formation of the functional residual capacity (FRC). To see if sustained lung inflation at initial resuscitation of preterm babies would facilitate the removal of lung fluid, establish the FRC, and allow an even distribution of alveolar opening, permitting less aggressive ventilation, leading to a reduction in pulmonary inflammation and subsequent BPD. The outcomes of 52 babies of less than 31 weeks gestation, resuscitated at birth using either a sustained lung inflation of five seconds or a conventional lung inflation of two seconds for the first assisted breath of resuscitation, were examined. Evidence of pulmonary inflammation was determined by quantification of interleukins 6, 10, and 1beta and tumour necrosis factor alpha in bronchoalveolar lavage fluid by enzyme linked immunosorbent assay. There were no significant differences in any of the cytokines. Death occurred in 3/26 babies in the conventional group and 6/26 babies in the sustained lung inflation group. Survival without BPD occurred in 13/26 and 14/26 respectively. The use of sustained lung inflation at resuscitation did not reduce lung injury, as measured by inflammatory markers.


[Role of enteral nutrition in correction of protein-energy metabolism and quality of life indices in liver cirrhosis of viral etiology].
The aim of this work is to improve the efficiency of treatment and life quality of patients with HCV hepatic cirrhosis (HC) Class C by means of correction of protein-energy insufficiency (PEI) using enteral nutritive mixtures with branched-chain amino acids (BCAA). OBJECT AND METHODS OF RESEARCH: A randomized prospective controlled open research of the efficiency of therapy with enteral nutritive mixtures with BCAA for patients with HCV hepatic cirrhosis Class C (score: 10-12) was conducted. It evaluated life quality of the patients (by questionnaire SF-36), the degree of hepatic encephalopathy (by number connection test) as well as the protein-energy insufficiency indexes (weight index, arm muscles circumference, skin-fat fold for triceps and albumin). Nutritive support with BCAA prevents progression of protein-energy insufficiency, improves functionality class of patients with HCV hepatic cirrhosis Class C and reduces severity of hepatic encephalopathy, p < 0.003. Enteral nutrition with BCAA improves life quality of patients with HCV hepatic cirrhosis Class C, p < 0.012. Enteral nutrition with BCAA for patients with HCV hepatic cirrhosis Class C (score: 10-12) improves treatment efficiency and is safe.


Climate Change, Food Supply, and Dietary Guidelines.
Food production is affected by climate change, and, in turn, food production is responsible for 20-30% of greenhouse gases. The food system must increase output as the population increases and must meet nutrition and health needs while simultaneously assisting in achieving the Sustainable Development Goals. Good nutrition is important for combatting infection, reducing child mortality, and controlling obesity and chronic disease throughout the life course. Dietary guidelines provide advice for a healthy diet, and the main principles are now well established and compatible with sustainable development. Climate change will have a significant effect on food supply; however, with political commitment and substantial investment, projected improvements will be sufficient to provide food for the healthy diets needed to achieve the Sustainable Development Goals. Some changes will need to be made to food production, nutrient content will need monitoring, and more equitable distribution is required to meet the dietary guidelines. Increased breastfeeding rates will improve infant and adult health while helping to reduce greenhouse gases.


Disseminated tuberculosis presenting with polymorphonuclear effusion and septic shock in an HIV-seropositive patient: a case report.
Because a substantial number of patients present with few or atypical symptoms, the recognition of tuberculosis remains challenging. Disseminated tuberculosis presenting with septic shock has already been described in some case reports, but, to the best of our knowledge, it has never been associated with polymorphonuclear effusion. We describe the case of a 27-year-old man from western Africa who was seropositive for human immunodeficiency virus. He presented with pleural and abdominal polymorphonuclear effusions and quickly developed septic shock due to disseminated Mycobacterium tuberculosis infection leading to multiple organ failure and death. In high-risk patients, Mycobacterium tuberculosis infection should be considered even in exceptional clinical presentations, such as septic shock and polymorphonuclear effusions.


[Case report--Crossed aphasia].
A case study of crossed aphasia is presented. A 60-year-old right-handed individual suffered stroke in the right hemisphere leaving him with Broca's aphasia and severe verbal apraxia. A CT scan 3 days after hospitalization showed a new frontotemporal infarct in the right hemisphere, insula and frontal portion of the superior and middle temporal gyrus. MRI 2 weeks later showed more diverse changes involving the parietal lobe. In addition to the Broca's aphasia and verbal apraxia AA had prosodic difficulties involving intonation, stress and conversational vocal variations. Interesting phonological problems were also present, such as total loss of so-called preaspiration, a characteristic of the Icelandic phonological system. In 70% of crossed aphasia cases the symptoms are similar to those of aphasia in the left hemisphere but AA clearly does not fall into that group.


A Randomized Fellow-Eye Clinical Trial to Evaluate Patient Preference for Dexamethasone Intracanalicular Insert or Topical Prednisolone Acetate for Control of Postoperative Symptoms Following Bilateral Femtosecond Laser in Site Keratomileusis (LASIK).
To determine the preference of patients undergoing bilateral LASIK for either the dexamethasone intracanalicular insert or topical prednisolone acetate for control of postoperative symptoms and ocular surface signs. In this randomized clinical trial, one eye was randomized to receive the dexamethasone insert or topical prednisolone acetate 1% four times daily for one week and 2 times daily for a second week; the fellow eye received the alternate therapy. One month postoperatively, patient preference for these two therapies was assessed using an adapted COMTOL questionnaire. Ocular comfort was assessed using the SPEED questionnaire. Corneal staining and uncorrected distance visual acuity (UDVA) were also assessed. Twenty patients participated. At Month 1, 80% of patients preferred the dexamethasone insert, 10% preferred prednisolone acetate, and 10% expressed no preference (p<0.001). SPEED scores measuring ocular comfort/discomfort related to dry eye symptoms were similar between groups (p=0.72), and both the incidence of patient-reported ocular dryness and the corneal staining scores were similar between groups. Both groups attained the same final UDVA. Patients undergoing elective bilateral femtosecond LASIK surgery overwhelmingly (by an 8-to-1 margin) preferred the dexamethasone insert to topical prednisolone acetate for postoperative treatment. The insert produced comparable ocular comfort, corneal staining, and visual acuity outcomes to topical prednisolone. The insert is an appropriate means of postoperative symptom control in this quality of life-conscious population.


The role of tobacco smoke, iron ore mine dusts, viruses, and chemicals in experimental cancer.
Assessment of long-term studies on the carcinogenic potential of certain environmental agents has indicated that all of the following appear to activate and/or promote the inherent tumors of the host strains of the animals used irrespective of the extent of additional immunological modulation accompanying the agents: tobacco smoke inhalation, the implantation and inhalation of the respirable fraction of iron ore mine dusts, acute neonatal reovirus 3 infection, urethane, and tobacco smoke inhalation following urethane treatment. It is proposed that these environmental agents function at the onc-gene level as promoters/activators rather than carcinogens, and that this now requires an understanding of the means by which certain environmental agents function at the onc-gene level.


Growth hormone receptor gene expression in porcine skeletal and cardiac muscles is selectively regulated by postnatal undernutrition.
During mild postnatal undernutrition, growth hormone receptor (GHR) mRNA abundance decreases in liver but increases in longissimus dorsi muscle. We tested the following hypotheses: 1) GHR gene expression is related to the metabolic and contractile characteristics of different muscles, and 2) the GHR response to nutrition depends on muscle type. Eight pairs of littermate pigs were weaned at 3 wk and given an optimal [60 g/(kg.d)] or low [(20 g/(kg.d)] food intake for the next 3 wk. All pigs grew, but at a slower rate in the low food intake group (P: < 0.001). Functionally distinct muscles were assessed for GHR mRNA (RNase protection analysis), oxidative myofibers (succinate dehydrogenase histochemistry) and type I slow myofibers (myosin immunocytochemistry). There were striking muscle-specific differences in GHR gene expression (P: < 0.001) and in its regulation by nutritional status. Relative expression of GHR mRNA in the optimal food intake group occurred in ascending order as follows: longissimus < diaphragm approximately rhomboideus < cardiac < soleus. There was a positive correlation with the proportion of oxidative myofibers (P: < 0.001) but not with type I myofibers (P: > 0.10). Compared with the high intake pigs, hepatic GHR mRNA was downregulated in the low intake pigs by 59% (P: < 0.01), whereas in the four muscles examined it was upregulated as follows: longissimus, 124% (P: < 0.05); rhomboideus, 19% (P: > 0.4); soleus, 65% (P: < 0. 05); cardiac, 51% (P: < 0.05). Moreover, the proportion of skeletal muscle fibers with high oxidative capacity was also greater in the low intake group (P: < 0.05). We conclude that postnatal GHR gene expression and its regulation by mild undernutrition are related to the metabolic, contractile and specific functional properties of different muscles.


Characteristics of an OSLD in the diagnostic energy range.
Optically stimulated luminescence (OSL) dosimetry has been recently introduced in radiation therapy as a potential alternative to the thermoluminescent dosimeter (TLD) system. The aim of this study was to investigate the feasibility of using OSL point dosimeters in the energy range used in diagnostic imaging. NanoDot OSL dosimeters (OSLDs) were used in this study, which started with testing the homogeneity of a new packet of nanoDots. Reproducibility and the effect of optical treatment (bleaching) were then examined, followed by an investigation of the effect of accumulated dose on the OSLD indicated doses. OSLD linearity, angular dependence, and energy dependence were also studied. Furthermore, comparison with LiF:Mg,Ti TLD chips using standard CT dose phantoms at 80 and 120 kVp settings was performed. Batch homogeneity showed a coefficient of variation of <5%. Single-irradiation measurements with bleaching after each OSL readout was found to be associated with a 3.3% reproducibility (one standard deviation measured with a 8 mGy test dose), and no systematic change in OSLDs sensitivity could be noted from measurement to measurement. In contrast, the multiple-irradiation readout without bleaching in between measurements was found to be associated with an uncertainty (using a 6 mGy test dose) that systematically increased with accumulated dose, reaching 42% at 82 mGy. Good linearity was shown by nanoDots under general x-ray, CT, and mammography units with an R2 > 0.99. The angular dependence test showed a drop of approximately 70% in the OSLD response at 90 degrees in mammography (25 kVp). With the general radiography unit, the maximum drop was 40% at 80 kVp and 20% at 120 kVp, and it was only 10% with CT at both 80 and 120 kVp. The energy dependence study showed a range of ion chamber-to-OSLDs ratios between 0.81 and 1.56, at the energies investigated (29-62 keV). A paired t-test for comparing the OSLDs and TLDs showed no significant variation (p > 0.1). OSLDs exhibited good batch homogeneity (<5%) and reproducibility (3.3%), as well as a linear response. In addition, they showed no statistically significant difference with TLDs in CT measurements (p > 0.1). However, high uncertainty (42%) in the dose estimate was found as a result of relatively high accumulated dose. Furthermore, nanoDots showed high angular dependence (up to 70%) in low kVp techniques. Energy dependence of about 60% was found, and correction factors were suggested for the range of energies investigated. Therefore, if angular and energy dependences are taken into consideration and the uncertainty associated with accumulated dose is avoided, OSLDs (nanoDots) can be suitable for use as point dosimeters in diagnostic settings.


Altered beta adrenergic receptor function in subjects with symptomatic mitral valve prolapse.
Individuals with mitral valve prolapse (MVP) frequently show symptoms of a hyperadrenergic state. beta adrenergic receptor characteristics were compared in the lymphocytes of subjects with symptomatic MVP and control subjects during rest and exercise. At rest, the proportion of receptors binding agonist with high affinity, as determined from isoproterenol competition for (-)[125I]-iodopindolol binding sites, was greater in MVP subjects than in controls. With exercise, the proportion of high-affinity receptors in MVP subjects decreased to control levels. Isoproterenol stimulation of lymphocyte 3',5'-cyclic adenosine monophosphate (cyclic AMP) also was greater in MVP subjects than in controls at rest, but not during exercise. Plasma catecholamine concentrations in MVP subjects were normal during both rest and exercise. Unlike exercise, isoproterenol infusion elicited clinical manifestations of increased adrenergic responsiveness in MVP subjects. The beta receptor in exercised MVP subjects exhibited unusually high affinity agonist binding (i.e. a lower dissociation constant KH than in either the same subjects at rest or exercised controls) and also abnormal coupling to the stimulatory guanine nucleotide-binding regulatory protein (GS) of adenylate cyclase, as reflected by the inability of guanine nucleotide to convert the receptor to a low-affinity state. These findings suggest that functional alteration of the beta adrenergic receptor, in the absence of abnormal plasma catecholamine levels, might contribute to the hyperadrenergic state of MVP subjects at rest. However, desensitization of high affinity beta receptors or altered receptor-GS coupling might preserve normal adrenergic responsiveness during exercise.


Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans.
Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.


Feasibility and acceptability study of risk reduction approach for stroke prevention in primary care in Western India.
Stroke is among the leading cause of morbidity and mortality and prevention is the need of the hour. Risk assessment of stroke could be done at primary care. A study was hence planned to assess if an information, education, and communication (IEC) intervention module could be used to address risk factors of stroke among attendees of primary care in Western India. Patients (>30 years) attending primary care center were enrolled (n = 215). Knowledge, attitude, and practice (KAP) questionnaire was administered at baseline and end line, and detailed diagnosis (hypertension and/diabetes, stroke, coronary artery disease, etc.) was noted from written records. A predesigned IEC module was administered about stroke, risk factors, and their prevention. Body mass index (BMI) and waist-to-hip ratio were taken before and after 16 weeks. A total of 215 participants (M: F = 85:130; mean age = 51.66 ± 13.32 years) had risk factors such as hypertension (26.7%), diabetes (32.5%), history of stroke (n = 3; = 1.39%), and 7.4% (16/215) had coronary artery disease. Before and after comparison of KAP scores indicated significant difference (62.23 ± 19.73 vs. 75.32 ± 13.03); P ≤ 0.0001). Change of waist-to-hip ratio occurred from baseline 0.91-0.9 (P ≤ 0.001). Comparison of the proportion of patients taking antihypertensives before and after IEC intervention was statistically significant (P < 0.05), indicating improvement in drug compliance. BMI comparison changed marginally (26.5 ± 4.7 vs. 26.2 ± 4.5) before and after but was not significant (P ≥ 0.05). The intervention was found to be feasible and acceptable. IEC intervention appears to be a low-cost, feasible, and acceptable implementation model for addressing risk factors for stroke in primary care.


Diagnostic criteria for traumatic grief.
This article reviews the rationale for the development of diagnostic criteria for Traumatic Grief. Traumatic Grief is a new nosologic entity that a panel of experts recently proposed. It is a direct descendent of the concept of pathologic grief, and it has roots in attachment behavior, separation distress, and traumatic distress. We present consensus, diagnostic criteria for Traumatic Grief and discuss them in relation to another recently proposed set of criteria. In conclusion, we recommend the development of empirically tested, consensus, diagnostic criteria for Traumatic Grief. Diagnostic criteria would facilitate early detection and intervention for those bereaved persons afflicted by this disorder and lead to additional studies of the prevalence, the nature, and the treatment of the disorder.


Do Satisfied Older Employees Perceive More Social Support Over Time? A Cross-Lagged Examination.
Perceived social support has traditionally been examined as an antecedent of well-being, including job satisfaction. The current study offers a new perspective in which job satisfaction can be both an antecedent and outcome of support in older employees. Two wave data from 910 older employees who participated in the Health and Retirement Study were used to test the hypotheses using a cross-lagged panel model. The results indicate that job satisfaction predicts subsequent perceived support from both supervisors and coworkers. However, perceived support from either supervisors or coworkers does not predict subsequent job satisfaction. The discussion suggests that unsatisfied employees, who likely are in greater need of support from their supervisors and peers, perceive having less support available to them. Practically, interventions aimed at increasing satisfaction might also benefit employees' perceived support, and organizations could leverage our findings to create more favorable work environments.


Auditory spatial attention to speech and complex non-speech sounds in children with autism spectrum disorder.
One of the earliest observable impairments in autism spectrum disorder (ASD) is a failure to orient to speech and other social stimuli. Auditory spatial attention, a key component of orienting to sounds in the environment, has been shown to be impaired in adults with ASD. Additionally, specific deficits in orienting to social sounds could be related to increased acoustic complexity of speech. We aimed to characterize auditory spatial attention in children with ASD and neurotypical controls, and to determine the effect of auditory stimulus complexity on spatial attention. In a spatial attention task, target and distractor sounds were played randomly in rapid succession from speakers in a free-field array. Participants attended to a central or peripheral location, and were instructed to respond to target sounds at the attended location while ignoring nearby sounds. Stimulus-specific blocks evaluated spatial attention for simple non-speech tones, speech sounds (vowels), and complex non-speech sounds matched to vowels on key acoustic properties. Children with ASD had significantly more diffuse auditory spatial attention than neurotypical children when attending front, indicated by increased responding to sounds at adjacent non-target locations. No significant differences in spatial attention emerged based on stimulus complexity. Additionally, in the ASD group, more diffuse spatial attention was associated with more severe ASD symptoms but not with general inattention symptoms. Spatial attention deficits have important implications for understanding social orienting deficits and atypical attentional processes that contribute to core deficits of ASD. Autism Res 2017, 10: 1405-1416. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.


Functional changes in the rat distal colon after whole-body irradiation: dose-response and temporal relationships.
The aim of this study was to determine the acute radiation response of the rat distal colon by in vivo and in vitro measurements of the functions of the colon over a range of radiation doses. Rats received a whole-body irradiation of 2 to 12 Gy and were studied from 1 to 7 days after exposure. In vivo water and electrolyte absorption was measured by insertion of an agarose cylinder in the colon of anesthetized rats. In vitro transepithelial electrical parameters (potential difference, short-circuit current, transepithelial conductance) were measured in Ussing chambers in basal and agonist-stimulated conditions. In vivo and in vitro functional studies were completed by standard histological analyses. The majority of functional modifications appeared at 4 days after exposure. At this time, a dose-dependent decrease in absorption of water and sodium/chloride ions in the colon was noted. In contrast, a twofold increase in potassium secretion was observed for every radiation dose studied. The response to secretagogues was attenuated at doses >8 Gy. Modifications of basal transepithelial electrical parameters together with marked histological alterations were observed at 4 days with the higher doses (>/=10 Gy). In conclusion, these results show that functions of the colon are affected by irradiation and may contribute to diarrhea induced by ionizing radiation.


[The modular MML revision system in knee revision and tumor arthroplasty].
Increasing age and a higher level of mobility lead to an increasing incidence in revision arthroplasty after total knee replacement and tumor surgery. So far, the reconstruction of large defects in bony and soft tissue environments can be accomplished by the modern modular components of revision implants. The consecutive reconstruction of the extensor mechanism in extended revision has its own drawbacks and is often associated with significant functional limitations for the patient. Specially designed implants and methods are required to generate good functional results. The modular knee revision system MML provides specific modifications of the tibial component for reconstruction of the extensor mechanism. Combined with artificial strips, an excellent functional outcome could be achieved. In this study, 70 patients were operated with the MML endoprosthesis in knee revision or tumor surgery. An excellent functional outcome could be determined. At 7 years after surgery, an average of 32+/-13 points was achieved on the Oxford Knee Score. The outcome measurement using the functional scoring system of the American Knee Society (AKS score) showed similarly good results with 71+/-25 points out of 100. A minor deficit of only 2 degrees in active extension could be observed after reconstruction of the extensor mechanism. In conclusion, we have demonstrated that the MML modular revision system is appropriate for reconstruction of segmental bone defects.


The reliability and validity of general psychotic rating scales with people with mild and moderate intellectual disabilities: an empirical investigation.
Whilst assessment tools have been developed to diagnose schizophrenia in people with mild intellectual disabilities (IDs), little attention has been paid to developing reliable and valid dimensional measures of psychotic experiences with this population. This study investigates the reliability and validity of two such measures developed for the general adult psychiatric population, the Positive and Negative Syndrome Scale (PANSS) and the Psychotic Symptom Rating Scales (PSYRATS), with a population of adults with mild IDs. Sixty-two adults with mild IDs were interviewed using the PANSS and PSYRATS, and independently interviewed using the Psychiatric Assessment Schedule--Adults with Developmental Disability (PAS-ADD) to obtain psychiatric diagnoses to the criteria of the International Classification of Diseases--Tenth Revision (ICD-10). On the basis of ICD-10 diagnosis, participants were divided into three groups: psychosis (n=11); other mental health problem (n=14); no mental health problem (n=37). PANSS and PSYRATS subscale scores were compared across these three groups and were correlated with PAS-ADD symptom scores across a number of PAS-ADD symptom domains. All PANSS and PSYRATS subscales showed adequate internal reliability, largely good test-retest reliability, and logical inter-correlations between subscales. The PANSS positive symptoms and the PSYRATS auditory hallucinations subscales differentiated between the psychosis group and the other groups; the PANSS general symptoms subscale differentiated between the psychosis and no mental health problem groups; and the PANSS negative symptoms and the PSYRATS delusions subscales did not differentiate between the three groups. The PANSS and PSYRATS are promising measures for use with people with mild IDs and psychotic experiences, although further investigation of items relating to negative symptoms and delusions is warranted.


Evaluating a protocol to train hospice staff in administering individualized music.
The ongoing extension of the average human lifespan in most parts of the world forecasts an unprecedented number of aging adults developing Alzheimer's disease or related dementia. Behavioural and psychological symptoms of dementia, commonly referred to as agitated behaviours, are estimated to occur in over 80% of patients and are typically treated using antipsychotic medications, posing significant morbidity and mortality risks. An evidence-based protocol known as individualized music (IM) offers a non-pharmacological intervention to reduce agitation. This project, using a one-group pre-test-post-test design, was implemented by training a self-selected sample of 24 hospice professionals to use the IM protocol with dementia patients. The effectiveness of the training on increasing the participants' knowledge of and confidence in using IM was explored. Paired t-tests were employed to analyze the data and the results of the analysis were encouraging, suggesting that it is feasible to educate multidisciplinary hospice staff in implementing the IM protocol. Thus, there is potential for using IM in the palliative treatment of persons with advanced dementia.


Gay, lesbian, and bisexual patients' recommendations for genetic counselors: a qualitative investigation.
Gay, lesbian, and bisexual (GLB) individuals comprise a growing patient population in genetic counseling. However, only one article from a genetic counseling journal provides empirical data on GLB patients' genetic counseling experiences and genetic counselor attitudes and practices regarding GLB patients. The present study, an extension of the aforementioned article, gathered further information about patients' genetic counseling experiences through semi-structured telephone interviews. Twelve of the previous study's 29 patient respondents (n = 10 lesbian women, n = 1 gay man, n = 1 bisexual woman) participated. Interview questions concerned the use of medically inclusive forms, factors influencing patient disclosure, counselors' ability to relate to them, and their expectations of genetic counselors. Inductive analysis of the interviews yielded seven themes: 1) Medically inclusive forms with gender neutral terms are important; 2) Genetic counselor ability to relate to a GLB person depends more on the relationship established during the session and less on external symbols; 3) The presence of GLB-friendly symbols increases comfort when disclosing one's orientation; 4) Inclusion of the patient's partner is important and best done by encouraging their active participation in sessions; 5) When GLB patients disclose their orientation, they expect to be treated like any other patient; 6) Providers should ask about orientation if medically pertinent and the remaining discussion should take orientation into consideration; and 7) When a provider inquires about orientation it should be done in a safe and appropriate way. Illustrative quotations, genetic counseling practice implications, and research recommendations are presented.


Ethical Advice for an Intensive Care Triage Protocol in the COVID-19 Pandemic: Lessons Learned from The Netherlands.
At the height of the COVID-19 crisis in the Netherlands a shortness of intensive care beds was looming. Dutch professional medical organizations asked a group of ethicists for assistance in drafting guidelines and criteria for selection of patients for intensive care (IC) treatment in case of absolute scarcity, when medical selection criteria would no longer suffice. This article describes the Dutch context, the process of drafting the advice and reflects on the role of ethicists and lessons learned. We argue that timely interaction between clinical and ethical expertise is necessary since the distinction between medical and non-medical considerations is not as clearcut as sometimes assumed. Furthermore, pragmatic considerations related to the specifics of an epidemic are of importance, for example, in relation to prioritizing health care workers. As a consequence, any protocol already present before the pandemic would need alterations to fit the current situation. The 'fair innings' criterion we proposed, rephrased as an argument of intergenerational solidarity, was considered reasonable by professionals as well as patient organizations. While it is desirable to draft ethical guidelines in 'peacetime' as a matter of pandemic preparedness, the pressure of an actual crisis facilitates decision-making, although it will also complicate a more democratic approach.