Aortic stiffness in lone atrial fibrillation: a novel risk factor for arrhythmia recurrence.
Recent community-based research has linked aortic stiffness to the development of atrial fibrillation. We posit that aortic stiffness contributes to adverse atrial remodeling leading to the persistence of atrial fibrillation following catheter ablation in lone atrial fibrillation patients, despite the absence of apparent structural heart disease. Here, we aim to evaluate aortic stiffness in lone atrial fibrillation patients and determine its association with arrhythmia recurrence following radio-frequency catheter ablation. We studied 68 consecutive lone atrial fibrillation patients who underwent catheter ablation procedure for atrial fibrillation and 50 healthy age- and sex-matched community controls. We performed radial artery applanation tonometry to obtain central measures of aortic stiffness: pulse pressure, augmentation pressure and augmentation index. Following ablation, arrhythmia recurrence was monitored at months 3, 6, 9, 12 and 6 monthly thereafter. Compared to healthy controls, lone atrial fibrillation patients had significantly elevated peripheral pulse pressure, central pulse pressure, augmentation pressure and larger left atrial dimensions (all P<0.05). During a mean follow-up of 2.9±1.4 years, 38 of the 68 lone atrial fibrillation patients had atrial fibrillation recurrence after initial catheter ablation procedure. Neither blood pressure nor aortic stiffness indices differed between patients with and without atrial fibrillation recurrence. However, patients with highest levels (≥75(th) percentile) of peripheral pulse pressure, central pulse pressure and augmentation pressure had higher atrial fibrillation recurrence rates (all P<0.05). Only central aortic stiffness indices were associated with lower survival free from atrial fibrillation using Kaplan-Meier analysis. Aortic stiffness is an important risk factor in patients with lone atrial fibrillation and contributes to higher atrial fibrillation recurrence following catheter ablation procedure.


Salmonella enterica in swine production: assessing the association between amplified fragment length polymorphism and epidemiological units of concern.
The aims of this study were to determine the ability of amplified fragment length polymorphism (AFLP) to differentiate Salmonella isolates from different units of swine production and to demonstrate the relatedness of Salmonella between farms and abattoirs by AFLP. Twenty-four farms in the midwestern United States were visited four times from 2006 to 2009. At each farm or abattoir visit, 30 fecal samples or 30 mesenteric lymph nodes were collected, respectively. A total of 220 Salmonella isolates were obtained, serotyped, and genotyped by multilocus sequence typing (MLST) and AFLP. These 220 isolates clustered into 21 serotypes, 18 MLST types, and 14 predominant AFLP clusters based on a genetic similarity threshold level of 60%. To assess genetic differentiation between farms, harvest cohorts, and pigs, analysis of molecular variance was conducted using AFLP data. The results showed 65.62% of overall genetic variation was attributed to variance among pigs, 27.21% to farms, and 7.17% to harvest cohorts. Variance components at the farm (P = 0.003) and pig (P = 0.001) levels were significant, but not at the harvest cohort level (P = 0.079). A second analysis, a permutation test using AFLP data, indicated that on-farm and at-abattoir Salmonella from pigs of the same farms were more related than from different farms. Therefore, among the three subtyping methods, serotyping, MLST, and AFLP, AFLP was the method that was able to differentiate among Salmonella isolates from different farms and link contamination at the abattoir to the farm of origin.


Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease.
Motor dysfunction, cognitive impairment, and regional cortical atrophy indicate cerebral cortical involvement in Huntington disease (HD). To address the hypothesis that abnormal corticostriatal connectivity arises from polyglutamine-related alterations in cortical gene expression, we isolated layer 5 cortical neurons by laser-capture microdissection and analyzed transcriptome-wide mRNA changes in them. Enrichment of transcription factor mRNAs including foxp2, tbr1, and neuroD6, and neurotransmission- and plasticity-related RNAs including sema5A, pclo, ntrk2, cntn1, and Lin7b were observed. Layer 5 motor cortex neurons of transgenic R6/2 HD mice also demonstrated numerous transcriptomic changes, including decreased expression of mRNAs encoding the Lin7 homolog b ([Lin7b] also known as veli-2 and mals2). Decreases in LIN7B and CNTN1 RNAs were also detected in human HD layer 5 motor cortex neurons. Lin7 homolog b, a scaffold protein implicated in synaptic plasticity, neurite outgrowth, and cellular polarity, was decreased at the protein level in layer 5 cortical neurons in R6/2 mice and human HD brains. Decreases in Lin7b and Lin7a mRNAs were detected in R6/2 cortex as early as 6 weeks of age, suggesting that this is an early pathogenetic event. Thus, decreased cortical LIN7 expression may contribute to abnormal corticostriatal connectivity in HD.


Regression and data mining methods for analyses of multiple rare variants in the Genetic Analysis Workshop 17 mini-exome data.
Group 14 of Genetic Analysis Workshop 17 examined several issues related to analysis of complex traits using DNA sequence data. These issues included novel methods for analyzing rare genetic variants in an aggregated manner (often termed collapsing rare variants), evaluation of various study designs to increase power to detect effects of rare variants, and the use of machine learning approaches to model highly complex heterogeneous traits. Various published and novel methods for analyzing traits with extreme locus and allelic heterogeneity were applied to the simulated quantitative and disease phenotypes. Overall, we conclude that power is (as expected) dependent on locus-specific heritability or contribution to disease risk, large samples will be required to detect rare causal variants with small effect sizes, extreme phenotype sampling designs may increase power for smaller laboratory costs, methods that allow joint analysis of multiple variants per gene or pathway are more powerful in general than analyses of individual rare variants, population-specific analyses can be optimal when different subpopulations harbor private causal mutations, and machine learning methods may be useful for selecting subsets of predictors for follow-up in the presence of extreme locus heterogeneity and large numbers of potential predictors.


High XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma.
We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome. XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1). Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44-8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16(INK4a)-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52-4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06-0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36-15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08-0.92, respectively; P = 0.037). In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment.


Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison.
Twenty-seven patients with recurrent unipolar depression and 22 with bipolar II illness in remission for at least six months were randomly assigned on a double-blind basis to treatment regimens using lithium carbonate, imipramine hydrochloride, lithium carbonate plus imipramine, or placebo. Lithium carbonate was found to help prevent depressive relapse among patients with unipolar disease, and relapse of any type among those with bipolar II disease. No effect or interaction of imipramine was found in either group. These results add to a growing body of data that suggest the usefulness of lithium carbonate in the prophylaxis of unipolar depressive illness. The relative usefulness of lithium carbonate and imipramine requires further study.


3 T MR cholangiopancreatography appearances of biliary ascariasis.
To evaluate the 3 T MR cholangiopancreatography (MRCP) appearances of biliary ascariasis. Nine patients with a MRCP diagnosis of biliary ascariasis were reviewed. All patients had endoscopic retrograde cholangiopancreatography (ERCP) or surgical confirmation of the disease. On thin-slab MRCP imaging, Ascaris worms are clearly demarcated within the biliary tree. All the identified worms demonstrated a characteristic three-parallel-lines appearance. The middle high-signal intensity line is sandwiched between two low-signal intensity lines and they are in turn surrounded by high signal bile. On thick-slab MRCP the worms also show the three-line sign but with less clarity. However, thick-slab MRCP has the advantage of providing three-dimensional ERCP-like images of the pancreaticobiliary system. The "three-line" sign appears to be a characteristic sign of biliary ascariasis on 3 T MRCP.


Lactational oestrus and reproductive performance following a delayed limited nursing schedule in primiparous sows.
With conventional lactation management, sows only conceive after weaning. However, intermittent suckling (IS) enables follicle growth and ovulation during lactation by reducing the suckling-induced inhibition of gonadotrophins. The current study evaluated IS regimes initiated at Day 21 or Day 28 post farrowing compared to conventional weaning on Day 28, in primiparous sows. Sows (Large White and Large White x Landrace) were randomly allocated to Control (C28; n = 44), IS21 (n = 29) and IS28 (n = 34) treatments at Day 20. Sows in IS21 and IS28 were subjected to intermittent suckling from Day 21 or Day 28 post farrowing. During IS, sows were separated from their piglets for 8 h daily, then weaned 7 d later at Day 28 and Day 35 respectively, whereas piglets in the C28 treatment had continuous access to sows until weaning at Day 28. Percentage of IS sows that showed oestrus during lactation was 59% (16/27) in IS21 and 72% (21/29) in IS28 (P > 0.05). Cumulatively over the lactation and 7 d post-weaning period, 93% of IS21, 85% of IS28 and 93% (31/33) of C28 sows showed oestrus (P > 0.05). Pregnancy rate at Day 30 post mating, for sows that were mated during lactation was 93% (15/16) in IS21 and 95% (20/21) in IS28, whereas C28 sows had a 96% (30/31) pregnancy rate (P > 0.05). No difference was found in the time of oestrus relative to weaning (C28) or onset of IS (IS21 and IS28) (P > 0.05). The IS sows that did not ovulate before weaning all showed oestrus within 7 days from weaning, and the weaning to oestrus interval was similar to control sows (P > 0.05). However, for all IS sows (across IS treatments) that showed lactational ovulation, LH secretion pattern at onset of IS was different (P < 0.05) from the sows that did not ovulate in lactation. Plasma progesterone concentration tended to be lower in the IS21 treatment (P < 0.10) compared to the C28 sows at 4 d after ovulation. The subsequent litter size was not affected by treatments although numerically lower for IS21 (P > 0.05). The present study showed that in modern primiparous sows, lactational oestrus can be induced and pregnancy can be maintained at a similar rate and producing comparable subsequent litter sizes to conventionally weaned sows when IS commenced at four weeks post farrowing. However, when IS commences at three weeks post farrowing, this may affect the percentage of sows showing oestrus in lactation and may potentially influence subsequent litter size.


Carcinoembryonic antigen (CEA) presentation and specific T cell-priming by human dendritic cells transfected with CEA-mRNA.
The feasibility of dendritic cells (DC) for cancer immunotherapy after transfection by electroporation with mRNA encoding the human carcinoembryonic antigen (CEA) was investigated. Both, total RNA from the CEA(+) colon cancer cell line SW480 and mRNA transcribed in vitro from cDNA3.1-plasmids (pcDNA3.1+/-HisC) with a CEA-insert (ivt-CEA-mRNA, ivt-CEA/HisC-mRNA) were used. Labelled ivt-CEA-mRNA was detectable in DC by light and electron microscopy and by fluorescence-activated cell-sorting (FACS) even 15 min after electroporation. Four hours after transfection with ivt-CEA/HisC-mRNA, we detected specific expression of CEA and the histidine-tag by immunofluorescence microscopy and by FACS. CEA-specific T lymphocytes were successfully primed by transfected DC and were able to lyse CEA-expressing target cells, even from the CEA-expressing human colon adenocarcinoma cell line SW480. Thus, DC transfected by electroporation with CEA-mRNA are valuable tools for the immunotherapy of CEA(+) tumour entities.


The impact of hyperhidrosis on patients' daily life and quality of life: a qualitative investigation.
An understanding of the daily life impacts of hyperhidrosis and how patients deal with them, based on qualitative research, is lacking. This study investigated the impact of hyperhidrosis on the daily life of patients using a mix of qualitative research methods. Participants were recruited through hyperhidrosis patient support groups such as the Hyperhidrosis Support Group UK. Data were collected using focus groups, interviews and online surveys. A grounded theory approach was used in the analysis of data transcripts. Data were collected from 71 participants, out of an initial 100 individuals recruited. Seventeen major themes capturing the impacts of hyperhidrosis were identified; these covered all areas of life including daily life, psychological well-being, social life, professional /school life, dealing with hyperhidrosis, unmet health care needs and physical impact. Psychosocial impacts are central to the overall impacts of hyperhidrosis, cutting across and underlying the limitations experienced in other areas of life.


Laparoscopic gastrectomy for gastric cancer: early experience among the elderly.
The data are scarce on the outcome for elderly patients presenting with resectable gastric cancer in the West who have been treated with minimally invasive surgery. This report presents the authors' early experience with totally laparoscopic gastric resections for cancer in elderly patients. A total of 20 patients underwent laparoscopic gastrectomy procedures: 14 distal, 5 subtotal, and 1 total gastrectomy. The male-to-female ratio was 15 to 5. The ages ranged from 75 to 88 years (mean, 80 years). All cases were managed laparoscopically with R0 resection. Four patients needed high-dependency unit care postoperatively. There were no perioperative deaths. The median time required for the procedure was 212 min, and time to diet was 4 days. The hospital stay was 8 days. Four patients experienced significant complications, with two patients requiring reoperation. The pathology was adenocarcinoma for 17 patients and high-grade dysplasia for 3 patients. Among elderly patients for whom conventional gastric surgery carries a high morbidity and mortality risk, minimal access surgery may offer equivalent oncologic integrity but with superior safety and economy. The primary aim is to remove the tumor with at least a D1 lymphadenectomy.


Lack of specificity of cyclosporine immunoassays. Results of a College of American Pathologists Study.
To evaluate the cross-reactivity of the 6 most abundant cyclosporine A (CsA) metabolites in commonly used assays for CsA. Whole blood samples containing either only 62 ng/mL CsA (A) or 62 ng/mL CsA and between 49 and 86 ng/mL of 1 of the 6 most abundant CsA metabolites (B) were lyophilized. One sample of A and 1 of B were mailed to each of the laboratories participating in the College of American Pathologists Proficiency Testing Program quarterly during a 3-year period (1999-2001). Method means and coefficients of variation were calculated for each mailing. The study showed significant cross-reactivity of metabolites in all the immunoassay systems studied. Overall degree of interference decreased from Abbott TDx polyclonal > Abbott TDx monoclonal > DiaSorin > Syva EMIT. High-performance liquid chromatography methods gave results close to those found using mass spectrometric techniques. Significant metabolite interference was found to occur with the immunoassay systems studied.


Improved staging in node-positive breast cancer patients using lymph node ratio: results in 1,788 patients with long-term follow-up.
Axillary lymph node status remains the most important prognostic factor in breast cancer. Established staging systems emphasize the absolute number of positive nodes, without regard for the total number of lymph nodes examined. We sought to confirm that a ratio of positive nodes to total nodes examined (LNR) has prognostic value beyond the current TNM classification for women with node-positive breast cancer. Using the Duke University Medical Center breast cancer tumor registry, we identified women diagnosed with node-positive breast cancer between 1985 and 2005 (n = 1,788). Variables analyzed for impact on disease-free survival (DFS) included the number of positive nodes, N classification, and the calculated LNR. Based on LNR, the patients were divided into low- (< or =0.2), intermediate- (>0.2 and < or =0.65), and high- (>0.65) risk groups. Kaplan-Meier survival analysis was performed with groups compared by the log-rank test. Values of p < 0.05 were considered significant. For all patients, the 10-year actuarial DFS rates for the low-, intermediate-, and high-risk LNR groups were 69%, 60%, and 45%, respectively. The DFS curves for the 3 LNR groups were significantly different (p < 0.0001). Furthermore, when patients were stratified by pN status, the DFS curves for the LNR groups remained significantly different. The LNR discerned groups of patients with divergent survival probabilities across all pN groups. Our data show that LNR has prognostic value in assessing breast cancer survival beyond the current TNM classification. This study supports the inclusion of LNR for enhanced risk stratification beyond traditional pN classification.


DNA polymerases beta and lambda bypass thymine glycol in gapped DNA structures.
Here we investigated the ability of the human X-family DNA polymerases beta and lambda to bypass thymine glycol (Tg) in gapped DNA substrates with the damage located in a defined position of the template strand. Maximum velocities and the Michaelis constant values were determined to study DNA synthesis in the presence of either Mg(2+) or Mn(2+). Additionally, the influence of hRPA (human replication protein A) and hPCNA (human proliferating cell nuclear antigen) on TLS (translesion synthesis) activity of DNA polymerases beta and lambda was examined. The results show that (i) DNA polymerase lambda is able to catalyze DNA synthesis across Tg, (ii) the ability of DNA polymerase lambda to elongate from a base paired to a Tg lesion is influenced by the size of the DNA gap, (iii) hPCNA increases the fidelity of Tg bypass and does not influence normal DNA synthesis catalyzed by DNA polymerase lambda, (iv) DNA polymerase beta catalyzes the incorporation of all four dNTPs opposite Tg, and (v) hPCNA as well as hRPA has no specific effect on TLS in comparison with the normal DNA synthesis catalyzed by DNA polymerase beta. These results considerably extend our knowledge concerning the ability of specialized DNA polymerases to cope with a very common DNA lesion such as Tg.


Insight into the interface between Fe3O4 (001) surface and water overlayers through multiscale molecular dynamics simulations.
In this work, we investigate the Fe3O4 (001) surface/water interface by combining several theoretical approaches, ranging from a hybrid functional method (HSE06) to density-functional tight-binding (DFTB) to molecular mechanics (MM). First, we assess the accuracy of the DFTB method to correctly reproduce HSE06 results on structural details and energetics and available experimental data for adsorption of isolated water, dimers, and trimers up to a water monolayer. Second, we build two possible configurations of a second and a third overlayer and perform molecular dynamics simulations with DFTB, monitoring the water orientation, the H-bond network, and the ordered water structure formation. To make our models more realistic, we then build a 12 nm-thick water multilayer on top of the Fe3O4 (001) surface slab model, which we investigate through MM-molecular dynamics (MD). The water layer structuring, revealed by the analysis of the atomic positions from a long MM-MD run for this large MM model, extends up to about 6-7 Å and nicely compares with that observed for a water trilayer model. However, MM and DFTB MD simulations show some discrepancy due to the poor description of the Fe⋯OH2 distance in MM that calls for further work in the parameterization of the model.


Philip Morris's failed experiment in Pittsburgh.
The campaign for passage and implementation of Pittsburgh's Smoking Control Ordinance in 1987 illustrates the role controversy plays in tobacco control. Proponents of the ordinance sought at first to keep it noncontroversial, while the tobacco industry tried to defeat the ordinance by generating controversy, claiming that severe economic and social disruption would occur. After the ordinance had been in force for a year, Philip Morris tried to take over its implementation, seeking to redefine the central issue as one of social accommodation rather than health. To succeed, Philip Morris's effort had to be widely accepted and noncontroversial. Proponents of the ordinance countered with controversy to undermine the campaign and expose the company's intentions. The controversy made the established health organizations uncomfortable, causing them to play only a marginal role. Surprisingly, the people who prevailed were the nonsmokers' rights activists, a small group with limited resources.


Intra-arterial stroke therapy: an assessment of demand and available work force.
Intra-arterial therapy is currently applicable to a small subset of patients with ischemic stroke, but it will likely have an expanding role as new devices are introduced. This review evaluates the demand for such therapy and the physician work force available to provide such therapy in the United States. The available literature was reviewed to assess how many patients might need intra-arterial therapy annually and how many skilled neurointerventionalists are available to provide intra-arterial therapy for acute stroke. The number of acute ischemic strokes in the United States that will be amenable to intra-arterial therapy can only be crudely estimated, but it is certainly less than 126,000 per year and will quite likely be no more than 20,000 cases per year. The future demand for intra-arterial reperfusion techniques may change, but the number of patients who require intra-arterial thrombolysis is currently quite low. The overall number of neurointerventionists is currently adequate, though there might be local shortages.


Low-energy states of manganese-oxo corrole and corrolazine: multiconfiguration reference ab initio calculations.
Manganese(V)-oxo corrole and corrolazine have been studied with ab initio multiconfiguration reference methods (CASPT2 and RASPT2) and large atomic natural orbital (ANO) basis sets. The calculations confirm the expected singlet d(δ)(2) ground states for both complexes and rule out excited states within 0.5 eV of the ground states. The lowest excited states are a pair of Mn(V) triplet states with d(δ)(1)d(π)(1) configurations 0.5-0.75 eV above the ground state. Manganese(IV)-oxo macrocycle radical states are much higher in energy, ≥1.0 eV relative to the ground state. The macrocyclic ligands in the ground states of the complexes are thus unambiguously 'innocent'. The approximate similarity of the spin state energetics of the corrole and corrolazine complexes suggests that the latter macrocycle on its own does not afford any special stabilization for the Mn(V)O center. The remarkable stability of an Mn(V)O octaarylcorrolazine thus appears to be ascribable to the steric protection afforded by the β-aryl groups.


A hospital study of community acquired pneumonia in the elderly.
Studies on community acquired pneumonia in the United States in patients over the age of 65 years have shown that Gram negative bacilli account for an appreciable proportion of cases, in addition to usual pathogens such as Streptococcus pneumoniae and Haemophilus influenzae. There have been no reports of community acquired pneumonia in the elderly in the United Kingdom. We undertook such a study to determine the clinical features, aetiology, and outcome. Seventy three patients (38 men) with ages ranging from 65 to 97 (median 79) years were studied prospectively. Pneumonia was defined as an acute lower respiratory tract infection with new, previously unrecorded shadowing on a chest radiograph. Patients with severe chronic illness in whom pneumonia was an expected terminal event were excluded. Nearly all the patients (96%) had respiratory symptoms or signs but many had features that might obscure the true diagnosis of pneumonia. Over half the patients had non-respiratory symptoms and over a third had no systemic signs of infection. A pathogen was identified in 43% of patients, most commonly Streptococcus pneumoniae, Haemophilus influenzae and influenza B virus. Gram negative bacilli were not seen. The mortality rate was high (33%). Early deaths were due to infection whereas later deaths were associated with other factors, such as stroke (two patients) and pulmonary embolism (two patients). Prognostic indicators for mortality were apyrexia, systolic hypotension, increasing hypoxaemia, and new urinary incontinence. As the range of pathogens causing pneumonia was the same in the elderly in this study as in other age groups it is suggested that initial antibiotic treatment for patients in this age group should always cover S pneumoniae and H influenzae.


A new species of Cetopsorhamdia (Siluriformes: Heptapteridae) from the Upper Amazon River basin.
A new species of Cetopsorhamdia is described from material collected on rapid inventories and ichthyological expeditions in the Amazon region of Peru, Ecuador and Colombia. The new species can be differentiated from all other species of Cetopsorhamdia by the colouration pattern on fins, number of vertebrae, number of ribs, level insertion of dorsal fin, number of rays on dorsal and pectoral fin, osteological characters and several other morphometric characters. The new species is distributed along tributaries of the upper Amazon River basin in Peru, Colombia and Ecuador.


Experienced and novice officers' generalized communication suspicion and veracity judgments.
Deception detection research has shown that police officers are less truth-biased and make their veracity judgments with greater confidence than do nonofficers. Here we examined nonofficers, novice officers, and experienced officers' response bias, confidence, and generalized communicative suspicion. In Experiment 1, novice officers aligned with nonofficers in terms of both generalized communicative suspicion scores and confidence, with both these groups scoring lower than experienced officers. Generalized communicative suspicion scores and veracity judgments were not significantly related for either sample. However, novice officers aligned with experienced officers in terms of judgments: both police groups were lie-biased, whereas nonofficers were truth-biased. These findings suggest that unlike experienced officers, who have embraced the police culture to a greater degree, novice officers are not dispositionally suspicious (generalized communicative suspicion); however, they are able to mirror the prototypical police behavior (deception judgments) in police-related contexts. Experiment 2 supported these notions.


The coevolution of cooperation and cognition in humans.
Cooperative behaviours in archaic hunter-gatherers could have been maintained partly due to the gains from cooperation being shared with kin. However, the question arises as to how cooperation was maintained after early humans transitioned to larger groups of unrelated individuals. We hypothesize that after cooperation had evolved via benefits to kin, the consecutive evolution of cognition increased the returns from cooperating, to the point where benefits to self were sufficient for cooperation to remain stable when group size increased and relatedness decreased. We investigate the theoretical plausibility of this hypothesis, with both analytical modelling and simulations. We examine situations where cognition either (i) increases the benefits of cooperation, (ii) leads to synergistic benefits between cognitively enhanced cooperators, (iii) allows the exploitation of less intelligent partners, and (iv) the combination of these effects. We find that cooperation and cognition can coevolve-cooperation initially evolves, favouring enhanced cognition, which favours enhanced cooperation, and stabilizes cooperation against a drop in relatedness. These results suggest that enhanced cognition could have transformed the nature of cooperative dilemmas faced by early humans, thereby explaining the maintenance of cooperation between unrelated partners.


GABAB receptor activation inhibits exocytosis in rat pancreatic beta-cells by G-protein-dependent activation of calcineurin.
We have investigated the regulation of hormone secretion from rat pancreatic islets by the GABAB receptors (GABABRs). Inclusion of the specific GABABR antagonist CGP 55845 in the extracellular medium increased glucose-stimulated insulin secretion 1.6-fold but did not affect the release of glucagon and somatostatin. Conversely, addition of the GABABR agonist baclofen inhibited glucose-stimulated insulin secretion by approximately 60%. Using RT-PCR, transcription of GABABR1a-c,f and GABABR2 subunits was detected in beta-cells. Measurements of membrane currents and cell capacitance were applied to single beta-cells to investigate the mechanisms by which GABABR activation inhibits insulin secretion. In perforated-patch measurements, baclofen inhibited exocytosis elicited by 500-ms voltage-clamp depolarizations to 0 mV by < or = 80% and voltage-gated Ca2+ entry by only approximately 30%. Both effects were concentration-dependent with IC50 values of approximately 2 microm. The inhibitory action of baclofen was abolished in the presence of CGP 55845. The ability of baclofen to suppress exocytosis was prevented by pre-treatment with pertussis toxin and by inclusion of GDPbetaS in the intracellular medium, and became irreversible in the presence of GTPgammaS as expected for a process involving inhibitory G-proteins (Gi/o-proteins). The inhibitory effect of baclofen resulted from activation of the serine/threonine protein phosphatase calcineurin and pre-treatment with cyclosporin A or intracellular application of calcineurin autoinhibitory peptide abolished the effect. Addition of baclofen had no effect on [Ca2+]i and electrical activity in glucose-stimulated beta-cells. These data indicate that GABA released from beta-cells functions as an autocrine inhibitor of insulin secretion in pancreatic islets and that the effect is principally due to direct suppression of exocytosis.


Brain MRI and neurological deficit measurements in focal stroke: rapid throughput validated with isradipine.
Isradipine, a calcium channel blocker, provides consistent protection of the brain from injury and reduces neurological deficits produced by ischemic stroke in hypertensive rats. In these experiments, isradipine was utilized to cross-validate both the serial MRI measurement of brain infarctions with histology measurements and to validate a series of simple neurological deficit tests in order to establish a more rapid, higher throughput approach to screening compounds for utility in stroke. Spontaneously hypertensive rats were treated with vehicle, or 2.5 or 5.0 mg/kg isradipine and middle cerebral artery occlusion. T(2)-weighted MRI image analysis was compared to standard triphenyltetrazolium chloride-stained histological image analysis of brain sections to quantify isradipine neuroprotection 1, 3, and 30 days after middle cerebral artery occlusion (MCAO; stroke). In addition, serial evaluation (i.e. 1, 2, 5, 12, 20 and 30 days after MCAO) of four simple neurobehavioral tests were completed for each animal. Tests included assessment of hindlimb and forelimb function, and balance beam and proprioception performance. At 1, 3 and 30 days there was a significant positive correlation of the percent hemispheric infarct for T(2)-weighted MRI and histology (p < 0.05). Practically identical isradipine dose-response neuroprotection curves were observed for both measurement procedures. Isradipine produced a dose-related reduction in all neurological deficits scored by the four neurological deficit tests (p < 0.05). In addition, a significant time-related recovery from neurological deficits in vehicle-treated rats was observed (p < 0.05). The four different neurological deficit tests did provide unique time-related profiles of neurological recovery. The present study validates the use of serial MRI in experimental stroke and establishes several simple neurological tests that can be used to measure neurological/behavioral deficits associated with brain injury and brain recovery of function over time. Under these conditions, T(2)-weighted MRI and neurological testing required only about 10 min each per animal, thus providing rapid data collection and analysis and requiring reduced scientific personnel.


Release of cell wall phenolic esters during hydrothermal pretreatment of rice husk and rice straw.
Rice husk and rice straw represent promising sources of biomass for production of renewable fuels and chemicals. For efficient utilisation, lignocellulosic components must first be pretreated to enable efficient enzymatic saccharification and subsequent fermentation. Existing pretreatments create breakdown products such as sugar-derived furans, and lignin-derived phenolics that inhibit enzymes and fermenting organisms. Alkali pretreatments have also been shown to release significant levels of simple, free phenolics such as ferulic acid that are normally esterified to cell wall polysaccharides in the intact plant. These phenolics have recently been found to have considerable inhibitory properties. The aim of this research has been to establish the extent to which such free phenolic acids are also released during hydrothermal pretreatment of rice straw (RS) and rice husk (RH). RS and RH were subjected to hydrothermal pretreatments over a wide range of severities (1.57-5.45). FTIR analysis showed that the pretreatments hydrolysed and solubilised hemicellulosic moieties, leading to an enrichment of lignin and crystalline cellulose in the insoluble residue. The residues also lost the capacity for UV autofluorescence at pH 7 or pH 10, indicating the breakdown or release of cell wall phenolics. Saponification of raw RS and RH enabled identification and quantification of substantial levels of simple phenolics including ferulic acid (tFA), coumaric acid (pCA) and several diferulic acids (DiFAs) including 8-O-4'-DiFA, 8,5'-DiFA and 5,5'-DiFA. RH had higher levels of pCA and lower levels of tFA and DiFAs compared with RS. Assessment of the pretreatment liquors revealed that pretreatment-liberated phenolics present were not free but remained as phenolic esters (at mM concentrations) that could be readily freed by saponification. Many were lost, presumably through degradation, at the higher severities. Differences in lignin, tFA, DiFAs and pCA between RS and RH reflect differences in cell wall physiology, and probably contribute to the higher recalcitrance of RH compared with RS. Hydrothermal pretreatments, unlike alkali pretreatments, release cinnamic acid components as esters. The potential for pretreatment-liberated phenolic esters to be inhibitory to fermenting microorganisms is not known. However, the present study shows that they are found at concentrations that could be significantly inhibitory if released as free forms by enzyme activity.


Uses of NHANES Biomarker Data for Chemical Risk Assessment: Trends, Challenges, and Opportunities.
Each year, the U.S. NHANES measures hundreds of chemical biomarkers in samples from thousands of study participants. These biomarker measurements are used to establish population reference ranges, track exposure trends, identify population subsets with elevated exposures, and prioritize research needs. There is now interest in further utilizing the NHANES data to inform chemical risk assessments. This article highlights a) the extent to which U.S. NHANES chemical biomarker data have been evaluated, b) groups of chemicals that have been studied, c) data analysis approaches and challenges, and d) opportunities for using these data to inform risk assessments. A literature search (1999-2013) was performed to identify publications in which U.S. NHANES data were reported. Manual curation identified only the subset of publications that clearly utilized chemical biomarker data. This subset was evaluated for chemical groupings, data analysis approaches, and overall trends. A small percentage of the sampled NHANES-related publications reported on chemical biomarkers (8% yearly average). Of 11 chemical groups, metals/metalloids were most frequently evaluated (49%), followed by pesticides (9%) and environmental phenols (7%). Studies of multiple chemical groups were also common (8%). Publications linking chemical biomarkers to health metrics have increased dramatically in recent years. New studies are addressing challenges related to NHANES data interpretation in health risk contexts. This article demonstrates growing use of NHANES chemical biomarker data in studies that can impact risk assessments. Best practices for analysis and interpretation must be defined and adopted to allow the full potential of NHANES to be realized.


New evidence for hybrid acrylic/TiO2 films inducing bacterial inactivation under low intensity simulated sunlight.
This study addresses the preparation and characterization of hybrid films prepared from Titanium dioxide (TiO2) Pickering stabilized acrylic polymeric dispersion as well as their bacterial inactivation efficiency under sunlight irradiation. Complete bacterial inactivation under low intensity simulated solar light irradiation (55 mW/cm(2)) was observed within 240 min for the films containing 10 weight based on monomers (wbm) % of TiO2, whereas 360 min were needed for the films containing 20 wbm% of TiO2. The hybrid films showed repetitive Escherichia coli (E. coli) inactivation under light irradiation. TiO2 released from the films surfaces was measured by inductively coupled plasma mass spectrometry (IPC-MS), obtaining values of ∼ 0.5 and 1 ppb/cm(2) for the films containing 10 wbm% and 20 wbm% of TiO2, respectively, far below the allowed cytotoxicity level for TiO2 (200 ppb). Transmission electron microscopy (TEM) of the hybrid films showed that TiO2 nanoparticles (NPs) were located at the polymer particle's surface forming a continuous inorganic network inside the film matrix. Atomic force microscopy (AFM) images showed differences in the TiO2 dispersion between the air-film and film-substrate interfaces. Films containing 10 wbm% of TiO2 had higher roughness (Rg) at both interfaces than the one containing 20 wbm% of TiO2 inducing an increase in the bacterial adhesion as well as the bacterial inactivation kinetics. The highly oxidative OH-radicals participating in the bacterial inactivation were determined by fluorescence.


A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.
Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10-8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.


A genomic approach to bacterial taxonomy: an examination and proposed reclassification of species within the genus Neisseria.
In common with other bacterial taxa, members of the genus Neisseria are classified using a range of phenotypic and biochemical approaches, which are not entirely satisfactory in assigning isolates to species groups. Recently, there has been increasing interest in using nucleotide sequences for bacterial typing and taxonomy, but to date, no broadly accepted alternative to conventional methods is available. Here, the taxonomic relationships of 55 representative members of the genus Neisseria have been analysed using whole-genome sequence data. As genetic material belonging to the accessory genome is widely shared among different taxa but not present in all isolates, this analysis indexed nucleotide sequence variation within sets of genes, specifically protein-coding genes that were present and directly comparable in all isolates. Variation in these genes identified seven species groups, which were robust to the choice of genes and phylogenetic clustering methods used. The groupings were largely, but not completely, congruent with current species designations, with some minor changes in nomenclature and the reassignment of a few isolates necessary. In particular, these data showed that isolates classified as Neisseria polysaccharea are polyphyletic and probably include more than one taxonomically distinct organism. The seven groups could be reliably and rapidly generated with sequence variation within the 53 ribosomal protein subunit (rps) genes, further demonstrating that ribosomal multilocus sequence typing (rMLST) is a practicable and powerful means of characterizing bacteria at all levels, from domain to strain.


Functional FLT1 Genetic Variation is a Prognostic Factor for Recurrence in Stage I-III Non-Small-Cell Lung Cancer.
We propose that single-nucleotide polymorphisms (SNPs) in genes of the vascular endothelial growth factor pathway of angiogenesis will associate with survival in non-small-cell lung cancer (NSCLC) patients. Fifty-three SNPs in vascular endothelial growth factor-pathway genes were genotyped in 150 European stage I-III NSCLC patients and tested for associations with patient survival. Replication was performed in an independent cohort of 142 European stage I-III patients. Reporter gene assays were used to assess the effects of SNPs on transcriptional activity. In the initial cohort, five SNPs associated (q < 0.05) with relapse-free survival (RFS). The minor alleles of intronic FLT1 SNPs, rs7996030 and rs9582036, associated with reduced RFS (hazard ratio [HR] = 1.67 [95% confidence interval, CI, 1.22-2.29] and HR = 1.51 [95% CI, 1.14-2.01], respectively) and reduced transcriptional activity. The minor alleles of intronic KRAS SNPs, rs12813551 and rs10505980, associated with increased RFS (HR = 0.64 [0.46-0.87] and HR = 0.64 [0.47-0.87], respectively), and the minor allelic variant of rs12813551 also reduced transcriptional activity. Lastly, the minor allele of the intronic KRAS SNP rs10842513 associated with reduced RFS (HR = 1.65 [95% CI, 1.16-2.37]). Analysis of the functional variants suggests they are located in transcriptional enhancer elements. The negative effect of rs9582036 on RFS was confirmed in the replication cohort (HR = 1.69 [0.99-2.89], p = 0.028), and the association was significant in pooled analysis of both cohorts (HR = 1.67 [1.21-2.30], p = 0.0001). The functional FLT1 variant rs9582036 is a prognostic determinant of recurrence in stage I-III NSCLC. Its predictive value should be tested in the adjuvant setting of stage I-III NSCLC.


Identification and proteomic profiling of exosomes in human urine.
Urine provides an alternative to blood plasma as a potential source of disease biomarkers. One urinary biomarker already exploited in clinical studies is aquaporin-2. However, it remains a mystery how aquaporin-2 (an integral membrane protein) and other apical transporters are delivered to the urine. Here we address the hypothesis that these proteins reach the urine through the secretion of exosomes [membrane vesicles that originate as internal vesicles of multivesicular bodies (MVBs)]. Low-density urinary membrane vesicles from normal human subjects were isolated by differential centrifugation. ImmunoGold electron microscopy using antibodies directed to cytoplasmic or anticytoplasmic epitopes revealed that the vesicles are oriented "cytoplasmic-side inward," consistent with the unique orientation of exosomes. The vesicles were small (<100 nm), consistent with studies of MVBs and exosomes from other tissues. Proteomic analysis of urinary vesicles through nanospray liquid chromatography-tandem mass spectrometry identified numerous protein components of MVBs and of the endosomal pathway in general. Full liquid chromatography-tandem MS analysis revealed 295 proteins, including multiple protein products of genes already known to be responsible for renal and systemic diseases, including autosomal dominant polycystic kidney disease, Gitelman syndrome, Bartter syndrome, autosomal recessive syndrome of osteopetrosis with renal tubular acidosis, and familial renal hypomagnesemia. The results indicate that exosome isolation may provide an efficient first step in biomarker discovery in urine.


Factors associated with first- versus second-generation long-acting antipsychotics prescribed under ordinary clinical practice in Italy.
For many years, long-acting intramuscular (LAI) antipsychotics have been prescribed predominantly to chronic and severe patients, as a last resort when other treatments failed. Recently, a broader and earlier use of LAIs, particularly second-generation LAIs, has been emphasized. To date, few studies attempted to frame how this change in prescribing took place in real-world practice. Therefore, this study aimed to describe the clinical features of patients prescribed with LAIs, and to explore possible prescribing differences between first- and second-generations LAIs under ordinary clinical practice in Italy. The STAR Network "Depot" Study is an observational, longitudinal, multicenter study involving 35 centers in Italy. In the cross-sectional phase, patients prescribed with LAIs were consecutively recruited and assessed over a period of 12 months. Descriptive statistics and multivariable logistic regression analyses were employed. Of the 451 recruited patients, 61% were males. The level of social and working functioning was heterogeneous, as was the severity of disease. Seventy-two per cent of the patients had a diagnosis of the schizophrenia spectrum. Seventy per cent were prescribed with second-generation antipsychotic (SGA) LAIs (mostly paliperidone, aripiprazole and risperidone). Compared to first-generation antipsychotic (FGA) LAIs, patients prescribed with SGA LAIs were more often younger; employed; with a diagnosis of the schizophrenia spectrum or bipolar disorder; with higher levels of affective symptoms; with fewer LAI prescriptions in the past. LAIs' prescribing practices appear to be more flexible as compared to the past, although this change is mostly restricted to SGA LAIs.


Limits to the reproductive success of two insect parasitoid species in the field.
Debates on the relative importance of different factors in limiting the realized fitness of insect parasitoids and herbivores have continued for decades. One major reason for the duration of these debates is the paucity of empirical evidence regarding the reproductive success of minute insects under field conditions. We used a novel technique to estimate lifetime reproductive success in two Anagrus spp. parasitoids, whose hosts are eggs of leafhoppers that feed on grape leaves. Females were collected soon after they died naturally, and the number of eggs in their ovaries was counted. We used these data to estimate the lifetime oviposition success of individual females. We found that more than 10% of females from the field exhausted their entire supply of eggs before they died. The lifetime reproductive success of females was positively related to their body size and was higher at field sites with more abundant hosts, although we could not rule out a causal role for other site-specific factors. In addition, we found that females from habitats rich with hosts emerged with more eggs, suggesting that they might be adapted to local conditions. The results are consistent with theoretical predictions from models considering the risk of egg limitation.


Eating behaviors moderate the associations between risk factors in the first 1000 days and adiposity outcomes at 6 years of age.
Several risk factors in the first 1000 d are linked with increased obesity risk in later childhood. The role of potentially modifiable eating behaviors in this association is unclear. This study examined whether the association between cumulated risk factors in the first 1000 d and adiposity at 6 y is moderated by eating behaviors. Participants were 302 children from the GUSTO (Growing Up in Singapore Towards healthy Outcomes) cohort. Risk factors included maternal prepregnancy and paternal overweight, excessive gestational weight gain, raised fasting plasma glucose during pregnancy, short breastfeeding duration, and early introduction of solid foods. Composite risk scores reflecting the prevalence and the importance of the risk factors present were computed. Adiposity outcomes were child BMI and sum of skinfolds (SSF), and candidate eating behavior moderators were portion size, eating rate, and energy intake during lunch and in an eating in the absence of hunger task. Higher composite risk score predicted higher BMI z scores (B = 0.08; 95% CI: 0.04, 0.13) and larger SSF (0.70 mm; 0.23, 1.18 mm), and was associated with larger self-served food portions (5.03 kcal; 0.47, 9.60 kcal), faster eating rates (0.40 g/min; 0.21, 0.59 g/min), and larger lunch intakes (7.05 kcal; 3.37, 10.74 kcal). Importantly, the association between composite risk score and adiposity was moderated by eating behaviors. The composite risk score was unrelated to SSF in children who selected smaller food portions, ate slower, and consumed less energy, but was positively associated with SSF among children who selected larger food portions, ate faster, and consumed more energy (eating behavior × risk score interactions: P < 0.05). The association between risk factors in the first 1000 d and adiposity at 6 y varies by eating behaviors, highlighting modifiable behavioral targets for interventions.This trial was registered at clinicaltrials.gov as NCT01174875.


Pressure injuries in people with darker skin tones: A literature review.
In this article, we aimed to explore the literature to ascertain what research evidence exists in relation to the identification of pressure injuries in people with dark skin tones. Pressure injuries development has been widely researched and documented; however, much of this work does not address ethnicity or race and assumes Caucasian-ness. Thus, the perceptions of people with dark skin tones and the influence of skin pigmentation on identification and management of pressure injuries is under examined. Literature review. A comprehensive electronic database search was undertaken of PubMed, Cumulative Index for Nursing and Allied Health Literature, Cochrane and British Nursing Index (BNI) between 1990-July 2016. Alongside the electronic data, journals, books, papers from conferences, relevant national and international organisations and reference lists were also used to help source key studies. A search of the literature revealed 11 relevant articles. The foci of studies included the following: risk of sustaining a pressure injuries based on skin tones, identification of pressure injuries amongst people with dark skin tones, pressure injuries and place of care and socio-economic impact on pressure injuries development. Overall, findings indicate that people with darker skin tones are more likely to develop higher stage pressure injuries. Reasons for this are not fully elucidated; however, it may be associated with current skin assessment protocols being less effective for people who have darker skin tones resulting in early damage arising from pressure not being recognised. From the literature reviewed, it can be seen that there is a lack of guidance and evidence, and people with darker skin tones are more likely in comparison with people presenting as Caucasian to develop higher stage pressure injuries. The current literature suggests a need for researchers and clinicians to consider skin tone variances rather than ethnicity when exploring comprehensive skin assessment.


Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C.
As many as 70% of individuals with chronic hepatitis C (CHC) are managed solely in primary care. The aims of this study were to determine the prevalence of elevated liver stiffness measurement (LSM) in a cohort of community managed patients with CHC and to evaluate predictors of advanced liver disease and liver-related events. A prospective cohort of adult patients with CHC were recruited from 21 primary care practices throughout Victoria, Australia. Inclusion criteria included the presence of CHC for >6 months, no recent (<18 months) specialist input and no history of hepatocellular carcinoma. Clinical assessment, LSM and phlebotomy were carried out in primary care. A hospital cohort was recruited for comparison. Participants were followed longitudinally and monitored for liver-related events. Over 26 months, 780 community patients were recruited and included in the analysis. The median LSM was 6.9 kPa in the community, with 16.5% of patients at risk of advanced fibrosis (LSM ≥12.5 kPa); of these 8.5% had no laboratory features of advanced liver disease. The proportion at risk of cirrhosis was no different between the community and hospital cohorts (p = 0.169). At-risk alcohol consumption, advancing age, elevated body mass index and alanine aminotransferase were independent predictors of elevated LSM. Over a median follow-up of 15.2 months, liver-related events occurred in 9.3% of those with an LSM ≥12.5 kPa. An LSM of 24 kPa had the highest predictive power for liver-related events (hazard ratio152; p <0.001). The prevalence of advanced fibrosis, as determined by LSM, in primary care managed CHC is significant and comparable to a hospital cohort. Furthermore, this study supports the use of LSM as a community screening tool in a CHC population and indicates a possible role in predicting liver-related events. The prevalence of advanced liver disease in primary care managed hepatitis C is unknown. Our data suggests that rates of advanced fibrosis in the community are significant (16.5%), often underdiagnosed and comparable to rates seen in specialist referral centres. Liver stiffness measurement is a feasible community screening tool prior to hepatitis C therapy and can predict liver-related adverse events.


The Development of a Community-Based, Pharmacist-Provided Falls Prevention MTM Intervention for Older Adults: Relationship Building, Methods, and Rationale.
The objectives of this article are to discuss the process of community engagement experienced to plan and implement a pilot study of a pharmacist-provided MTM intervention focused on reducing the use of medications associated with falling, and to present the research methods that emerged from the community engagement process to evaluate the feasibility, acceptance, and preliminary impact of the intervention. Key lessons learned from the community engagement process also are presented and discussed. The relationship building and planning process took twelve months. The RE-AIM framework broadly guided the planning process since an overarching goal for the community partners was developing a program that could be implemented and sustained in the future. The planning phase focused on identifying research questions that were of most interest to the community partners, the population to study, the capacity of partners to perform activities, process evaluation. Much of the planning phase was accomplished with face-to-face meetings. After all study processes, study materials, and data collection tools were developed, a focus group of older adults who represented the likely targets of the MTM intervention provided feedback related to the concept and process of the intervention. Nine key lessons were identified from the community engagement process. One key to successful community engagement is partners taking the time to educate each other about experiences, processes, and success and failures. Additionally, partners must actively listen to each other to better understand barriers and facilitators that likely will impact the planning and implementation process. Successful community engagement will be important to develop both formative and summative evaluation processes that will help to produce valid evidence about the effectiveness of pharmacists in modifying drug therapy and preventing falls as well as promote adoption and implementation of the intervention in other communities.


Membrane Peeling-Induced Retinal Alterations on Intraoperative OCT in Vitreomacular Interface Disorders From the PIONEER Study.
To assess retinal architectural alterations that occur following membrane peeling procedures and the impact of peel technique on these alterations utilizing intraoperative optical coherence tomography (iOCT). This is a subanalysis of the prospective PIONEER iOCT study of eyes undergoing a membrane peeling for a vitreomacular interface (VMI) disorder. Intraoperative scanning was performed with a microscope-mounted OCT system. Macroarchitectural alterations (e.g., full-thickness retinal elevations) and microarchitectural alterations (e.g., relative layer thickness alterations) were analyzed. Video/iOCT correlation was performed to identify instrument-tissue manipulations resulting in macroarchitectural alterations. One hundred sixty-three eyes were included in the macroarchitectural analysis. Instrumentation utilized for membrane peeling included forceps alone for 73 eyes (45%), combined diamond-dusted membrane scraper (DDMS) and forceps for 87 eyes (53%), and other techniques in three eyes (2%). Focal retinal elevations were identified in 45 of 163 eyes (28%). Video/iOCT correlation identified 69% of alterations involved forceps compared to 26% due to DDMS. Sixteen percent of retinal alterations persisted 1 month following surgery. The microarchitectural analysis included 134 eyes. Immediately following membrane peeling, there was a significant increase in the ellipsoid zone to retinal pigment epithelium height (+20%, P < 0.00001) and the cone outer segment tips to retinal pigment epithelium height (+18%, P < 0.00001). Significant subclinical retinal architectural changes occur during membrane peeling for VMI conditions. Differences in surgical instruments may impact these architectural alterations.


The Impact of COVID-19 Vaccination on the Italian Healthcare System: A Scenario Analysis.
During 2020, the only instruments for fighting against the pandemic peaks were lockdowns, physical distancing, closure of schools and non-essential businesses, and travel restrictions. The new vaccination strategy adopted in Italy in 2021 represented a new perspective for policymakers. The aim of this study was to estimate the effects of the national immunisation strategy for coronavirus disease 2019 (COVID-19) in Italy on the national healthcare system. An epidemiological scenario analysis was developed in order to simulate the impact of the COVID-19 pandemic on the Italian national healthcare system in 2021. Hospitalisations, intensive care unit (ICU) admissions and death rates were modelled based on 2020 data. Costs were estimated using hospital admissions from the Policlinico of Tor Vergata Hospital in Rome. Two scenarios were tested, one with vaccination and the second without. The roll-out of vaccinations to protect against COVID-19 was estimated to prevent 52,115 deaths in 2021, 45.2% less than what was expected in the absence of immunisation. Based on the assumptions underlying the two epidemiological scenarios, our model predicted an overall reduction of 2.4 million hospital admissions and 259,000 ICU admissions (74.9% and 71.3% less, respectively, than the world without vaccinations between June and December 2021). Overall, in Italy, the model estimated over €3.0 billion costs of hospitalisations due to COVID-19 in 2020. In 2021, vaccines prevented around 36% of the overall costs. This is the first study highlighting the effect of vaccines on the Italian healthcare system in terms of avoided cases, hospitalisations and costs. Our results have the potential to inform policymakers and the general population on the benefits of vaccinations.


Multitasking Immune Sp185/333 Protein, rSpTransformer-E1, and Its Recombinant Fragments Undergo Secondary Structural Transformation upon Binding Targets.
The purple sea urchin, Strongylocentrotus purpuratus, expresses a diverse immune response protein family called Sp185/333. A recombinant Sp185/333 protein, previously called rSp0032, shows multitasking antipathogen binding ability, suggesting that the protein family mediates a flexible and effective immune response to multiple foreign cells. Bioinformatic analysis predicts that rSp0032 is intrinsically disordered, and its multiple binding characteristic suggests structural flexibility to adopt different conformations depending on the characteristics of the target. To address the flexibility and structural shifting hypothesis, circular dichroism analysis of rSp0032 suggests that it transforms from disordered (random coil) to α helical structure. This structural transformation may be the basis for the strong affinity between rSp0032 and several pathogen-associated molecular patterns. The N-terminal Gly-rich fragment of rSp0032 and the C-terminal His-rich fragment show unique transformations by either intensifying the α helical structure or changing from α helical to β strand depending on the solvents and molecules added to the buffer. Based on these results, we propose a name change from rSp0032 to rSpTransformer-E1 to represent its flexible structural conformations and its E1 element pattern. Given that rSpTransformer-E1 shifts its conformation in the presence of solvents and binding targets and that all Sp185/333 proteins are predicted to be disordered, many or all of these proteins may undergo structural transformation to enable multitasking binding activity toward a wide range of targets. Consequently, we also propose an overarching name change for the entire family from Sp185/333 proteins to SpTransformer proteins.


Baroreceptor reflex effects on transient and steady-state hemodynamics of salt-loading hypertension in dogs.
Intact dogs were compared with barorecptor-denervated dogs to determine the extent to which the baroreceptor reflexes delay the onset and offset transients and alter the final steady-state levels of salt-loading hypertension. Two months after their renal mass had been reduced to about one-third of normal, hypertension was produced in both groups of dogs by continuous intravenous infusion of isotonic saline (190 ml/kg day-1). Major hemodynamic variables were recorded continuously 24 hours/day throughout the experimental period. Both groups of dogs had similar control 24-hour arterial blood pressure values: intact dogs averaged 112 plus or minus 4.1 (SE) mm Hg, and denervated dogs averaged 110 plus or minus 4.3 mm Hg. Both groups reached the same average plateau of elevated arterial blood pressure: intact dogs averaged 142 plus or minus 4.8 mm Hg, and denervated dogs averaged 142 plus or minus 8.7 mm Hg. After the start of salt loading, the denervated dogs reached their plateau level of arterial blood pressure in an average of 8 hours compared with nearly 24 hours for the intact dogs. Cardiac output also rose more rapidly in the denervated dogs and reached a maximum elevation of 26% above the control level in an average of 7.4 hours compared with a maximum elevation of 40% above control in the intact dogs in 18 hours. Total peripheral resistance fell below the control level during the entire first day of infusion in the intact dogs but was somewhat elevated in the denervated dogs. When the saline infusion stopped, arterial blood pressure in both groups returned to control levels within 24 hours. The results indicate that the major action of the baroreceptor reflexes on the onset of salt-loading hypertension is to slow the development of hypertension by modifying the total peripheral resistance; the final steady-state level of hypertension is unaffected by the baroreceptor reflexes.


Neuro-fuzzy decoding of sensory information from ensembles of simultaneously recorded dorsal root ganglion neurons for functional electrical stimulation applications.
Functional electrical stimulation (FES) is used to improve motor function after injury to the central nervous system. Some FES systems use artificial sensors to switch between finite control states. To optimize FES control of the complex behavior of the musculo-skeletal system in activities of daily life, it is highly desirable to implement feedback control. In theory, sensory neural signals could provide the required control signals. Recent studies have demonstrated the feasibility of deriving limb-state estimates from the firing rates of primary afferent neurons recorded in dorsal root ganglia (DRG). These studies used multiple linear regression (MLR) methods to generate estimates of limb position and velocity based on a weighted sum of firing rates in an ensemble of simultaneously recorded DRG neurons. The aim of this study was to test whether the use of a neuro-fuzzy (NF) algorithm (the generalized dynamic fuzzy neural networks (GD-FNN)) could improve the performance, robustness and ability to generalize from training to test sets compared to the MLR technique. NF and MLR decoding methods were applied to ensemble DRG recordings obtained during passive and active limb movements in anesthetized and freely moving cats. The GD-FNN model provided more accurate estimates of limb state and generalized better to novel movement patterns. Future efforts will focus on implementing these neural recording and decoding methods in real time to provide closed-loop control of FES using the information extracted from sensory neurons.


Robust transport over networks.
We consider transportation over a strongly connected, directed graph. The scheduling amounts to selecting transition probabilities for a discrete-time Markov evolution which is designed to be consistent with initial and final marginal constraints on mass transport. We address the situation where initially the mass is concentrated on certain nodes and needs to be transported in a certain time period to another set of nodes, possibly disjoint from the first. The random evolution is selected to be closest to a prior measure on paths in the relative entropy sense-such a construction is known as a Schrödinger bridge between the two given marginals. It may be viewed as an atypical stochastic control problem where the control consists in suitably modifying the prior transition mechanism. The prior can be chosen to incorporate constraints and costs for traversing specific edges of the graph, but it can also be selected to allocate equal probability to all paths of equal length connecting any two nodes (i.e., a uniform distribution on paths). This latter choice for prior transitions relies on the so-called Ruelle-Bowen random walker and gives rise to scheduling that tends to utilize all paths as uniformly as the topology allows. Thus, this Ruelle-Bowen law (𝔐RB) taken as prior, leads to a transportation plan that tends to lessen congestion and ensures a level of robustness. We also show that the distribution 𝔐RB on paths, which attains the maximum entropy rate for the random walker given by the topological entropy, can itself be obtained as the time-homogeneous solution of a maximum entropy problem for measures on paths (also a Schrödinger bridge problem, albeit with prior that is not a probability measure). Finally we show that the paradigm of Schrödinger bridges as a mechanism for scheduling transport on networks can be adapted to graphs that are not strongly connected, as well as to weighted graphs. In the latter case, our approach may be used to design a transportation plan which effectively compromises between robustness and other criteria such as cost. Indeed, we explicitly provide a robust transportation plan which assigns maximum probability to minimum cost paths and therefore compares favourably with Optimal Mass Transportation strategies.


Chiral separation of new sulfonamide derivatives and evaluation of their enantioselective affinity for human carbonic anhydrase II by microscale thermophoresis and surface plasmon resonance.
The aim of this study was to develop a method combining chiral separation and biophysical techniques to evaluate the enantioselective affinity of original sulfonamide derivatives towards their therapeutic target, the human carbonic anhydrase II (hACII). The first step consisted in the preparation of the enantiomers by chromatographic separation. The performances of HPLC and Supercritical Fluid Chromatography (SFC) were studied at the analytical scale by optimization of various experimental conditions using adsorbed polysaccharide chiral stationary phases (amylose AD-H and cellulose OD-H). Since SFC allowed obtaining higher enantioresolutions per time unit, it was selected for the semi-preparative scale and successfully used to isolate each enantiomer with a satisfactory enantiomeric purity (>98%). Secondly, microscale thermophoresis (MST) method and surface plasmon resonance (SPR) used as reference method were developed to measure potential enantioselective affinities of these enantiomers towards the hACII. The optimizations of both methods were performed using a reference compound, i.e. acetazolamide, which affinity for hCAII has previously been demonstrated. For all compounds, KD values obtained using MST and SPR were in good agreement, leading to similar affinity scales despite both approaches totally differ (labeling for MST versus immobilization of the protein for SPR). The equilibrium dissociation constants of our original compounds for the hCAII were in the range 100-1000nM and an enantioselectivity was observed using the MST and SPR methods for the diarylpyrazole 2. Finally, by comparing the MST and SPR techniques, MST appears especially adapted for further screening of a series of sulfonamide derivatives due to the lower time required to estimate a binding constant while consuming as little hCAII as SPR.


Antigenic Drift Defines a New D4 Subgenotype of Measles Virus.
The measles virus hemagglutinin (MeV-H) protein is the main target of protective neutralizing antibodies. Using a panel of monoclonal antibodies (MAbs) that recognize known major antigenic sites in MeV-H, we identified a D4 genotype variant that escapes neutralization by MAbs targeting the neutralizing epitope (NE) antigenic site. By site-directed mutagenesis, L249P was identified as the critical mutation disrupting the NE in this genotype D4 variant. Forty-two available D4 genotype gene sequences were subsequently analyzed and divided into 2 groups according to the presence or absence of the L249P MeV-H mutation. Further analysis of the MeV-N gene sequences of these 2 groups confirmed that they represent clearly definable, sequence-divergent D4 subgenotypes, which we named subgenotypes D4.1 and D4.2. The subgenotype D4.1 MeVs were isolated predominantly in Kenya and Ethiopia, whereas the MAb-resistant subgenotype D4.2 MeVs were isolated predominantly in France and Great Britain, countries with higher vaccine coverage rates. Interestingly, D4.2 subgenotype viruses showed a trend toward diminished susceptibility to neutralization by human sera pooled from approximately 60 to 80 North American donors. Escape from MAb neutralization may be a powerful epidemiological surveillance tool to monitor the evolution of new MeV subgenotypes.IMPORTANCE Measles virus is a paradigmatic RNA virus, as the antigenic composition of the vaccination has not needed to be updated since its discovery. The vaccine confers protection by inducing neutralizing antibodies that interfere with the function of the hemagglutinin protein. Viral strains are indistinguishable serologically, although characteristic nucleotide sequences differentiate 24 genotypes. In this work, we describe a distant evolutionary branch within genotype D4. Designated subgenotype D4.2, this virus is distinguishable by neutralization with vaccine-induced monoclonal antibodies that target the neutralizing epitope (NE). The subgenotype D4.2 viruses have a higher predominance in countries with intermediary levels of vaccine coverage. Our studies demonstrate that subgenotype D4.2 lacks epitopes associated with half of the known antigenic sites, which significantly impacts our understanding of measles virus evolution.


Idiopathic Ventricular Tachycardia: Transcatheter Ablation or Antiarrhythmic Drugs?
Ventricular tachycardia or frequent premature ventricular contractions (PVCs) can occur in the absence of any detectable structural heart disease. In this clinical setting, these arrhythmias are termed idiopathic. Usually, they carry a benign prognosis and any potential ablative intervention is carried out if patients are highly symptomatic or, more importantly, if frequent ventricular arrhythmias can lead to ventricular dysfunction. In this paper, different forms of idiopathic ventricular tachycardia are reviewed. Outflow tract ventricular tachycardia from the right ventricle is the most frequent form of the so-called idiopathic ventricular tachycardia. Other forms of idiopathic ventricular arrhythmias include ventricular tachycardia/PVCs arising from tricuspid annulus, from the mitral annulus, inter-fascicular ventricular tachycardia and papillary muscle ventricular tachycardia. When interventional treatment is deemed necessary, detailed mapping ( earliest activation during VT/PVC, pace mapping ) is crucial as to identify the successful ablation site. Catheter ablation more than antiarrhythmic drug treatment is usually highly effective in eliminating idiopathic ventricular arrhythmias and providing prevention of recurrence. Idiopathic VTs are not considered life-threatening arrhythmias and, prevention of recurrences is often achieved by means of catheter ablation that provides an improvement of quality of life. The overall acute success rate of catheter ablation is about 85-90% with a long-term prevention of arrhythmia recurrence of about 75-80%. It is advisable that the procedure is carried out by electrophysiologists with expertise in VT catheter ablation and extensive knowledge of cardiac anatomy as to ensure a high success rate and reduce the likelihood of major complications.


Overview of the prevalence, impact, and management of depression and anxiety in chronic obstructive pulmonary disease.
More than one third of individuals with chronic obstructive pulmonary disease (COPD) experience comorbid symptoms of depression and anxiety. This review aims to provide an overview of the burden of depression and anxiety in those with COPD and to outline the contemporary advances and challenges in the management of depression and anxiety in COPD. Symptoms of depression and anxiety in COPD lead to worse health outcomes, including impaired health-related quality of life and increased mortality risk. Depression and anxiety also increase health care utilization rates and costs. Although the quality of the data varies considerably, the cumulative evidence shows that complex interventions consisting of pulmonary rehabilitation interventions with or without psychological components improve symptoms of depression and anxiety in COPD. Cognitive behavioral therapy is also an effective intervention for managing depression in COPD, but treatment effects are small. Cognitive behavioral therapy could potentially lead to greater benefits in depression and anxiety in people with COPD if embedded in multidisciplinary collaborative care frameworks, but this hypothesis has not yet been empirically assessed. Mindfulness-based treatments are an alternative option for the management of depression and anxiety in people with long-term conditions, but their efficacy is unproven in COPD. Beyond pulmonary rehabilitation, the evidence about optimal approaches for managing depression and anxiety in COPD remains unclear and largely speculative. Future research to evaluate the effectiveness of novel and integrated care approaches for the management of depression and anxiety in COPD is warranted.


[General anesthesia outside the operating room in patients with Pierre-Robin syndrome].
Anesthesiologists are increasingly asked to involve in administering general anesthesia outside the operating room for such procedures as computed tomography, magnetic resonance imaging or angiography. Especially, pediatric patients require some kind of sedation or general anesthesia during these procedures. We report general anesthesia outside the operating room in patients with Pierre-Robin syndrome, who are expected to have possible difficult airway. A one-year-old girl and a 16-year-old boy were anesthetized for cardiac catheterization. General anesthesia was given at the angiography room which was located outside the operating room. Anesthesia was induced with oxygen, nitrous oxide and sevoflurane while portable storage unit for difficult airway was prepared including various types and size of laryngoscopes, laryngeal mask airway, fiberoptic intubation equipment and surgical airway access. Fortunately, tracheas were successfully intubated without using special devices, although cautious care during induction was taken. According to development of medical and surgical procedures, it is readily presumed that anesthesiologists will be more often involved in the sedation or anesthesia conducted outside the operating room in future. Anesthesiologists should always ensure enough staffing, proper monitoring and equipment when sedation or anesthesia is conducted outside the operating room, particularly if patients have anesthetic risks.


Does Koopmans' Paradigm for 1-Electron Oxidation Always Hold? Breakdown of IP/Eox Relationship for p-Hydroquinone Ethers and the Role of Methoxy Group Rotation.
Koopmans' paradigm states that electron loss occurs from HOMO, thus forming the basis for the observed linear relationships between HOMO/IP, HOMO/Eox, and IP/Eox. In cases where a molecule undergoes dramatic structural reorganization upon 1-electron oxidation, the IP/Eox relationship does not hold, and the origin of which is not understood. For example, X-ray crystallography of the neutral and cation radicals of bicyclo[2.2.1]heptane-annulated p-hydroquinone ethers ((T)HE and (M)HE) showed that they undergo electron-transfer-induced conformational reorganization and show breakdown of the IP/Eox relationship. DFT calculations revealed that Koopmans' paradigm still holds true because the electron-transfer-induced subtle conformational reorganization, responsible for the breakdown of IP/Eox relationship, is also responsible for the reordering of HOMO and HOMO-1. Perceived failure of Koopmans' paradigm in cases of (T)HE and (M)HE assumes that both vertical and adiabatic electron detachments involve the same HOMO; however, this study demonstrates that the vertical ionization and adiabatic oxidation occur from different molecular orbitals due to reordering of HOMO/HOMO-1. The underpinnings of this finding will spur widespread interest in designing next-generation molecules beyond HQEs, whose electronic structures can be modulated by electron-transfer-induced conformation reorganization.


Predicting the outcome of initial non-surgical endodontic procedures by periapical status and quality of root canal filling: a cohort study.
To assess the previous periapical status and the quality of root canal filling as predictors of the outcome in initial non-surgical endodontic procedures. A retrospective cohort study was designed in which the presence of a previous periapical lesion was determined radiographically. The quality of the root filling was evaluated in terms of homogeneity, taper, and apical extension. The response variable was dichotomized to success and failure. Bivariate analyzes and a mixed generalized linear model interpreted the association between the explanatory variables and the outcome of the initial non-surgical endodontic procedures. A total of 349 roots were evaluated, and a failure rate of 13.18% was established. Poor filling quality was determined in 8.3% of the roots. As a main result, the presence of a preoperative periapical lesion did not determine a significant risk to the failure of the initial treatment. Unlike, a poor quality of the obturation determined association with an unfavorable outcome like this: (1) homogeneity (OR 2.32; p = 0.0181); (2) taper (OR 5.8; p = 0.0); and, (3) extension (OR 3.41; p = 0.0). Therefore, a significant association between inadequate quality of the root filling and failure of the primary non-surgical endodontic procedures was found. Short length of filling was highly associated with failure. The presence of previous periapical lesion was not found to be a significant predictor for treatment outcomes.


Validation of disability status, a claims-based measure of functional status for cancer treatment and outcomes studies.
In prior research, we developed a claims-based prediction model for poor patient disability status (DS), a proxy measure for performance status, commonly used by oncologists to summarize patient functional status and assess ability of a patient to tolerate aggressive treatment. In this study, we implemented and validated the DS measure in 4 cohorts of cancer patients: early and advanced non-small cell lung cancers (NSCLC), stage IV estrogen receptor-negative (ER-) breast cancer, and myelodysplastic syndromes (MDS). SEER-Medicare data (1999-2007) for the 4 cohorts of cancer patients. Bivariate and multivariate logistic regression tested the association of the DS measure with designated cancer-directed treatments: early NSCLC (surgery), advanced NSCLC (chemotherapy), stage IV ER- breast cancer (chemotherapy), and MDS (erythropoiesis-stimulating agents). Treatment model fit was compared across model iterations. In both unadjusted and adjusted results, predicted poor DS was strongly associated with a lower likelihood of cancer treatment receipt in all 4 cohorts [early NSCLC (N=20,280), advanced NSCLC (N=31,341), stage IV ER- breast cancer (N=1519), and MDS (N=6058)] independent of other patient, contextual, and disease characteristics, as well as the Charlson Comorbidity Index. Inclusion of the DS measure into models already controlling for other variables did not significantly improve model fit across the cohorts. The DS measure is a significant independent predictor of cancer-directed treatment. Small changes in model fit associated with both DS and the Charlson Comorbidity Index suggest that unobserved factors continue to play a role in determining cancer treatments.


Achieving Participation-Focused Intervention Through Shared Decision Making: Proposal of an Age- and Disorder-Generic Framework.
Introduction The World Health Organization's International Classification of Functioning, Disability and Health calls on speech-language pathologists (SLPs) to provide care that impacts all aspects of an individual's experience with a communication disorder, including their participation in valued life situations. However, SLPs often report feeling unprepared to implement and document interventions that target life participation. The purpose of this article is to propose a framework to guide participation-focused intervention practices. This age- and disorder-generic framework is designed to be applicable with clients across the variety of settings in which SLPs work. Method In this clinical focus article, we draw on past research and clinical experience to propose a restructuring of World Health Organization's International Classification of Functioning, Disability and Health components such that participation is the primary focus and outcomes indicator for intervention. In this framework, a specific communicative participation situation is identified and assessed quantitatively, and a corresponding participation-focused goal is established through shared decision making. Following that, assessments are conducted and goals are established in the areas of communication skills, physical and social environments, and personal perspectives. Results The proposed framework provides a concrete organizational structure as well as assessment, goal-writing, and intervention examples to assist SLPs in translating theoretical biopsychosocial frameworks into clinical practices. Conclusions SLPs can and do provide holistic communication services to clients to help them achieve their life participation goals. This article provides an example as to how we can document the need for, as well as the value and impact of our important work, meeting the diverse life participation needs of clients. Supplemental Material https://doi.org/10.23641/asha.12360758.


Magnetic Resonance Imaging Characterization and Clinical Outcomes After NeoCart Surgical Therapy as a Primary Reparative Treatment for Knee Cartilage Injuries.
Autologous cartilage tissue implants, including the NeoCart implant, are intended to repair focal articular cartilage lesions. Short-term results from United States Food and Drug Administration (FDA) phase I and phase II clinical trials indicated that the NeoCart implant was safe when surgically applied as a cell-based therapy and efficacious compared with microfracture. Quantitative magnetic resonance imaging (MRI) analysis would reveal NeoCart tissue maturation through to 60-month follow-up. Case series; Level of evidence, 4. Patients with symptomatic full-thickness cartilage lesions of the distal femoral condyle were treated with NeoCart in FDA clinical trials. Safety and efficacy were evaluated prospectively by MRI and clinical patient-reported outcomes (PROs) through to 60-month follow-up. Qualitative MRI metrics were quantified according to modified MOCART (magnetic resonance observation of cartilage repair tissue) criteria, with an independent evaluation of repair tissue signal intensity. Subjective PROs and objective range of motion (ROM) were obtained at baseline and through to 60 months. Twenty-nine patients treated with NeoCart were observed over a mean of 52.0 ± 15.5 months (median, 60 months). MOCART analyses indicated significant improvement ( P < .001) in cartilage quality from 3 to 24 months, with stabilization from 24 to 60 months. Signal intensity of the repair tissue evolved from hyperintense at early follow-up to isointense after 6 months and to hypointense after 24 months. The temporal progression toward hypointense T2 signals at later time points observed here indicated a further reorganization of the repair tissue toward a dense tissue that was less similar to the surrounding native tissue. However, 80% of patients showed evidence of subchondral bone changes on MRI at all time points; 4 patients (14%) showed no improvement of MRI criteria. Compared with baseline values, significant improvement ( P < .001) was seen in PROs (mean [±SD] baseline to mean [±SD] final follow-up), including the International Knee Documentation Committee score (47.9 ± 17.4 to 75.5 ± 22.1), physical component summary of the Short Form-36 (40.5 ± 7.2 to 51.4 ± 8.1), and all 5 domains of the Knee injury and Osteoarthritis Outcome Score (Pain: 64.8 ± 12.1 to 86.1 ± 17.3; Activities of Daily Living: 75.5 ± 14.8 to 91.6 ± 13.8; Quality of Life: 28.6 ± 15.5 to 69.4 ± 28.0; Symptoms: 65.8 ± 13.8 to 86.6 ± 13.4; Sports and Recreation: 41.4 ± 24.3 to 72.4 ± 28.8). Significant ( P < .0001) decreases from baseline scores for the visual analog scale for pain (34.6 ± 22.5) were seen by 6 months and sustained at final follow-up (14.3 ± 18.4). ROM significantly ( P < .0001) improved from baseline (131.5° ± 7.9°) to final follow-up (140.7° ± 6.3°). Longitudinal MRI analysis demonstrated that NeoCart-based repair tissue is durable and evolves over time. For a majority of patients, this progression trended from an initial hyperintense signal to a hypointense signal at later follow-ups. Changes in radiographic measures over time corresponded with improvement in clinical measures, with maximum benefits experienced at 24-month follow-up. Similarly, clinical efficacy for the total cohort, determined by clinical outcome scores, reached a maximum at 24 months without decline to 60 months. Results from safety and exploratory clinical trials indicate that NeoCart is a safe and effective treatment for articular cartilage lesions through to 5-year follow-up. Registration: NCT00548119 ( ClinicalTrials.gov identifier).


Replication of boid inclusion body disease-associated arenaviruses is temperature sensitive in both boid and mammalian cells.
Boid inclusion body disease (BIDB) is a fatal disease of boid snakes, the etiology of which has only recently been revealed following the identification of several novel arenaviruses in diseased snakes. BIBD-associated arenaviruses (BIBDAV) are genetically divergent from the classical Old and New World arenaviruses and also differ substantially from each other. Even though there is convincing evidence that BIBDAV are indeed the etiological agent of BIBD, the BIBDAV reservoir hosts--if any exist besides boid snakes themselves--are not yet known. In this report, we use University of Helsinki virus (UHV; a virus that we isolated from a Boa constrictor with BIBD) to show that BIBDAV can also replicate effectively in mammalian cells, including human cells, provided they are cultured at 30°C. The infection induces the formation of cytoplasmic inclusion bodies (IB), comprised mainly of viral nucleoprotein (NP), similar to those observed in BIBD and in boid cell cultures. Transferring infected cells from 30°C to 37°C ambient temperature resulted in progressive declines in IB formation and in the amounts of viral NP and RNA, suggesting that BIBDAV growth is limited at 37°C. These observations indirectly indicate that IB formation is linked to viral replication. In addition to mammalian and reptilian cells, UHV infected arthropod (tick) cells when grown at 30°C. Even though our findings suggest that BIBDAV have a high potential to cross the species barrier, their inefficient growth at mammalian body temperatures indicates that the reservoir hosts of BIBDAV are likely species with a lower body temperature, such as snakes. The newly discovered boid inclusion body disease-associated arenaviruses (BIBDAV) of reptiles have drastically altered the phylogeny of the family Arenavirus. Prior to their discovery, known arenaviruses were considered mainly rodent-borne viruses, with each arenavirus species having its own reservoir host. BIBDAV have so far been demonstrated in captive boid snakes, but their possible reservoir host(s) have not yet been identified. Here we show, using University of Helsinki virus as a model, that these viruses are able to infect mammalian (including human) and arthropod cells. Our results provide in vitro proof of the considerable ability of arenaviruses to cross species barriers. However, our data indicate that BIBDAV growth occurs at 30°C but is inhibited at 37°C, implying that crossing of the species barrier would be hindered by the body temperature of mammalian species.


Arbuscular Mycorrhiza Improves Substrate Hydraulic Conductivity in the Plant Available Moisture Range Under Root Growth Exclusion.
Arbuscular mycorrhizal fungi (AMF) proliferate in soils and are known to affect soil structure. Although their contribution to structure is extensively investigated, the consequences of those processes for soil water extractability and transport has, so far, gained surprisingly little attention. Therefore we asked, whether AMF can affect water retention and unsaturated hydraulic conductivity under exclusion of root ingrowth, in order to minimize plant driven effects. We carried out experiments with tomato inoculated with Rhizoglomus irregulare in a soil substrate with sand and vermiculite that created variation in colonization by mixed pots with wild type (WT) plants and mycorrhiza resistant (RMC) mutants. Sampling cores were introduced and used to assess substrate moisture retention dynamics and modeling of substrate water retention and hydraulic conductivity. AMF reduced the saturated water content and total porosity, but maintained air filled porosity in soil spheres that excluded root ingrowth. The water content between field capacity and the permanent wilting point (6-1500 kPa) was only reduced in mycorrhizal substrates that contained at least one RMC mutant. Plant available water contents correlated positively with soil protein contents. Soil protein contents were highest in pots that possessed the strongest hyphal colonization, but not significantly affected. Substrate conductivity increased up to 50% in colonized substrates in the physiologically important water potential range between 6 and 10 kPa. The improvements in hydraulic conductivity are restricted to substrates where at least one WT plant was available for the fungus, indicating a necessity of a functional symbiosis for this effect. We conclude that functional mycorrhiza alleviates the resistance to water movement through the substrate in substrate areas outside of the root zone.


The use of cannabis for Hyperemesis Gravidarum (HG).
Hyperemesis Gravidarum (HG) responds only partially to standard antiemetic medications. Cannabis has been known to possess antiemetic effects and there are several medicinal cannabinoids used as anti -emetics for cancer chemotherapy. Its favorable use for HG has been described in social media, but not in the medical literature. We evaluated 4 women with HG counseled by the Motherisk Program, before and following the use of cannabis. Using the validated Pregnancy Unique Quantification of Emesis (PUQE) scoring system and employing the Student's paired t test, we compared changes in symptoms following initiation of cannabis. There was a highly significant improvement in symptoms: PUQE score improved from 14.5+/- 1 to 7.5+/- 0.58(p = 0.0004). Cannabis use was associated with a significant increase in the PUQE Quality of Life scale, from 2+/- 0.82 to 7+/- 0.82 (p = 0.0012). The results suggest that cannabis may be effective for HG, and should be studied in appropriately powered, controlled studies, fully considering potential fetal risks.


Relation between prognosis and the blood pressure before and during treatment of hypertensive patients.
1. A study was conducted amongst 1247 treated hypertensive patients to determine the predictive power of untreated baseline and achieved treated blood pressures in the development of the complications of hypertension. In addition the relative importance of systolic and diastolic pressures was calculated. 2. Statistical analysis was done by calculating univariate differences in blood pressure between cases with and without complications. The higher the univariate distance, the greater the predictive power. 3. Blood pressures achieved during treatment were more important than baseline pressures for predicting stroke in both men and women, confirming the benefits of antihypertensive therapy in preventing strokes. 4. There was some evidence of prevention of myocardial infarction in men and of angina in women as a result of therapy. 5. There was no evidence to suggest that any one group of drugs, including beta-adrenoreceptor-blocking drugs and thiazides, conferred any extra benefit in preventing coronary heart disease. 6. The systolic blood pressures achieved during treatment predicted stroke better than diastolic pressure, but no consistent trends were found for coronary heart disease.