Clostridium difficile: novel insights on an incessantly challenging disease.
This review comprises recent insights on epidemiology, risk factors, diagnostic approaches, pathophysiologic mechanisms, novel treatment options and prevention strategies of Clostridium difficile infection (CDI). Incidence of Clostridium difficile continues to rise and hypervirulent subtypes such as polymerase chain reaction (PCR) ribotype 027 and 078 have emerged worldwide. Children and postpartum women are increasingly recognized as being at risk for development of CDI and community-associated infection is no longer rare. PCR technology may replace complicated two-step test algorithms in the future, because it is rapid, sensitive and specific. Pathophysiological studies have provided evidence that either one of the two exotoxins A and B is important in conferring virulence - the role of binary toxin requires further investigation. Proton pump inhibitors are now established as important risk factors for acquiring, complicating CDI, and developing recurrences. Fidaxomycin, monoclonal antibodies and intestinal microbiota transplantation are promising new treatment options, especially regarding prevention of recurrent disease. Future prevention strategies involve vaccination and novel insights on reservoirs for ongoing transmission, including the food chain. Important advances in research on CDI include novel diagnostic approaches, better understanding of the underlying pathophysiological mechanisms of disease and the development of new approaches to treatment.


Mechanistic Study on the Formation of Cl-/Br-/I-Trihalomethanes during Chlorination/Chloramination Combined with a Theoretical Cytotoxicity Evaluation.
Chlorination followed by chloramination can be used to mitigate the formation of potentially toxic iodinated disinfection byproducts (I-DBPs) while controlling the formation of regulated chloro-bromo-DBPs (Cl-/Br-DBPs). Water samples containing dissolved organic matter (DOM) isolates were subjected to 3 disinfection scenarios: NH2Cl, prechlorination followed by ammonia addition, and HOCl alone. A theoretical cytotoxicity evaluation was carried out based on the trihalomethanes (THMs) formed. This study demonstrates that the presence of bromide not only enhances the yield and rate of iodate formation, it also increases the formation of brominated I-THM precursors. A shift in the speciation from CHCl2I to the more toxic CHBr2I, as well as increased iodine incorporation in THMs, was observed in the presence of bromide. For low bromide concentrations, a decrease in I-THM formation and theoretical cytotoxicity was achieved only for high prechlorination times, while for high bromide concentrations, a short prechlorination time enabled the full conversion of iodide to iodate. For low DOM concentrations or DOM with low reactivity, Br-/I-THMs were preferentially formed for short prechlorination times, inducing high cytotoxicity. However, for high chlorine exposures, the cytotoxicity induced by the formation of regulated THMs might outweigh the benefit of I-THM mitigation. For high DOM concentrations or DOM with higher reactivity, mixed I-THMs were formed together with high concentrations of regulated THMs. In this case, based on the cytotoxicity of the THMs formed, the use of NH2Cl is recommended.


A Survey of Medical Professionals in an Apex Tertiary Care Hospital to Assess Awareness, Interest, Practices, and Knowledge in Palliative Care: A Descriptive Cross-sectional Study.
Medical discipline in India focuses on cure rather than comfort care. Palliative care is concerned with improving quality of life and relieving sufferings in patients with advanced incurable terminal diseases. Palliative care in India is still in infancy stage due to lack of knowledge, attitude and skills among health care providers. The reason being lack of training in under graduate as well as postgraduate teaching curriculum and lack of sensitization among policy makers. To assess the awareness, interest, practices and knowledge in palliative care among medical professionals working in a tertiary care hospital. All participants were mailed proforma to be filled in a fixed format including details of their qualification, demographic data, their field of work, their training in palliative care and multiple choice questions regarding awareness interest, practices and knowledge of palliative care. Out of 186 respondents, 56% had not received any basic training in palliative care. 81% wanted palliative care education to be included in undergraduate curriculum. Poor program was identified as the most common barrier in learning palliative care. 77% respondents had no idea about home based palliative care services. 50.8% patients dies in hospital in their terminal stage. 88% were interested in learning safe opioid practices. Although 89.8% were aware of the need of palliative care in metastatic cancer but less than 50% were aware of the fact that palliative care is also required in MDR-TB and mental illness. This study reflects data of an apex cancer institute of the country. The result of awareness is not very encouraging despite a dedicated palliative care department. So, we can assume what will be the palliative care status in other parts of India where there is no palliative care at all. We strongly recommends that palliative care teaching should be incorporated in undergraduate curriculum to sensitize the students from the beginning. Budding residents in their learning phase can play an important role by learning and providing palliative care as the first person to come into contact with the patients are residents. There is a strong need of spreading palliative care awareness all over the country.


Oral Microbiome of Crohn's Disease Patients With and Without Oral Manifestations.
Microbiome dysbiosis is associated with inflammatory destruction in Crohn's disease [CD]. Although gut microbiome dysbiosis is well established in CD, the oral microbiome is comparatively under-studied. This study aims to characterize the oral microbiome of CD patients with/without oral manifestations. Patients with CD were recruited with age-, gender- and race-matched controls. Potential confounders such as dental caries and periodontal condition were recorded. The oral microbiome was collected using saliva samples. Microbial DNA was extracted and sequenced using shotgun sequencing. Metagenomic taxonomic and functional profiles were generated and analysed. The study recruited 41 patients with CD and 24 healthy controls. Within the CD subjects, 39.0% had oral manifestations with the majority presenting with cobblestoning and/or oral ulcers. Principal coordinate analysis demonstrated distinct oral microbiome profiles between subjects with and without CD, with four key variables responsible for overall oral microbiome variance: [1] diagnosis of CD, [2] concomitant use of steroids, [3] concomitant use of azathioprine and 4] presence of oral ulcers. Thirty-two significant differentially abundant microbial species were identified, with the majority associated with the diagnosis of CD. A predictive model based on differences in the oral microbiome found that the oral microbiome has strong discriminatory function to distinguish subjects with and without CD [AUROC 0.84]. Functional analysis found that an increased representation of microbial enzymes [n = 5] in the butyrate pathway was positively associated with the presence of oral ulcers. The oral microbiome can aid in the diagnosis of CD and its composition was associated with oral manifestations.


Junction Potentials Bias Measurements of Ion Exchange Membrane Permselectivity.
Ion exchange membranes (IEMs) are versatile materials relevant to a variety of water and waste treatment, energy production, and industrial separation processes. The defining characteristic of IEMs is their ability to selectively allow positive or negative ions to permeate, which is referred to as permselectivity. Measured values of permselectivity that equal unity (corresponding to a perfectly selective membrane) or exceed unity (theoretically impossible) have been reported for cation exchange membranes (CEMs). Such nonphysical results call into question our ability to correctly measure this crucial membrane property. Because weighing errors, temperature, and measurement uncertainty have been shown to not explain these anomalous permselectivity results, we hypothesized that a possible explanation are junction potentials that occur at the tips of reference electrodes. In this work, we tested this hypothesis by comparing permselectivity values obtained from bare Ag/AgCl wire electrodes (which have no junction) to values obtained from single-junction reference electrodes containing two different electrolytes. We show that permselectivity values obtained using reference electrodes with junctions were greater than unity for CEMs. In contrast, electrodes without junctions always produced permselectivities lower than unity. Electrodes with junctions also resulted in artificially low permselectivity values for AEMs compared to electrodes without junctions. Thus, we conclude that junctions in reference electrodes introduce two biases into results in the IEM literature: (i) permselectivity values larger than unity for CEMs and (ii) lower permselectivity values for AEMs compared to those for CEMs. These biases can be avoided by using electrodes without a junction.


Light-Induced Movements of Chloroplasts and Nuclei Are Regulated in Both Cp-Actin-Filament-Dependent and -Independent Manners in Arabidopsis thaliana.
Light-induced chloroplast movement and attachment to the plasma membrane are dependent on actin filaments. In Arabidopsis thaliana, the short actin filaments on the chloroplast envelope, cp-actin filaments, are essential for chloroplast movement and positioning. Furthermore, cp-actin-filament-mediated chloroplast movement is necessary for the strong-light-induced nuclear avoidance response. The proteins CHLOROPLAST UNUSUAL POSITIONING 1 (CHUP1), KINESIN-LIKE PROTEIN FOR ACTIN-BASED CHLOROPLAST MOVEMENT 1 (KAC1) and KAC2 are required for the generation and/or maintenance of cp-actin filaments in Arabidopsis. In land plants, CHUP1 and KAC family proteins play pivotal roles in the proper movement of chloroplasts and their attachment to the plasma membrane. Here, we report similar but distinct phenotypes in chloroplast and nuclear photorelocation movements between chup1 and kac1kac2 mutants. Measurement of chloroplast photorelocation movement indicated that kac1kac2, but not chup1, exhibited a clear strong-light-induced increase in leaf transmittance changes. The chloroplast movement in kac1kac2 depended on phototropin 2, CHUP1 and two other regulators for cp-actin filaments, PLASTID MOVEMENT IMPAIRED 1 and THRUMIN 1. Furthermore, kac1kac2 retained a weak but significant nuclear avoidance response although chup1 displayed a severe defect in the nuclear avoidance response. The kac1kac2chup1 triple mutant was completely defective in both chloroplast and nuclear avoidance responses. These results indicate that CHUP1 and the KACs function somewhat independently, but interdependently mediate both chloroplast and nuclear photorelocation movements.


Incidence of silicosis among ceramic workers in central Italy.
The incidence of radiological silicosis was studied among 2480 male workers employed in the ceramics industry. The subjects entered the surveillance program during 1974-1987 and were followed through 1991 with annual chest radiographs. The cumulative risk of silicosis (1/1 or greater; p,q,r) reached 48% (95% confidence interval 41.5-54.9) after 30 years of employment. In a multivariate Cox's proportional hazards model, the effect of duration of exposure increased linearly up to the category of 25-29 years; an extremely high hazard risk of 14.6 was found among those with 30 years or more of exposure in comparison with those employed 10 years or less. Smoking habit also significantly contributed to the model, although its role in the biological process is unclear. In conclusion, exposure to silica dust has been associated with a high incidence of silicosis among ceramics workers. The risk estimates are consistent with the recent findings of silicosis incidence among South African gold miners.


Airborne Observations of Reactive Inorganic Chlorine and Bromine Species in the Exhaust of Coal-Fired Power Plants.
We present airborne observations of gaseous reactive halogen species (HCl, Cl2, ClNO2, Br2,BrNO2, and BrCl), sulfur dioxide (SO2), and nonrefractory fine particulate chloride (pCl) and sulfate(pSO4) in power plant exhaust. Measurements were conducted during the Wintertime INvestigation of Transport, Emissions, and Reactivity campaign in February-March of 2015 aboard the NCAR-NSF C-130 aircraft. Fifty air mass encounters were identified in which SO2 levels were elevated ~5 ppb above ambient background levels and in proximity to operational power plants. Each encounter was attributed to one or more potential emission sources using a simple wind trajectory analysis. In case studies, we compare measured emission ratios to those reported in the 2011 National Emissions Inventory and present evidence of the conversion of HCl emitted from power plants to ClNO2. Taking into account possible chemical conversion downwind, there was general agreement between the observed and reported HCl: SO2 emission ratios. Reactive bromine species (Br2, BrNO2, and/or BrCl) were detected in the exhaust of some coal-fired power plants, likely related to the absence of wet flue gas desulfurization emission control technology. Levels of bromine species enhanced in some encounters exceeded those expected assuming all of the native bromide in coal was released to the atmosphere, though there was no reported use of bromide salts (as a way to reduce mercury emissions) during Wintertime INvestigation of Transport, Emissions, and Reactivity observations. These measurements represent the first ever in-flight observations of reactive gaseous chlorine and bromine containing compounds present in coal-fired power plant exhaust.


SNP-based heritability and genetic architecture of tarsal osteochondrosis in North American Standardbred horses.
Osteochondrosis is a common developmental orthopedic disease characterized by a failure of endochondral ossification. Standardbred horses are recognized as being predisposed to tarsal osteochondrosis. Prior heritability estimates for tarsal osteochondrosis in European Standardbreds and related trotting breeds have been based on pedigree data and range from 17-29%. Here, we report on genetic architecture and heritability based on high-density genotyping data in a cohort of North American Standardbreds (n = 479) stringently phenotyped for tarsal osteochondrosis. Whole-genome array genotyping data were imputed to ~2 million single nucleotide polymorphisms (SNPs). SNP-based heritability of osteochondrosis in this population was explained by 2326 SNPs. The majority of these SNPs (86.6%) had small effects, whereas fewer SNPs had moderate or large effects (10% and 2.9% respectively), which is consistent with a polygenic/complex disease. Heritability was estimated at 0.24 ± 0.16 using two methods of restricted maximum likelihood analysis, as implemented in gcta (with and without a weighted relatedness matrix) and ldak software. Estimates were validated using bootstrapping. Heritability estimates were within the range previously reported and suggest that osteochondrosis is moderately heritable but that a significant portion of disease risk is due to environmental factors and/or genotype × environment interactions. Future identification of the genes/variants that have the most impact on disease risk may allow early recognition of high-risk individuals.


[Effect of alpha4beta2 nicotinic acetylcholine receptor agonists and antagonists on learning in female rats during different phases of ovary cycle].
The present work was devoted to the comparative analysis of alpha4beta2 nicotinic acetylcholine receptors (nAChRs) in learning/ memory processes during ovary cycle assessed in adult female rats. RJR-2403 (1.0 mg/kg, i.p.), alpha4beta2 nAChRs agonist and mecamylamine (1.0 mg/kg, i.p.), alpha4beta2 nAChRs antagonist were injected chronically during 14 days. The processes of learning/memory were assessed in different models of learning: passive avoidance performance and Morris water maze. Chronic RJR-2403 administration to female rats improved the passive avoidance performance in proestrous and estrous as compared to the control animals. Also, RJR-2403 restored spatial learning during proestrous phases in Morris water maze, and stimulated the dynamics of spatial learning during estrous phases. On the contrary, chronic mecamylamine administration impaired non-spatial, and especially, spatial learning in females during key phases of ovary cycle. The results of the study suggest positive effect of alpha4beta2 nAChRs stimulation in learning/ memory processes during ovary cycle in the adult female rats.


Observer variation in an audit of charts of patients with rheumatoid arthritis.
Arthritis Society physiotherapists (PTs) in Ontario adopted Problem Oriented Records (POR) to monitor patient care; goals were to encourage patient specific treatment plans and standardized records. After nine months in practice, the POR system was evaluated by an audit on charts of patients with Rheumatoid Arthritis. Audit teams of two PTs were created within each of five geographic areas. Auditors attended an audit instruction workshop. Two charts, selected randomly from the discharged patients of each of 38 therapists, were independently scored on 56 items by an audit team. The extent of agreement within the auditor team (observer variation) was measured, and adequacy scores computed for each chart. Adequate reliability of the audit instrument was established before examination of adequacy scores and making inferences about quality of care. The auditor agreement measures (kappa) varied from 0.13 to 0.97, mean = 0.74 and SD = 0.16; these estimates were indicative of adequate reliability of the audit form, although agreement scores were different amongst the five areas (P2 less than .01). POR adequacy scores varied from 10.0 to 93.1, mean = 64.5 and SD = 16.9. There were no differences in adequacy scores amongst the five areas (P2 = .61). To reduce observer variation, increased pre-audit emphasis is needed on auditor guidelines and training for items relating to assessment findings, problem identification, and treatment planning.


Maimonides' appreciation for medicine.
Moses Maimonides, the illustrious medieval rabbi and philosopher, dedicated the last decade of his life primarily to medicine. His strong interest in medicine was an integral component of his religious-philosophical teachings and world view. In this paper various sources from his rabbinic writings are presented that explain Maimonides' motivation regarding and deep appreciation for medicine: (A) The physician fulfills the basic biblical obligation to return lost objects to their owner, for with his knowledge and experience the physician can restore good health to his sick fellow human being; (B) medicine provides a unique opportunity to practice imitatio dei, as it reflects the religious duty to maintain a healthy life-style; (C) as an important natural science, medicine offers tools to recognize, love, and fear God. These three aspects address man's relationship and obligation towards his fellow-man, himself and God. Biographical insights supported by additional sources from Maimonides' writings are discussed.


No serologic evidence of an association found between Gulf War service and Mycoplasma fermentans infection.
Occult occupational infection with Mycoplasma fermentans has been proposed as a cause for illness among Persian Gulf War veterans. Symptom data and sera from a 1994-1995 cross-sectional survey of Navy Seabees were used to select symptomatic and asymptomatic Gulf War veterans and nondeployed veterans to evaluate this hypothesis. Survey sera from 96 Seabees were matched to prewar (before September 1990) archived sera. Immunoblot serologic analyses were performed for M. fermentans in a controlled, blinded fashion. Both Gulf War veterans and nondeployed veterans had prewar and postwar serologic evidence of M. fermentans infection consistent with natural infection data. Among study subjects collectively, and stratified by Gulf War service, none of the immunoblot banding profiles (prewar or postwar) or their changes over time were associated with postwar symptoms. These serologic data do not support the hypothesis that Gulf War veterans have experienced Gulf War-related morbidity from M. fermentans infection.


New miRNA Signature Heralds Human NK Cell Subsets at Different Maturation Steps: Involvement of miR-146a-5p in the Regulation of KIR Expression.
Natural killer cells are cytotoxic innate lymphoid cells that play an important role for early host defenses against infectious pathogens and surveillance against tumor. In humans, NK cells may be divided in various subsets on the basis of the relative CD56 expression and of the low-affinity FcγRIIIA CD16. In particular, the two main NK cell subsets are represented by the CD56bright/CD16-/dim and the CD56dim/CD16bright NK cells. Experimental evidences indicate that CD56bright and CD56dim NK cells represent different maturative stages of the NK cell developmental pathway. We identified multiple miRNAs differentially expressed in CD56bright/CD16- and CD56dim/CD16bright NK cells using both univariate and multivariate analyses. Among these, we found a few miRNAs with a consistent differential expression in the two NK cell subsets, and with an intermediate expression in the CD56bright/CD16dim NK cell subset, representing a transitional step of maturation of NK cells. These analyses allowed us to establish the existence of a miRNA signature able to efficiently discriminate the two main NK cell subsets regardless of their surface phenotype. In addition, by analyzing the putative targets of representative miRNAs we show that hsa-miR-146a-5p, may be involved in the regulation of killer Ig-like receptor (KIR) expression. These results contribute to a better understanding of the physiologic significance of miRNAs in the regulation of the development/function of human NK cells. Moreover, our results suggest that hsa-miR-146a-5p targeting, resulting in KIR down-regulation, may be exploited to generate/increment the effect of NK KIR-mismatching against HLA-class I+ tumor cells and thus improve the NK-mediated anti-tumor activity.


Impact of tobacco and/or nicotine products on health and functioning: a scoping review and findings from the preparatory phase of the development of a new self-report measure.
Measuring self-reported experience of health and functioning is important for understanding the changes in the health status of individuals switching from cigarettes to less harmful tobacco and/or nicotine products (TNP) or reduced-risk products (RRP) and for supporting tobacco harm reduction strategies. This paper presents insights from three research activities from the preparatory phase of the development of a new self-report health and functioning measure. A scoping literature review was conducted to identify the positive and negative impact of TNP use on health and functioning. Focus groups (n = 29) on risk perception and individual interviews (n = 40) on perceived dependence in people who use TNPs were reanalyzed in the context of health and functioning, and expert opinion was gathered from five key opinion leaders and five technical consultants. Triangulating the findings of the review of 97 articles, qualitative input from people who use TNPs, and expert feedback helped generate a preliminary conceptual framework including health and functioning and conceptually-related domains impacted by TNP use. Domains related to the future health and functioning measurement model include physical health signs and symptoms, general physical appearance, functioning (physical, sexual, cognitive, emotional, and social), and general health perceptions. This preliminary conceptual framework can inform future research on development and validation of new measures for assessment of overall health and functioning impact of TNPs from the consumers' perspective.


Human sperm sex chromosome disomy and sperm DNA damage assessed by the neutral comet assay.
Is there an association between human sperm sex chromosome disomy and sperm DNA damage? An increase in human sperm XY disomy was associated with higher comet extent; however, there was no other consistent association of sex chromosome disomies with DNA damage. There is limited published research on the association between sex chromosome disomy and sperm DNA damage and the findings are not consistent across studies. We conducted a cross-sectional study of 190 men (25% ever smoker, 75% never smoker) from subfertile couples presenting at the Massachusetts General Hospital Fertility Clinic from January 2000 to May 2003. Multiprobe fluorescence in situ hybridization for chromosomes X, Y and 18 was used to determine XX, YY, XY and total sex chromosome disomy in sperm nuclei using an automated scoring method. The neutral comet assay was used to measure sperm DNA damage, as reflected by comet extent, percentage DNA in the comet tail, and tail distributed moment. Univariate and multiple linear regression models were constructed with sex chromosome disomy (separate models for each of the four disomic conditions) as the independent variable, and DNA damage parameters (separate models for each measure of DNA damage) as the dependent variable. Men with current or past smoking history had significantly greater comet extent (µm: regression coefficients with 95% CI) [XX18: 15.17 (1.98, 28.36); YY18: 14.68 (1.50, 27.86); XY18: 15.41 (2.37, 28.45); Total Sex Chromosome Disomy: 15.23 (2.09, 28.38)], and tail distributed moment [XX18: 3.01 (0.30, 5.72); YY18: 2.95 (0.24, 5.67); XY18: 3.04 (0.36, 5.72); Total Sex Chromosome Disomy: 3.10 (0.31, 5.71)] than men who had never smoked. In regression models adjusted for age and smoking, there was a positive association between XY disomy and comet extent. For an increase in XY disomy from 0.56 to 1.47% (representing the 25th to 75th percentile), there was a mean increase of 5.08 µm in comet extent. No other statistically significant findings were observed. A potential limitation of this study is that it is cross-sectional. Cross-sectional analyses by nature do not lend themselves to inference about directionality for any observed associations; therefore we cannot determine which variable is the cause and which one is the effect. A small sample size may be a further limitation. Comparison of these findings to other studies is limited due to methodological differences. Although consistent associations across sex chromosome disomies or DNA damage measures were not observed, this study highlights the need to explore etiologies of sperm DNA damage and sex chromosome disomy to better understand the potential mechanistic overlaps between the two. This work was supported by NIOSH Grant T42 OH008416, and NIH/NIEHS Grants ES 009718, ES 000002, and R01 ES017457. During the study M.E.M. was affiliated with the Department of Environmental Health at the Harvard School of Public Health. N/A.


The relation of attachment status, psychiatric classification, and response to psychotherapy.
The relation of patterns of attachment and psychiatric status was studied in 82 nonpsychotic inpatients and 85 case-matched controls using the Adult Attachment Interview (AAI). AAI transcripts rated (masked to case vs. control status and treatment) were classified using M. Main and R. Goldwyn's (1991) system. Psychiatric patients, diagnosed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.) I and II structured interviews, were more likely to be classified as preoccupied and unresolved with respect to loss or abuse. On Axis I, anxiety was associated with unresolved status, and AAI scales were able to discriminate depression and eating disorder. On Axis II, borderline personality disorder (BPD) was linked to experience of severe trauma and lack of resolution with respect to it. BPD patients were also rated significantly lower on a scale measuring awareness of mental states. Preliminary outcome results suggest that individuals rated as dismissing on the AAI are more likely to show improvements in psychotherapy.


Lethal experimental infections of rhesus monkeys by aerosolized Ebola virus.
The potential of aerogenic infection by Ebola virus was established by using a head-only exposure aerosol system. Virus-containing droplets of 0.8-1.2 microns were generated and administered into the respiratory tract of rhesus monkeys via inhalation. Inhalation of viral doses as low as 400 plaque-forming units of virus caused a rapidly fatal disease in 4-5 days. The illness was clinically identical to that reported for parenteral virus inoculation, except for the occurrence of subcutaneous and venipuncture site bleeding and serosanguineous nasal discharge. Immunocytochemistry revealed cell-associated Ebola virus antigens present in airway epithelium, alveolar pneumocytes, and macrophages in the lung and pulmonary lymph nodes; extracellular antigen was present on mucosal surfaces of the nose, oropharynx and airways. Aggregates of characteristic filamentous virus were present within type I pneumocytes, macrophages, and air spaces of the lung by electron microscopy. Demonstration of fatal aerosol transmission of this virus in monkeys reinforces the importance of taking appropriate precautions to prevent its potential aerosol transmission to humans.


Renal and immunologic markers for chloralkali workers with low exposure to mercury vapor.
The aim of this study was to investigate renal function and immunologic markers among chloralkali workers with long-term low exposure to mercury vapor. Forty-seven currently exposed workers were compared with reference workers matched for age in a cross-sectional design. The mean urinary mercury concentration was 5.9 (range 1.1-16.8) nmol/mmol creatinine (Cr) for the exposed workers and 1.3 (range 0.2-5.0) nmol/mmol Cr for the referents. The chloralkali workers had been exposed for an average of 13.3 (range 2.8-34.5) years. The activity of N-acetyl-beta-D-glucosaminidase in urine (U-NAG) was higher in the exposed workers (mean 0.18 U/mmol Cr versus 0.14 U/mmol Cr, P=0.02). Associations between current urinary mercury, cumulative urinary mercury, and cumulative urinary mercury per year (intensity) and U-NAG, autoantibodies to myeloperoxidase (anti-MPO) and proteinase 3 in serum, respectively, were observed. The activity of U-NAG and anti-MPO was increased in the workers with the highest exposure, as assessed by their mean intensity of exposure. The highest activity of U-NAG was observed in the exposed workers with the lower concentrations of selenium in whole blood. The study indicates an effect of exposure on the kidney proximale tubule cells, possibly modified by individual selenium status, and an effect mediated by neutrophil granulocytes.


The burden of disease in pyruvate kinase deficiency: Patients' perception of the impact on health-related quality of life.
This study explored how signs and symptoms of pyruvate kinase (PK) deficiency, a rare hemolytic anemia caused by mutations in the PKLR gene, impacts patients' health-related quality of life (HRQoL). Interviews with 21 adults with PK deficiency in the United States, Netherlands, and Germany were conducted. Participants were asked to describe signs, symptoms, and impacts of the disease on their daily lives. Interviews were transcribed and analyzed using qualitative analysis methods. The most common signs and symptoms reported were yellow eyes (n = 19), tiredness (n = 18), yellow skin (n = 17), fatigue (n = 15), low energy (n = 13), and shortness of breath (n = 13). Furthermore, signs and symptoms of PK deficiency negatively impact the ability to perform physical activities, appearance, social activities, emotional states, activities of daily living, leisure activities, work and/or school, sleep, and cognitive states of those living with PK deficiency. A conceptual model is presented that further demonstrates the profound impact that signs and symptoms of PK deficiency have on dimensions of patients' HRQoL. This is the first study that provides patient perspective on the burden of living with PK deficiency and lays the foundation for future studies to examine the effect of pharmacologic interventions on overall HRQoL for patients living with PK deficiency.


Protonation-induced red-coloured circularly polarized luminescence of [5]carbohelicene fused by benzimidazole.
Benzimidazole-fused [5]carbohelicene ([5]HeliBI) was newly synthesized to examine the spectroscopic and chiroptical properties. The reversible protonation and deprotonation processes of [5]HeliBI were successfully investigated using (1)H NMR, absorption and fluorescence spectral measurements. We also confirmed the circularly polarized luminescence of protonated [5]HeliBI (H(+)-[5]HeliBI). This is the first observation of red-coloured CPL of a helicene derivative.


Evolutionary Innovations and Where to Find Them: Routes to Open-Ended Evolution in Natural and Artificial Systems.
This article presents a high-level conceptual framework to help orient the discussion and implementation of open-endedness in evolutionary systems. Drawing upon earlier work by Banzhaf et al. (2016), three different kinds of open-endedness are identified: exploratory, expansive, and transformational. These are characterized in terms of their relationship to the search space of phenotypic behaviors. A formalism is introduced to describe three key processes required for an evolutionary process: the generation of a phenotype from a genetic description, the evaluation of that phenotype, and the reproduction with variation of individuals according to their evaluation. The formalism makes explicit various influences in each of these processes that can easily be overlooked. The distinction is made between intrinsic and extrinsic implementations of these processes. A discussion then investigates how various interactions between these processes, and their modes of implementation, can lead to open-endedness. However, an important contribution of the article is the demonstration that these considerations relate to exploratory open-endedness only. Conditions for the implementation of the more interesting kinds of open-endedness-expansive and transformational-are also discussed, emphasizing factors such as multiple domains of behavior, transdomain bridges, and non-additive compositional systems. In contrast to a traditional Darwinian analysis, these factors relate not to the generic evolutionary properties of individuals and populations, but rather to the nature of the building blocks out of which individual organisms are constructed, and the laws and properties of the environment in which they exist. The article ends with suggestions of how the framework can be used to categorize and compare the open-ended evolutionary potential of different systems, how it might guide the design of systems with greater capacity for open-ended evolution, and how it might be further improved.


Risk factors and behaviors associated with separation anxiety in dogs.
To determine potential risk factors and behaviors associated with separation anxiety and develop a practical index to help in the diagnosis of separation anxiety in dogs. Case-control study. 200 dogs with separation anxiety and 200 control dogs with other behavior problems. Medical records were reviewed for signalment, history of behavior problems, home environment, management, potentially associated behaviors, and concurrent problems. Dogs from a home with a single adult human were approximately 2.5 times as likely to have separation anxiety as dogs from multiple owner homes, and sexually intact dogs were a third as likely to have separation anxiety as neutered dogs. Several factors associated with hyperattachment to the owner were significantly associated with separation anxiety. Spoiling activities, sex of the dog, and the presence of other pets in the home were not associated with separation anxiety. Results do not support the theory that early separation from the dam leads to future development of separation anxiety. Hyperattachment to the owner was significantly associated with separation anxiety; extreme following of the owner, departure cue anxiety, and excessive greeting may help clinicians distinguish between canine separation anxiety and other separation-related problems.


Patients' complaints regarding healthcare encounters and communication.
To explore patient-reported complaints regarding communication and healthcare encounters and how these were responded to by healthcare professionals. A retrospective and descriptive design was used in a County Council in northern part of Sweden. Both quantitative and qualitative methods were used. The content of 587 patient-reported complaints was included in the study. Descriptive statistical analysis and a deductive content analysis were used to investigate the content in the patient-reported complaints. The results show that patients' dissatisfaction with encounters and communication concerned all departments in the healthcare organization. Patients were most dissatisfied when they were not met in a professional manner. There were differences between genders, where women reported more complaints regarding their dissatisfaction with encounters and communication compared with men. Many of the answers on the patient-reported complaints lack a personal apology and some of the patients failed to receive an answer to their complaints.


Blast exposure and dual sensory impairment: an evidence review and integrated rehabilitation approach.
Combat exposures to blast can result in both peripheral damage to the ears and eyes and central damage to the auditory and visual processing areas in the brain. The functional effects of the latter include visual, auditory, and cognitive processing difficulties that manifest as deficits in attention, memory, and problem solving--symptoms similar to those seen in individuals with visual and auditory processing disorders. Coexisting damage to the auditory and visual system is referred to as dual sensory impairment (DSI). The number of Operation Iraqi Freedom/Operation Enduring Freedom Veterans with DSI is vast; yet currently no established models or guidelines exist for assessment, rehabilitation, or service-delivery practice. In this article, we review the current state of knowledge regarding blast exposure and DSI and outline the many unknowns in this area. Further, we propose a model for clinical assessment and rehabilitation of blast-related DSI that includes development of a coordinated team-based approach to target activity limitations and participation restrictions in order to enhance reintegration, recovery, and quality of life.


Deleted in cancer 1 (DICE1) is an essential protein controlling the topology of the inner mitochondrial membrane in C. elegans.
DICE1 (deleted in cancer 1), first identified in human lung carcinoma cell lines, is a candidate tumor suppressor, but the details of its activity remain largely unknown. We have found that RNA interference of its C. elegans homolog (DIC-1) produced inviable embryos with increased apoptosis, cavities in cells and abnormal morphogenesis. In the dic-1(RNAi) germ line, ced-3-dependent apoptosis increased, and cell cavities appeared at the late-pachytene/oogenic stage, leading to defective oogenesis. Immunofluorescence microscopy of DIC-1 revealed its ubiquitous expression in the form of cytoplasmic foci, and cryoelectron microscopy narrowed down the location of the foci to the inner membrane of mitochondria. After dic-1 RNAi, mitochondria had an irregular morphology and contained numerous internal vesicles. Homozygous embryos from a heterozygous dic-1 mother arrested at the L3 larval stage, in agreement with the essential role of DIC-1 in mitochondria. In summary, C. elegans DIC-1 plays a crucial role in the formation of normal morphology of the mitochondrial cristae/inner membrane. Our results suggest that human DICE1 may have several functions in multiple intracellular locations.


High prevalence of elevated blood lead levels in both rural and urban Iowa newborns: Spatial patterns and area-level covariates.
Lead in maternal blood can cross the placenta and result in elevated blood lead levels in newborns, potentially producing negative effects on neurocognitive function, particularly if combined with childhood lead exposure. Little research exists, however, into the burden of elevated blood lead levels in newborns, or the places and populations in which elevated lead levels are observed in newborns, particularly in rural settings. Using ~2300 dried bloods spots collected within 1-3 days of birth among Iowa newborns, linked with the area of mother's residence at the time of birth, we examine the spatial patterns of elevated (>5 μg/dL) blood lead levels and the ecological-level predictors of elevated blood lead levels. We find that one in five newborns exceed the 5 μg/dL action level set by the US Centers for Disease Control & Prevention (CDC). Bayesian spatial zero inflated regression indicates that elevated blood lead in newborns is associated with areas of increased pre-1940s housing and childbearing-age women with low educational status in both rural and urban settings. No differences in blood lead levels or the proportion of children exceeding 5 μg/dL are observed between urban and rural maternal residence, though a spatial cluster of elevated blood lead is observed in rural counties. These characteristics can guide the recommendation for testing of infants at well-baby appointments in places where risk factors are present, potentially leading to earlier initiation of case management. The findings also suggest that rural populations are at as great of risk of elevated blood lead levels as are urban populations. Analysis of newborn dried blood spots is an important tool for lead poisoning surveillance in newborns and can direct public health efforts towards specific places and populations where lead testing and case management will have the greatest impact.


Copper(ii) complexes of functionalized 2,2':6',2''-terpyridines and 2,6-di(thiazol-2-yl)pyridine: structure, spectroscopy, cytotoxicity and catalytic activity.
Six new copper(ii) complexes with 2,2':6',2''-terpyridine (4'-Rn-terpy) [1 (R1 = furan-2-yl), 2 (R2 = thiophen-2-yl), and 3 (R3 = 1-methyl-1H-pyrrol-2-yl)] and 2,6-di(thiazol-2-yl)pyridine derivatives (Rn-dtpy) [4 (R1), 5 (R2), and 6 (R3)] have been synthesized by a reaction between copper(ii) chloride and the corresponding ligand. The complexes have been characterized by UV-vis and IR spectroscopy, and their structures have been determined by X-ray analysis. The antiproliferative potential of copper(ii) complexes of 2,2':6',2''-terpyridine and 2,6-di(thiazol-2-yl)pyridine derivatives towards human colorectal (HCT116) and ovarian (A2780) carcinoma as well as towards lung (A549) and breast adenocarcinoma (MCF7) cell lines was examined. Complex 1 and complex 6 were found to have the highest antiproliferative effect on A2780 ovarian carcinoma cells, particularly when compared with complex 2, 3 with no antiproliferative effect. The order of cytotoxicity in this cell line is 6 > 1 > 5 > 4 > 2 ≈ 3. Complex 2 seems to be much more specific towards colorectal carcinoma HCT116 and lung adenocarcinoma A549 cells. The viability loss induced by the complexes agrees with Hoechst 33258 staining and typical morphological apoptotic characteristics like chromatin condensation and nuclear fragmentation. The specificity towards different types of cell lines and the low cytotoxic activity towards healthy cells are of particular interest and are a positive feature for further developments. Complexes 1-6 were also tested in the oxidation of alkanes and alcohols with hydrogen peroxide and tert-butyl-hydroperoxide (TBHP). The most active catalyst 4 gave, after 120 min, 0.105 M of cyclohexanol + cyclohexanone after reduction with PPh3. This concentration corresponds to a yield of 23% and TON = 210. Oxidation of cis-1,2-dimethylcyclohexane with m-CPBA catalyzed by 4 in the presence of HNO3 gave a product of a stereoselective reaction (trans/cis = 0.47). Oxidation of secondary alcohols afforded the target ketones in yields up to 98% and TON = 630.


High Expression of Major Histocompatibility Complex Class I in Clear Cell Renal Cell Carcinoma Is Associated with Improved Prognosis.
In this study we analyzed major histocompatibility complex class I (MHCI) expression as a potential prognostic immune marker for patients with clear cell renal cell carcinoma (ccRCC). 34 patients with localized ccRCC (pT1-pT3) who had undergone nephrectomy and had at least 4 years of clinical follow-up data were included in the study. Immunohistochemical staining for MHCI was performed on tumor sections. An automated image analysis algorithm was applied to representative tumor areas to quantitate the proportion of stained pixels (positivity score = positive pixels/total pixels) on scanned digital slides. At the end of the study, the patients who were alive had increased MHCI expression (mean positivity score 0.80) compared to those who died of the disease (mean positivity score 0.53; p < 0.0001, t test). Patients who were alive with recurrence had increased MHCI expression (positivity score 0.81) compared to those who succumbed to their disease recurrence (positivity score 0.53; p < 0.0001, t test). Survival was higher among patients with high MHCI expression compared to patients with low MHCI expression (p < 0.0001, Mantel-Cox). With an automated high-throughput image analysis technique, this study shows that higher tumor cell MHCI expression promotes increased survival and reduced incidence of recurrence compared to patients with lower tumor cell MHCI expression.


Demands on surgical inpatient services after mass mammographic screening.
The changes in the demand for surgical inpatient care created by mammographic screening for breast cancer were analysed by comparing two counties, one with and one without a mass screening campaign. A comprehensive computerised register of inpatient care in the region was used. The results indicate that population based screening offered to women above 40 years and repeated every two to three years will increase the number of operations required for breast cancer and inpatient days by at least 150% during the initial screening round. During the second round the figures tend to return to previous levels. Of decisive importance for the demands on health service resources are the specificity of screening, the duration of the first screening round, and the age groups included.


Unrecognized Myocardial Infarction Assessed by Cardiac Magnetic Resonance Imaging--Prognostic Implications.
Clinically unrecognized myocardial infarctions (UMI) are not uncommon and may be associated with adverse outcome. The aims of this study were to determine the prognostic implication of UMI in patients with stable suspected coronary artery disease (CAD) and to investigate the associations of UMI with the presence of CAD. In total 235 patients late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging and coronary angiography were performed. For each patient with UMI, the stenosis grade of the coronary branch supplying the infarcted area was determined. UMIs were present in 25% of the patients and 67% of the UMIs were located in an area supplied by a coronary artery with a stenosis grade ≥70%. In an age- and gender-adjusted model, UMI independently predicted the primary endpoint (composite of death, myocardial infarction, resuscitated cardiac arrest, hospitalization for unstable angina pectoris or heart failure within 2 years of follow-up) with an odds ratio of 2.9; 95% confidence interval 1.1-7.9. However, this association was abrogated after adjustment for age and presence of significant coronary disease. There was no difference in the primary endpoint rates between UMI patients with or without a significant stenosis in the corresponding coronary artery. The presence of UMI was associated with a threefold increased risk of adverse events during follow up. However, the difference was no longer statistically significant after adjustments for age and severity of CAD. Thus, the results do not support that patients with suspicion of CAD should be routinely investigated by LGE-CMR for UMI. However, coronary angiography should be considered in patients with UMI detected by LGE-CMR. ClinicalTrials.gov NTC01257282.


Knoop microhardness of conventional and microwaved denture base acrylic resins.
Microwave polymerization reduces the time of acrylic resin processing, but it is important to select a proper cycle to avoid overheating, porosity, and impairment to the materials' properties. To evaluate the microhardness of conventional (Vipi Cril-VC) and microwaved (Vipi Wave-VW) acrylic resins after microwave polymerization cycles and the cycles recommended by the manufacturer. It was also evaluated the effect of thermocycling on the microhardness of these materials. Specimens (n = 10) were made: 1. WB (water-bath recommended for VC polymerization); 2. M630/25 (10 min at 270 W; 5 min at 0 W; 10 min at 360 W: recommended for VW polymerization); 3. M550/3 (3 min at 550 W); and 4. M650/5 (5 min at 650 W). After 48 h in distilled water at 37°C, specimens were subjected to Knoop test under 25 g during 5 s. The same specimens were submitted to thermocycling (5,000 cycles; 5°C and 55°C; 60 s) and the microhardness was again measured. The results were analyzed by repeated measures one-way analysis of variance/Bonferroni for each material (α = 0.05). For both materials, no difference was obtained for groups polymerized using the cycles recommended by the manufacturer (VC = 19.8 ± 0.9 KHN; VW = 21.0 ± 1.6 KHN) and M650/5 (VC = 19.9 ± 1.5 KHN; VW = 20.9 ± 0.8 KHN). After thermocycling, microhardness decreased in experimental cycles for VC (M550/3 = 17.0 ± 1.9 to 14.6 ± 1.2 KHN; M650/5 = 19.9 ± 1.5 to 17.8 ± 0.8 KHN) and in all microwave cycles for VW (M630/25 = 21.0 ± 1.6 to 18.3 ± 0.9 KHN; M550/3 = 17.5 ± 3.0 to 15.7 ± 2.0 KHN; M650/5 = 20.9 ± 0.8 to 18.2 ± 2.0 KHN) (P = 0.000). The lowest hardness was observed for both resins processed by M550/3 (P = 0.001). Both materials could be polymerized in microwave during 5 min showing hardness similar to the cycles recommended by the manufacturer. Thermocycling did not decrease the hardness of VC polymerized with both cycles recommended by the manufacturer and VW polymerized with the water-bath conventional cycle.


Alimentary lipemia enhances the membrane expression of platelet P-selectin without affecting other markers of platelet activation.
The present study was conducted to determine whether alimentary lipemia alters platelet activity in vivo. Normolipidemic volunteers were given a fatty meal and platelet function was assessed before, and 3 and 6 h after the meal. Platelet aggregability and secretion was determined using whole blood flow cytometry (expression of platelet P-selectin and fibrinogen binding), filtragometry ex vivo (reflecting platelet aggregability in vivo) and by measurements of platelet specific products in plasma (beta-thromboglobulin and platelet factor 4). Plasma triglycerides increased from 0.8 (0.6:1.1; median, 25th and 75th percentiles) to 1.7 (1.0:2.3) mmol/l at 3 h and returned to baseline after 6 h (P < 0.001, one-way ANOVA). Apo B-100 and apo B-48 were both markedly increased 3 h postprandially in the Sf 60-400 fraction (large VLDLs, P < 0.001 for both), whereas the Sf 20-60 (small VLDLs) and Sf 12-20 fractions (IDL) did not change. The platelet function assessments revealed that the percentage of platelets expressing P-selectin increased by 40% (5%; 64%) after 3 h and by 51% (- 7%; 85%) 6 h postprandially in unstimulated samples (P < 0.05 for both). In samples stimulated by ADP in vitro P-selectin expression increased by 45% (6%; 58%) after 3 h and by 30% (12%; 58%) (P<0.01 for both) after 6 h at 0.1 microM. Platelet P-selectin expression was less influenced at higher ADP concentrations. The plasma levels of beta-thromboglobulin (approximately 20 ng/ml) and platelet factor 4 (approximately 0.3 ng/ml) were not affected by the fat load. Flow cytometric analyses of fibrinogen binding and filtragometry measurements also failed to reveal any postprandial alterations. The present finding of enhanced platelet P-selectin expression suggests that platelets are mildly sensitized postprandially. Whether this is of importance for thrombus formation and atherosclerosis needs to be studied further.


Mindfulness practice reduces cortisol blunting during chemotherapy: A randomized controlled study of colorectal cancer patients.
The objective of this randomized clinical experiment was to test the influence of a mindfulness meditation practice, when delivered during 1 session of active chemotherapy administration, on the acute salivary cortisol response as a marker of neuroendocrine system activity in cancer patients. A mindfulness, attention-control, or resting exposure was assigned to 57 English- or Spanish-speaking colorectal cancer patients at 1 county oncology clinic and 1 university oncology clinic at the start of chemotherapy. Saliva samples were collected at the start of chemotherapy and at subsequent 20-minute intervals during the first 60 minutes of chemotherapy (4 samples in all). Self-reporting on biobehavioral assessments after chemotherapy included distress, fatigue, and mindfulness. An area-under-the-curve analysis (AUC) showed a relative increase in cortisol reactivity in the mindfulness group after adjustments for biological and clinical measures (β = 123.21; P = .03). More than twice as many patients in the mindfulness group versus the controls displayed a cortisol rise from the baseline to 20 minutes (69% vs 34%; P = .02). AUC values were uncorrelated with biobehavioral measure scores, although mindfulness scores were inversely correlated with fatigue (r = -0.46; P < .01) and distress scores (r = -0.54; P < .01). Findings suggest that mindfulness practice during chemotherapy can reduce the blunting of neuroendocrine profiles typically observed in cancer patients. Implications include support for the use of mindfulness practice in integrative oncology. Cancer 2017;123:3088-96. © 2017 American Cancer Society.


Risk factors for progression of low-grade dysplasia in patients with Barrett's esophagus.
Data vary on the progression of low-grade dysplasia (LGD) in patients with Barrett's esophagus (BE); in patients with LGD, we investigated the incidence of high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) and compared progression in patients with different forms of LGD (prevalent vs incident and multifocal vs unifocal). We assessed the effects of consensus diagnosis of LGD on progression rates to HGD and EAC among expert pathologists. In a multicenter outcomes project, 210 patients with BE and LGD (classified as incident, prevalent, or persistent) were included. Patients were followed up for an average of 6.2 years (959.6 patient-years). Persistent LGD was defined as detection of LGD on ≥2 consecutive occasions during the follow-up period and extent as either unifocal (LGD at one level of BE segment) or multifocal (>1 level). Histology specimens were reviewed by 2 blinded pathologists. Six patients developed EAC (incidence of 0.44%/year), and 21 developed HGD (incidence of 1.6%/year). The incidence of the combination of HGD and EAC was 1.83%/year. There were no associations between presence of prevalent, incident, or persistent LGD and the extent of LGD with progression rates. Based on consensus diagnosis of 88 reviewed specimens, there was no difference in the progression of LGD to either EAC (the incidence based on analyses by the local pathologist was 0.18%/year, the incidence when there was agreement between the local and one central pathologist was 0.21%/year, and the incidence when all 3 pathologists were in agreement was 0.39%/year) or combined HGD and EAC (0.94%/year, 0.87%/year, and 0.84%/year, respectively). Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.


Postmastectomy Radiotherapy in Patients with pT1-2N1 Breast Cancer Treated with Taxane-Based Chemotherapy: A Retrospective Multicenter Analysis (KROG 1418).
The purpose of this study was to evaluate the impact of postmastectomy radiotherapy (PMRT) on loco-regional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival (OS) in pT1-2N1 patients treated with taxane-based chemotherapy. We retrospectively reviewed the medical data of pathological N1 patients who were treated with modified radical mastectomy and adjuvant taxane-based chemotherapy in 12 hospitals between January 2006 and December 2010. We identified 714 consecutive patients. The median follow-up duration was 69 months (range, 1 to 114 months) and the 5-year LRRFS, DFS, and OS rates were 97%, 94%, and 98%, respectively, in patients who received PMRT (PMRT [+]). The corresponding figures were 96%, 90%, and 96%, respectively, in patients who did not receive PMRT (PMRT [-]). PMRT had no significant impact on survival. Upon multivariable analysis, only the histological grade (HG) was statistically significant as a prognostic factor for LRRFS and DFS. In a subgroup analysis of HG 3 patients, PMRT (+) showed better DFS (p=0.081). PMRT had no significant impact on LRRFS, DFS, or OS in pT1-2N1 patients treated with taxane-based chemotherapy. PMRT showed a marginal benefit for DFS in HG 3 patients. Randomized studies are needed to confirm the benefit of PMRT in high risk patients, such as those with HG 3.


Interaction of spatial and temporal factors in psychophysical estimates of surround suppression.
Recent psychophysical work has shown that performance on a direction discrimination task decreases with increasing stimulus size, provided the stimulus is high in contrast. This psychophysical surround suppression has been linked to the inhibitory spatial surrounds that have been observed throughout the primate visual system. In this work we have examined a temporal factor that may also contribute to psychophysical surround suppression. Consistent with previous work, we found that psychophysical surround suppression is strongest when a high-contrast motion stimulus is presented very briefly so that the appearance of the stimulus coincided with its motion. However, when a brief delay was inserted between the stimulus onset and the onset of motion, the counterintuitive effects of stimulus size disappeared. The effect of the motion onset asynchrony (MOA) was strongest when the stationary stimulus immediately preceded the stimulus motion and when stimulus orientation during the MOA was very similar to that during the motion presentation. We conclude that psychophysical surround suppression is partially linked to the temporal structure of the stimulus, more precisely to a masking effect caused by sudden stimulus onsets (and to a smaller degree stimulus offsets).


No evidence from genome-wide data of a Khazar origin for the Ashkenazi Jews.
The origin and history of the Ashkenazi Jewish population have long been of great interest, and advances in high-throughput genetic analysis have recently provided a new approach for investigating these topics. We and others have argued on the basis of genome-wide data that the Ashkenazi Jewish population derives its ancestry from a combination of sources tracing to both Europe and the Middle East. It has been claimed, however, through a reanalysis of some of our data, that a large part of the ancestry of the Ashkenazi population originates with the Khazars, a Turkic-speaking group that lived to the north of the Caucasus region ~1,000 years ago. Because the Khazar population has left no obvious modern descendants that could enable a clear test for a contribution to Ashkenazi Jewish ancestry, the Khazar hypothesis has been difficult to examine using genetics. Furthermore, because only limited genetic data have been available from the Caucasus region, and because these data have been concentrated in populations that are genetically close to populations from the Middle East, the attribution of any signal of Ashkenazi-Caucasus genetic similarity to Khazar ancestry rather than shared ancestral Middle Eastern ancestry has been problematic. Here, through integration of genotypes from newly collected samples with data from several of our past studies, we have assembled the largest data set available to date for assessment of Ashkenazi Jewish genetic origins. This data set contains genome-wide single-nucleotide polymorphisms in 1,774 samples from 106 Jewish and non-Jewish populations that span the possible regions of potential Ashkenazi ancestry: Europe, the Middle East, and the region historically associated with the Khazar Khaganate. The data set includes 261 samples from 15 populations from the Caucasus region and the region directly to its north, samples that have not previously been included alongside Ashkenazi Jewish samples in genomic studies. Employing a variety of standard techniques for the analysis of population-genetic structure, we found that Ashkenazi Jews share the greatest genetic ancestry with other Jewish populations and, among non-Jewish populations, with groups from Europe and the Middle East. No particular similarity of Ashkenazi Jews to populations from the Caucasus is evident, particularly populations that most closely represent the Khazar region. Thus, analysis of Ashkenazi Jews together with a large sample from the region of the Khazar Khaganate corroborates the earlier results that Ashkenazi Jews derive their ancestry primarily from populations of the Middle East and Europe, that they possess considerable shared ancestry with other Jewish populations, and that there is no indication of a significant genetic contribution either from within or from north of the Caucasus region.


The impact of prison reentry services on short-term outcomes: evidence from a multisite evaluation.
Renewed interest in prisoner rehabilitation to improve postrelease outcomes occurred in the 1990s, as policy makers reacted to burgeoning prison populations with calls to facilitate community reintegration and reduce recidivism. In 2003, the Federal government funded grants to implement locally designed reentry programs. Adult programs in 12 states were studied to determine the effects of the reentry programs on multiple outcomes. A two-stage matching procedure was used to examine the effectiveness of 12 reentry programs for adult males. In the first stage, "intact group matching" was used to identify comparison populations that were similar to program participants. In the second stage, propensity score matching was used to adjust for remaining differences between groups. Propensity score weighted logistic regression was used to examine the impact of reentry program participation on multiple outcomes measured 3 months after release. The study population was 1,697 adult males released from prisons in 2004-2005. Data consisted of interview data gathered 30 days prior to release and approximately 3 months following release, supplemented by administrative data from state departments of correction and the National Crime Information Center. Results suggest programs increased in-prison service receipt and produced modest positive outcomes across multiple domains (employment, housing, and substance use) 3 months after release. Although program participants reported fewer crimes, differences in postrelease arrest and reincarceration were not statistically significant. Incomplete implementation and service receipt by comparison group members may have resulted in insufficient statistical power to identify stronger treatment effects.


Smooth muscle-derived nitric oxide is elevated in isolated forearm veins in human alcoholic cirrhosis.
1. Cirrhosis is often complicated by disturbances in the systemic circulation. We have previously demonstrated decreased vascular responses to vasoconstrictors in forearm resistance arteries in subjects with alcoholic cirrhosis. In the current study we investigate the role of the potent endogenous vasodilator nitric oxide in the peripheral circulation of these patients. 2. Ten patients with alcoholic cirrhosis (Pugh grade A) and 10 age-matched control subjects were studied. The effect of blockade of nitric oxide synthesis was studied both in vivo in forearm resistance arteries using forearm venous occlusion plethysmography and in vitro in veins isolated from the forearm. The role of endothelium-derived nitric oxide was studied in vivo using the endothelium-dependent vasodilator acetylcholine. 3. Mean arterial pressure and forearm basal flow in vivo were similar in the two groups. The constrictor response (percentage decrease in forearm blood flow) to noradrenaline (100 ng/min) was 26% smaller in patients with cirrhosis (31.65 +/- 2.64%) than in control subjects (42.75 +/- 3.87%, P = 0.037). Constrictor responses to the nitric oxide synthase inhibitor NG-monomethyl-L-arginine were not different in the two groups. Dilator responses to acetylcholine were significantly attenuated in cirrhotic patients compared with control subjects. 4. To investigate the role of smooth muscle-derived nitric oxide in vitro, all veins were stripped of their endothelium. Responses to noradrenaline were significantly diminished in veins isolated from patients with cirrhosis compared with control subjects. Incubation with the nitric oxide synthase inhibitor N omega-nitro-L-arginine had no effect on responses to noradrenaline in veins from control subjects but significantly enhanced the maximal response to noradrenaline by 23.95% (range 3.77-100%, P = 0.043) in veins from patients with cirrhosis. 5. Responses to noradrenaline were attenuated in vivo in forearm resistance arteries in patients with alcoholic cirrhosis. This impairment was also apparent in forearm isolated veins, stripped of the endothelium. Our data exclude a major role for endothelium-derived nitric oxide but highlight a possible role for smooth muscle-derived nitric oxide.


Reelin Haploinsufficiency and Late-Adolescent Corticosterone Treatment Induce Long-Lasting and Female-Specific Molecular Changes in the Dorsal Hippocampus.
Reelin depletion and stress seem to affect similar pathways including GABAergic and glutamatergic signaling and both are implicated in psychiatric disorders in late adolescence/early adulthood. The interaction between reelin depletion and stress, however, remains unclear. To investigate this, male and female heterozygous reelin mice (HRM) and wildtype (WT) controls were treated with the stress hormone, corticosterone (CORT), during late adolescence to simulate chronic stress. Glucocorticoid receptors (GR), N-methyl-d-aspartate receptor (NMDAr) subunits, glutamic acid decarboxylase (GAD67) and parvalbumin (PV) were measured in the hippocampus and the prefrontal cortex (PFC) in adulthood. While no changes were seen in male mice, female HRM showed a significant reduction in GR expression in the dorsal hippocampus. In addition, CORT reduced GR levels as well as GluN2B and GluN2C subunits of NMDAr in the dorsal hippocampus in female mice only. CORT furthermore reduced GluN1 levels in the PFC of female mice. The combined effect of HRM and CORT treatment appeared to be additive in terms of GR expression in the dorsal hippocampus. Female-specific CORT-induced changes were associated with overall higher circulating CORT levels in female compared to male mice. This study shows differential effects of reelin depletion and CORT treatment on GR and NMDAr protein expression in male and female mice, suggesting that females are more susceptible to reelin haploinsufficiency as well as late-adolescent stress. These findings shed more light on female-specific vulnerability to stress and have implications for stress-associated mental illnesses with a female bias including anxiety and major depression.


Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation.
Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF70-80, is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF70-80 binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF70-80. Peptides with this TNFRI sequence, such as TNFRI206-211 bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI206-211 does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI206-211 inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.


Five-member gene family of Bartonella quintana.
Bartonella quintana, the agent of trench fever and an etiologic agent of bacillary angiomatosis, has an extraordinarily high hemin requirement for growth compared to other bacterial pathogens. We previously identified the major hemin receptor of the pathogen as a 30-kDa surface protein, termed HbpA. This report describes four additional homologues that share approximately 48% amino acid sequence identity with hbpA. Three of the genes form a paralagous cluster, termed hbpCAB, whereas the other members, hbpD and hbpE, are unlinked. Secondary structure predictions and other evidence suggest that Hbp family members are beta-barrels located in the outer membrane and contain eight transmembrane domains plus four extracellular loops. Homologs from a variety of gram-negative pathogens were identified, including Bartonella henselae Pap31, Brucella Omp31, Agrobacterium tumefaciens Omp25, and neisserial opacity proteins (Opa). Family members expressed in vitro-synthesized proteins ranging from ca. 26.5 to 35.1 kDa, with the exception of HbpB, an approximately 55.9-kDa protein whose respective gene has been disrupted by a approximately 510 GC-rich element containing variable-number tandem repeats. Transcription analysis by quantitative reverse transcriptase-PCR (RT-PCR) indicates that all family members are expressed under normal culture conditions, with hbpD and hbpB transcripts being the most abundant and the rarest, respectively. Mutagenesis of hbpA by allelic exchange produced a strain that exhibited an enhanced hemin-binding phenotype relative to the parental strain, and analysis by quantitative RT-PCR showed elevated transcript levels for the other hbp family members, suggesting that compensatory expression occurs.


Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial.
Data on vaccine immunogenicity against SARS-CoV-2 are needed for the 40 million people globally living with HIV who might have less functional immunity and more associated comorbidities than the general population. We aimed to explore safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV. In this single-arm open-label vaccination substudy within the protocol of the larger phase 2/3 trial COV002, adults aged 18-55 years with HIV were enrolled at two HIV clinics in London, UK. Eligible participants were required to be on antiretroviral therapy (ART), with undetectable plasma HIV viral loads (<50 copies per mL), and CD4 counts of more than 350 cells per μL. A prime-boost regimen of ChAdOx1 nCoV-19, with two doses was given 4-6 weeks apart. The primary outcomes for this substudy were safety and reactogenicity of the vaccine, as determined by serious adverse events and solicited local and systemic reactions. Humoral responses were measured by anti-spike IgG ELISA and antibody-mediated live virus neutralisation. Cell-mediated immune responses were measured by ex-vivo IFN-γ enzyme-linked immunospot assay (ELISpot) and T-cell proliferation. All outcomes were compared with an HIV-uninfected group from the main COV002 study within the same age group and dosing strategy and are reported until day 56 after prime vaccination. Outcomes were analysed in all participants who received both doses and with available samples. The COV002 study is registered with ClinicalTrials.gov, NCT04400838, and is ongoing. Between Nov 5 and Nov 24, 2020, 54 participants with HIV (all male, median age 42·5 years [IQR 37·2-49·8]) were enrolled and received two doses of ChAdOx1 nCoV-19. Median CD4 count at enrolment was 694·0 cells per μL (IQR 573·5-859·5). No serious adverse events occurred. Local and systemic reactions occurring during the first 7 days after prime vaccination included pain at the injection site (26 [49%] of 53 participants with available data), fatigue (25 [47%]), headache (25 [47%]), malaise (18 [34%]), chills (12 [23%]), muscle ache (19 [36%]), joint pain (five [9%]), and nausea (four [8%]), the frequencies of which were similar to the HIV-negative participants. Anti-spike IgG responses by ELISA peaked at day 42 (median 1440 ELISA units [EUs; IQR 704-2728]; n=50) and were sustained until day 56 (median 941 EUs [531-1445]; n=49). We found no correlation between the magnitude of the anti-spike IgG response at day 56 and CD4 cell count (p=0·93) or age (p=0·48). ELISpot and T-cell proliferative responses peaked at day 14 and 28 after prime dose and were sustained to day 56. Compared with participants without HIV, we found no difference in magnitude or persistence of SARS-CoV-2 spike-specific humoral or cellular responses (p>0·05 for all analyses). In this study of people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic, supporting vaccination for those well controlled on ART. UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.


Original research paper. Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats.
The study aims to compare, through histological and biochemical studies, the effects of quercetin, melatonin and their combination in regulation of immuno-inflammatory mediators and heat shock protein expressions in sodium nitrite induced hypoxia in rat lungs. The results revealed that NaNO2 injection caused a significant decrease in Hb in rats, while serum levels of TNF-α, IL-6 and CRP, VEGF and HSP70 were elevated compared to the control group. Administration of melatonin, quercetin or their combination before NaNO2 injection markedly reduced these parameters. Histopathological examination of the lung tissue supported these biochemical findings. The study suggests that melatonin and/or quercetin are responsible for lung tissue protection in hypoxia by downregulation of immuno-inflammatory mediators and heat shock protein expressions. Pre-treatment of hypoxic animals with a combination of melatonin and quercetin was effective in modulating most of the studied parameters to near-normal levels.


First Report of Anthracnose on Fruits of Duchesnea indica Caused by Colletotrichum acutatum in Northwestern Argentina.
Duchesnea indica (Andrews) Focke, a cosmopolitan wild species related to the cultivated strawberry that is widely distributed in northwestern Argentina, grows in close proximity to strawberry crops and has proven to be almost immune to Colletotrichum spp. isolated from diseased strawberry plants (1), hence it has never been considered a phytopathological risk. During a field survey of "La Heladera" (27°01'45″S, 65°39'20″W), Tafí del Valle (Tucumán, Argentina) from November 2009 to November 2010, a genotype of D. indica showing fruits with dark brown, necrotic, irregular, circular lesions of 5 to 20 mm in diameter were collected. Setose acervuli were observed on the center of the fruit lesions. Pathogens were obtained from 10 diseased fruit collected at random, and four fungal isolates were isolated per fruit on potato dextrose agar (PDA). To reduce the number of samples for evaluation, two isolates per fruit that were exhibiting stable but distinctive morphological features were chosen to continue the studies. Isolates were characterized by morphological, molecular, and phytopathological criteria. After 10 days of incubation on PDA medium at 28°C with continuous white light, colonies exhibited a gray, aerial mycelium, whereas the reverse of the colony is a pale maroon with a radial, pale salmon color. Masses of salmon-colored conidia formed in the center of the colonies. Conidia were hyaline, one celled, fusiform, tapered to a point at both ends, and measured 14.8 to 17.3 × 4.5 to 7.4 μm (n = 100). Setae were scarce and sclerotia were absent. All morphological characteristics that were observed indicated that the isolates were C. acutatum (3). To fulfill Koch's postulates and verify the pathogenicity on commercial varieties of strawberry, six healthy plants of D. indica and Fragaria × ananassa cv. Camarosa with mature fruits were used to test each isolate. Four plants were spray inoculated with conidial suspensions of the virulent isolates (1.5 × 106 conidia/ml) and two with sterile distilled water as controls. Both treatments were maintained under white light (2,000 lux, 12 h per day) at 28°C and 70% relative humidity. Nine days after the inoculation, dark brown lesions and salmon-colored masses of conidia were observed only in inoculated fruits of both genotypes. The fungus isolated from diseased fruits and the conidia that were produced were identical to the isolates used to inoculate the plants. To confirm pathogen identity, PCR amplification with the species-specific pair of primer CaInt2/ITS4 (4) were carried out using fungal total DNA from the original isolates and isolates obtained from inoculated fruits. An amplification product of approximately 490 bp, which is specific for C. acutatum, was observed in all DNA samples (4). Although C. acutatum has already been reported in Fragaria × ananassa in Argentina (2), to our knowledge, this is the first report of C. acutaum causing anthracnose in D. indica species. This result is relevant since this species grows close to strawberry fields and can be an alternative host and potential vector of the anthracnose disease agent. References: (1) M. E. Arias. Frutillas Silvestres y Especies Relacionadas con la Cultivada. EDUNT, Argentina, 2007. (2) C. J. Ramallo et al. Plant Dis. 84:706. 2000. (3) B. J. Smith and L. L. Black. Plant Dis. 74:69, 1990. (4) S. Sreenivasaprasad et al. Plant Pathol. 45:650, 1996.


Identification of an intracellular site of prion conversion.
Prion diseases are fatal, neurodegenerative disorders in humans and animals and are characterized by the accumulation of an abnormally folded isoform of the cellular prion protein (PrP(C)), denoted PrP(Sc), which represents the major component of infectious scrapie prions. Characterization of the mechanism of conversion of PrP(C) into PrP(Sc) and identification of the intracellular site where it occurs are among the most important questions in prion biology. Despite numerous efforts, both of these questions remain unsolved. We have quantitatively analyzed the distribution of PrP(C) and PrP(Sc) and measured PrP(Sc) levels in different infected neuronal cell lines in which protein trafficking has been selectively impaired. Our data exclude roles for both early and late endosomes and identify the endosomal recycling compartment as the likely site of prion conversion. These findings represent a fundamental step towards understanding the cellular mechanism of prion conversion and will allow the development of new therapeutic approaches for prion diseases.


Confronting an Upsurge in Opiate Deaths with Limited Resources.
The dramatic increase in drug-related deaths in the last decade has presented fiduciary and logistical difficulties to medicolegal jurisdictions of all types and sizes. New Hampshire, with a centralized state medical examiner system of death investigation, has been confronted with the task of investigating these drug-related deaths against the backdrop of statutory hurdles inhibiting a nimble response to the situation. This has led to a collaborative approach with law enforcement and the state Department of Justice in terms of triaging drug deaths to full autopsy versus external examination with toxicology testing. Preliminary data suggest that between 11 and 13% of suspected drug deaths have an alternative cause of death revealed by autopsy. Positive toxicological findings were documented in 97.5% of cases in which only an external examination was performed; however, some of these cases may have had undetected, significant internal findings that could have accounted for an alternative cause of death if an autopsy had been performed. While the case triage system described has temporarily addressed the acute problem, the issue of the medical examiner's appropriate role in the adequate evaluation of public health and safety remains extant. Furthermore, noncompliance with the National Association of Medical Examiners inspection and accreditation standards puts this agency, and others facing the same issues, at risk of losing full accreditation status until such resource issues are addressed by legislators and other stakeholders in the quality of medicolegal death investigation in the United States.


A comparative evaluation of teaching methods in an introductory neuroscience course for physical therapy students.
The use of computer-based instruction (CBI) in physical therapy education is growing, but its effectiveness compared to lecture is undefined. This study compared CBI to lecture in an introductory neuroscience course for students in their first year of a 3 year professional program leading to the Doctor of Physical Therapy Degree. Twenty-eight students participated in 2003 and 34 in 2004. A randomized, cross-over design was employed. The course was divided into two sections with an exam after each. Students in one group participated in CBI during the first half of the course and lecture during the second half with the order of participation reversed for the other group. A 6 months post-course review exam was also administered. Exam scores, study time, and student opinions regarding teaching methods were collected after each half of the course. Course development costs for both teaching approaches were also documented. There were no statistically significant differences in exam scores between participant groups. CBI students spent less time studying. Student did not distinguish a major preference for either instruction method. Many students preferred that CBI be used as a complementary rather than mutually exclusive instructional method. Lecture-based instruction was much less expensive than CBI. Lecture-based instruction was more cost effective than CBI, but CBI was more time efficient in terms of student learning.


A Model for Sustaining and Investing in Immunization Information Systems: Authors.
In the past three years, Scientific Technologies Corporation electronically sent one-hundred fifty million retail pharmacy patient immunization events to state and community public health immunization information systems. Today, as a conservative estimate, over 85% of the U.S. population has an immunization record in an electronic health information system. Health technology, data exchange and increasing online patient health records offer consumers, providers and the immunization community new platforms to proactively identify vaccine coverage gaps. As the value of online immunization information increases, the cost to sustain and leverage these new technologies escalates. Online immunization records and integrated decision support tools are being used extensively from the pharmacy to the emergency room. They are moving from health data vaults with few users to more ubiquitous point of care services and direct consumer engagement. The data and the supporting technology infrastructure empower the community within the immunization ecosystem. To use this opportunity to reduce the impact of vaccine preventable disease on populations, investment in sustaining and modernizing existing immunization health technology systems suggest models to articulate their value and return on investment. This paper illustrates cost and technology drivers that impact sustainability and modernization of the immunization information system infrastructure. It provides a model to support investment priority decisions and estimate costs. It reviews the technical evolution of public health immunization registries and their current legacy state providing a pathway to migrate to opportunistic third generation technology platforms. It will answer: How much should be budgeted? What can this budget achieve over the next five years? What investments should be prioritized? Is there opportunity for public-private partnerships to support sustainment cost sharing? It shows that an investment of fifty million will modernize a quarter of the current second generation immunization systems and support the remainder over the next five years.


Unique C. elegans telomeric overhang structures reveal the evolutionarily conserved properties of telomeric DNA.
There are two basic mechanisms that are associated with the maintenance of the telomere length, which endows cancer cells with unlimited proliferative potential. One mechanism, referred to as alternative lengthening of telomeres (ALT), accounts for approximately 10-15% of all human cancers. Tumours engaged in the ALT pathway are characterised by the presence of the single stranded 5'-C-rich telomeric overhang (C-overhang). This recently identified hallmark of ALT cancers distinguishes them from healthy tissues and renders the C-overhang as a clear target for anticancer therapy. We analysed structures of the 5'-C-rich and 3'-G-rich telomeric overhangs from human and Caenorhabditis elegans, the recently established multicellular in vivo model of ALT tumours. We show that the telomeric DNA from C. elegans and humans forms fundamentally different secondary structures. The unique structural characteristics of C. elegans telomeric DNA that are distinct not only from those of humans but also from those of other multicellular eukaryotes allowed us to identify evolutionarily conserved properties of telomeric DNA. Differences in structural organisation of the telomeric DNA between the C. elegans and human impose limitations on the use of the C. elegans as an ALT tumour model.


Family Communication at the End of Life.
People often feel awkward and ill at ease when faced with the opportunity for communication at the end of life, thus the overall theme for the articles in this special issue is the creation of more awareness and knowledge regarding the depth, breadth, and importance of current research exploring family communication at the end of life. This introductory essay attempts to accomplish the following: (1) discuss the importance of talk regarding death; (2) highlight the formative role of family interactions on the death and dying process; and (3) outline the articles in this special issue. Scholars contributing to this special issue on "Family Communication at the End of Life" have provided evidence that communication is important between and for terminally ill individuals, family members, and healthcare/palliative care specialists. Overall, research exploring communication at the end of life is especially relevant because every person experiences the death and loss of loved ones, and ultimately faces the reality of their own death.


Facility-level changes in receipt of pharmacotherapy for opioid use disorder: Implications for implementation science.
The U.S. is facing an opioid epidemic, but despite mandates for pharmacotherapy for opioid use disorder to be available at Veterans Health Administration (VHA) facilities, the majority of veterans with opioid use disorder do not receive these medications. In implementation research, facilities are often targeted for qualitative inquiry or quality improvement efforts based on quality measure performance during a one-year period. However, sites that experience quality performance changes from one year to the next may be highly informative because mechanisms that impact facility change may be more discoverable. The current study examined changes in receipt of pharmacotherapy for opioid use disorder in a national healthcare system to determine the extent to which sites fluctuated in performance over a two-year period and illustrate how changes in quality measures over time may be useful for implementation research and healthcare surveillance of quality measures. Using national VHA data from Fiscal Years (FY) 2016 and 2017, we calculated quality measure performance as the number of patients who received pharmacotherapy for opioid use disorder (i.e., methadone, buprenorphine, and naltrexone) divided by the number of patients with a current non-remitted opioid use disorder diagnosis for each FY at each facility (n = 129) and examined change from FY16 to FY17. The mean rate of receipt of pharmacotherapy for opioid use disorder was 38% (facility range = 3% to 74%) in FY16 and 41% (facility range = 2% to 76%) in FY17. The average facility-level change in performance was 3% and ranged from -19% to 26%. There were 32 facilities that decreased in provision of pharmacotherapy, 12 facilities with no change, and 85 facilities that increased. For facilities with average or high performance, it was difficult to maintain their performance over time. Identifying and learning from facilities with recent fluctuations may be more informative to guide the design of future quality improvement efforts than studying facilities with stable high or low performance.


Extensive endovascular repair of thoracic aorta: observational analysis of the results and effects on spinal cord perfusion.
The study aims to analyze retrospective results of extensive endovascular repair of the descending thoracic aorta with special attention to spinal cord malperfusion. From April 2002 through November 2011, 21 patients underwent stent-graft coverage of the thoracic aorta from the aortic arch at the origin of the left subclavian artery to the celiac trunk, 6 (mean age =72.3±8.1) for aneurysm disease, 13 (mean age =74.3±8.4) for type B aortic dissection and 2 (mean age =52.1±6.5) for aortic rupture. The mean of aortic diameter in cases with aneurysm disease was 7.1±1.6 cm and the causes of aortic rupture were post-traumatic and aneurysm pathology respectively. In all cases needing coverage of the left subclavian artery duplex ultrasonography and flowmetry were performed to evaluate patency and flow of both the vertebral arteries. Technical success was 100% with 0% in-hospital mortality. The left subclavian artery was crossed with the uncovered portion of the stent-graft in 11 cases (52.4%) and the covered segment in the other 10 patients (47.6%) without subclavian revascularization because no pre-operative hemodynamic alterations of vertebral arteries were revealed by duplex ultrasonography. The incidence of paraplegia was 9.5% in 2 patients who had prior abdominal aortic aneurysm repair: the first case with preoperative type B aortic dissection presented significant lower extremity paresis within 24 hours after the procedure and in the second patient with a large thoracic aneurysm the signs of paraplegia were evident 3 weeks after discharge from Hospital probably due to delayed occlusion of a major medullary artery. The cumulative survival rate after 1, 3 and 9 years was 91%, 81%, and 71%. The coverage of the entire thoracic aorta is an effective procedure with high probability of success. Spinal cord malperfusion remains a serious complication especially in patients with prior aortic surgery but if collateral blood supply is maintained the occlusion of intercostal arteries do not determine paraplegia or paraparesis. In order to consider acute or chronic occlusion of subclavian, lumbar or hypogastric arteries so preventing spinal cord ischemia, strong preoperative evaluation including analysis of previous surgery for abdominal aortic aneurysm repair and avoidance of T12 aortic segment coverage if feasible is mandatory.


The Long-term Outcome After Resection of Intraspinal Nerve Sheath Tumors: Report of 131 Consecutive Cases.
The existing literature on recurrence rates and long-term clinical outcome after resection of intraspinal nerve sheath tumors is limited. To evaluate progression-free survival, overall survival, and long-term clinical outcome in a consecutive series of 131 patients with symptomatic intraspinal nerve sheath tumors. Medical charts were retrospectively reviewed. Surviving patients voluntarily participated in a clinical history and physical examination that focused on neurological function and current tumor status. Follow-up data are 100% complete; median follow-up time was 6.1 years. All patients (100%) had surgery as the first line of treatment; gross total resection was performed in 112 patients (85.5%) and subtotal resection in 19 patients (14.5%). Five-year progression-free survival was 89%. The following risk factors for recurrence were identified: neurofibroma, malignant peripheral nerve sheath tumor, subtotal resection, neurofibromatoses/schwannomatosis, and advancing age at diagnosis. More than 95% of patients had neurological function compatible with an independent life at follow-up. The rate of tumor recurrence in nonneurofibromatosis patients undergoing total resection of a single schwannoma was 3% (3/93), in comparison with a recurrence rate of 32% (12/38) in the remaining patients. Gross total resection is the gold standard treatment for patients with intraspinal nerve sheath tumors. In a time of limited health care resources, we recommend that follow-up be focused on the subgroup of patients with a high risk of recurrence. The benefit of long-term, yearly magnetic resonance imaging follow-up with respect to recurrence in nonneurofibromatosis patients undergoing gross total resection of a single schwannoma is, in our opinion, questionable. 1NF2, neurofibromatosis 2NST, nerve sheath tumorOS, overall survivalPFS, progression-free survivalSTR, subtotal resectionWHO, World Health Organization.


Preservation of autonomic nerves in laparoscopic total radical hysterectomy.
The aim of this study was to evaluate the feasibility, complications, margin status, and functional outcome (on urinary and sexual functions) of nerve-sparing radical hysterectomy (NSRH) performed laparoscopically. Patients with cervical carcinoma of stage Ia2 and Ib1 underwent laparoscopic NSRH along with pelvic lymphadenectomy. We performed the technique in simple comprehensible steps with anatomic delineation of the autonomic nerves and selective cutting of the uterine and cervical branches. Laparoscopic NSRH was feasible in 85.7% of patients. Mean operative time was 160 minutes and all 7 patients had clear surgical margins. There were no complications and no blood transfusions were required. The median hospital stay was 3 days. The median return time for normal bladder function was 2 days and none of them required catheterization beyond 2 weeks. The mean residual urine volume was <50 mL. Urodynamic studies performed at 3 weeks after the operation showed no impairment of maximum flow rate (maximal flow rate: 20 ± 2 mL). The postoperative results of sexual dysfunction were inconclusive. Understanding this technique and the knowledge of laparoscopic anatomy of pelvic autonomic nerves is important in both benign and malignant pelvic surgeries. These preliminary results indicate that nerve sparing is easier done laparoscopically and its results are comparable to that of conventional laparoscopic radical hysterectomy in terms of lateral margin status and lymph node yield. Whether quality of life can be benefited by L-NRSH technique and its long-term oncological sequelae need further evaluation.


Relationships between horizontal interactions and functional architecture in cat striate cortex as revealed by cross-correlation analysis.
Anatomical studies in the visual cortex have shown the presence of long-range horizontal connections with clustered axonal collaterals, suggesting interactions over distances of several millimeters. We used cross-correlation analysis in cat striate cortex to detect interactions between cells over comparable distances. Using one cell as a reference, we recorded from other cells with a second electrode at varying distances and looked for correlated firing between the two recording sites. This technique allowed us to combine a physiological measure of the strength and type of connection between cells with a characterization of their receptive field properties. The observed interactions were excitatory, and extended over horizontal distances of several millimeters. Furthermore, the interactions were between orientation columns of like specificity, resulting in a waxing and waning in the strength of interaction as the electrodes passed through different orientation columns. We studied relationships between strength of correlation and other receptive field properties and found a tendency for facilitatory interactions between cells sharing the same eye preference. A large proportion of our correlations was due to common input. This feature, and the similarity of interactions between cells in the same column with the reference cell, suggest a high degree of interconnectivity between and within the columns. As the distance between the two electrodes increased, the overlap of the receptive fields of the cells participating in the interactions gradually diminished. At the furthest distances recorded, the cell pairs had nonoverlapping receptive fields separated by several degrees. The distribution and range of these interactions corresponded to the clustering and extent of the horizontal connections observed anatomically.