Chronic widespread pain in the population: a seven year follow up study.
To document the natural course of chronic widespread pain (CWP) in a general population sample over a seven year period and to identify comorbidities which predict persistence. A mailed survey questionnaire returned by 2334 adults registered with two general practices was used to obtain information on pain status (no pain, regional pain, or CWP) and other health and pain symptoms. Seven years later a second questionnaire was sent to responders who were still registered with the same general practice, asking about their current pain status. Information was obtained for 1386 adults (an adjusted response of 93%). The prevalence of CWP was similar for both surveys at 11% and 10% respectively. Of those with CWP initially, a third recorded CWP on the second survey and 15% were pain free. Only 2% of subjects with no initial pain had developed CWP at follow up. Of subjects with CWP on the initial survey who were aged over 50 years and reported dry eyes or mouth and daytime tiredness, 77% reported CWP seven years later. This contrasts with a persistence of only 9% for those aged under 50 and with neither symptom recorded at initial survey. The proportion of subjects from a general population sample changing from CWP to no pain, or vice versa, over a seven year period was very low. This suggests that pain, once established, is likely to persist (or recur) especially if accompanied by other somatic symptoms and older age.


Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2.
To estimate the fraction of cervical intraepithelial neoplasia 2 (CIN 2) that might regress if untreated using data from the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS). We compared the cumulative occurrence of CIN 2 (n=397) and CIN 3 or more severe (n=542) diagnosed by the Pathology Quality Control Group in three trial arms-immediate colposcopy, human papillomavirus (HPV) triage, and conservative management-over the 2-year duration of the ALTS trial. A nonparametric test of trend was used to test for differences in the number of CIN 2 cases relative to number of CIN 3 or more severe cases across study arms with an increasing percentage of women referred to colposcopy at baseline. There were no significant differences in the cumulative 2-year cumulative CIN 3 or more severe diagnoses by study arm (10.9%, conservative management; 10.3%, HPV; 10.9%, immediate colposcopy) (Ptrend=.8), but there was a significant increase in CIN 2 diagnoses (5.8%, conservative management; 7.8%, HPV triage; 9.9%, immediate colposcopy) (Ptrend<.001) in the study arms, with increasing number of women referred to colposcopy at baseline. The relative differences in cumulative CIN 2 by study arm among women who tested HPV-16 positive at baseline were less pronounced (Ptrend=.1) than women who tested positive for other high-risk-HPV genotypes (Ptrend=.01). There was evidence that approximately 40% of undiagnosed CIN 2 will regress over 2 years, but CIN 2 caused by HPV-16 may be less likely to regress than CIN 2 caused by other high-risk-HPV genotypes. II.


Savannahs of Asia: antiquity, biogeography, and an uncertain future.
The savannahs of Asia remain locally unrecognized as distinctive ecosystems, and continue to be viewed as degraded forests or seasonally dry tropical forests. These colonial-era legacies are problematic, because they fail to recognize the unique diversity of Asian savannahs and the critical roles of fire and herbivory in maintaining ecosystem health and diversity. In this review, we show that: the palaeo-historical evidence suggests that the savannahs of Asia have existed for at least 1 million years, long before widespread landscape modification by humans; savannah regions across Asia have levels of C4 grass endemism and diversity that are consistent with area-based expectations for non-Asian savannahs; there are at least three distinct Asian savannah communities, namely deciduous broadleaf savannahs, deciduous fine-leafed and spiny savannahs and evergreen pine savannahs, with distinct functional ecologies consistent with fire- and herbivory-driven community assembly. Via an analysis of savannah climate domains on other continents, we map the potential extent of savannahs across Asia. We find that the climates of African savannahs provide the closest analogues for those of Asian deciduous savannahs, but that Asian pine savannahs occur in climates different to any of the savannahs in the southern continents. Finally, we review major threats to the persistence of savannahs in Asia, including the mismanagement of fire and herbivory, alien woody encroachment, afforestation policies and future climate uncertainty associated with the changing Asian monsoon. Research agendas that target these issues are urgently needed to manage and conserve these ecosystems.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'.


Chronic cocaine administration increases CNS tyrosine hydroxylase enzyme activity and mRNA levels and tryptophan hydroxylase enzyme activity levels.
Cocaine is an inhibitor of dopamine and serotonin reuptake by synaptic terminals and has potent reinforcing effects that lead to its abuse. Tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) catalyze the rate-limiting steps in dopamine and serotonin biosynthesis, respectively, and are the subject of dynamic regulatory mechanisms that could be sensitive to the actions of cocaine. This study assessed the effects of chronic cocaine on brain TH and TPH activities. Cocaine was administered (0.33 mg/infusion, i.v.) to rats for 7 days every 8 min for 6 h per day. This administration schedule is similar to patterns of self-administration by rats when given ad libitum access to this dose. This chronic, response-independent administration increased TH enzyme activity in the substantia nigra (30%) and ventral tegmental area (43%). Moreover, TH mRNA levels were also increased (45 and 50%, respectively). In contrast to the enzymatic and molecular biological changes in the cell bodies, TH activity was unchanged in the terminal fields (corpus striatum and nucleus accumbens). Similarly, TPH activity was increased by 50% in the raphe nucleus (serotonergic cell bodies). In summary, the chronic response-independent administration of cocaine produces increases in the expression of TH mRNA and activity in both the cell bodies of motor (nigrostriatal) and reinforcement (mesolimbic) dopamine pathways. These increases are not manifested in the terminal fields of these pathways.


Expression and localization of messenger ribonucleic acid for the vitellogenin receptor in ovarian follicles throughout oogenesis in the rainbow trout, Oncorhynchus mykiss.
The expression and localization of vitellogenin (VTG) receptor (VTGR) mRNA were identified throughout ovarian development in the rainbow trout, Oncorhynchus mykiss. Northern blot confirmed the presence of a transcript (approximately 3.9 kilobases [kb]) that was specific to the ovary. The expression of VTGR mRNA varied throughout ovarian development and was highest in previtellogenic ovaries and in ovaries at the onset of vitellogenesis containing ovarian follicles (OF) from 35 to 600 microm in diameter. In situ hybridization using 35S riboprobes showed that the transcription of the VTGR gene was initiated in OF measuring 45-50 microm in diameter, with transcripts being exclusively localized in the ooplasm. A dramatic increase in mRNA synthesis occurred during previtellogenic growth (OF from 50 to 200 microm); this was followed by a gradual decrease during the vitellogenic growth phase. VTGR mRNA was not detected in OF greater than 1000 microm in diameter (oocytes actively sequestering VTG). Immunocytolocalization of yolk proteins derived from VTG demonstrated that oocytes started to sequester VTG when they were around 300 microm in diameter, shortly after the time of maximal density of VTGR mRNA in the ooplasm. The timing of transcription of the VTGR gene, predominantly during previtellogenesis, suggests that the VTGR is recycled to the oocyte surface during the vitellogenic growth phase.


Evaluation of the Preschool Situational Self-Regulation Toolkit (PRSIST) Program for Supporting children's early self-regulation development: study protocol for a cluster randomized controlled trial.
For children with low self-regulation in the preschool years, the likelihood of poorer intellectual, health, wealth and anti-social outcomes in adulthood is overwhelming. Yet this knowledge has not yielded a framework for understanding self-regulatory change, nor generated particularly successful methods for enacting this change. Reconciling insights from cross-disciplinary theory, research and practice, this study seeks to implement a newly developed program of low-cost and routine practices and activities for supporting early self-regulatory development within preschool contexts and to evaluate its effect on children's self-regulation, executive function and school readiness; and educator perceived knowledge, attitudes and self-efficacy related to self-regulation. The Early Start to Self-Regulation study is a cluster randomized, controlled trial for evaluating benefits of the Preschool Situational Self-Regulation Toolkit (PRSIST) program, when implemented by early childhood educators, compared with routine practice. The PRSIST program combines professional learning, adult practices, child activities and connections to the home to support children's self-regulation development. Fifty preschool centers in New South Wales, Australia, will be selected to ensure a range of characteristics, namely: National Quality Standards (NQS) ratings, geographic location and socioeconomic status. After collection of baseline child and educator data, participating centers will then be randomly allocated to one of two groups, stratified by NQS rating: (1) an intervention group (25 centers) that will implement the PRSIST program; or (2) a control group (25 centers) that will continue to engage in practice as usual. Primary outcomes at the child level will be two measures of self-regulation: Head-Toes-Knees-Shoulders task and the PRSIST observational assessment. Secondary outcomes at the child level will be adult-reported measures of child self-regulation, executive function and school readiness. Outcomes at the educator level will involve a survey of their perceived knowledge, attitudes and self-efficacy for supporting children's self-regulatory development. In all cases, data collectors will be blinded to group allocation. This is the first randomized controlled trial of a new program to foster early self-regulation, using low-cost practices and activities that are aligned with early-years contexts, routines and practices. Results will provide important information about the efficacy of this approach and evaluate its underlying model of self-regulatory change. Australian New Zealand Clinical Trials Registry, ACTRN12617001568303 . Registered on 21 November 2017.


Sevoflurane or halothane anesthesia: can we tell the difference?
This study was performed to evaluate the ability of anesthesiologists to differentiate between sevoflurane, a newer, more expensive anesthetic, and halothane. A total of 113 assessments were made by 36 anesthesiologists on 58 children, aged 6 mo to 6 yr, scheduled for bilateral myringotomy and tube placement. All patients received midazolam (0.5 mg/kg per os) approximately 30 min before the induction of anesthesia. Sevoflurane or halothane was randomly selected for anesthetic induction and maintenance. The anesthesiologists, who were unaware of the anesthetic being used, were asked to identify the anesthetic based on clinical signs and to assess the quality of induction, speed of induction, and speed of emergence using a visual analog scale (VAS; minimum score = 0, maximum score = 100). The anesthesiologists correctly identified the anesthetic only 56.6% of the time. This was not significantly different from the 50% that would result from random guessing (P = 0.08). Further, there were no significant differences in VAS scores between the two groups. This study suggests that in premedicated pediatric patients undergoing brief surgical procedures, anesthesiologists cannot correctly differentiate between sevoflurane and halothane. The lack of significant differences in VAS scores suggests that the speed of induction, the speed of emergence, and the quality of induction are similar under these clinical conditions. Any purported benefits of sevoflurane seem to be of minor consequence under the circumstances studied. When the anesthetic halothane or sevoflurane is administered in a blind, randomized fashion, anesthesiologists could not reliably identify which drug was being used to anesthetize children for a brief surgical procedure. These results suggest that the differences between the two drugs in clinical practice are small and may not justify the additional cost of sevoflurane.


Uracil recognition in archaeal DNA polymerases captured by X-ray crystallography.
Archaeal family B DNA polymerases bind tightly to template-strand uracil and stall replication on encountering the pro-mutagenic base. This article describes an X-ray crystal structure, at 2.8 A resolution, of Thermococcus gorgonarius polymerase in complex with a DNA primer-template containing uracil in the single-stranded region. The DNA backbone is distorted to position the uracil deeply within a pocket, located in the amino-terminal domain of the polymerase. Specificity arises from a combination of hydrogen bonds between the protein backbone and uracil, with the pocket shaped to prevent the stable binding of the four standard DNA bases. Strong interactions are seen with the two phosphates that flank the uracil and the structure gives clues concerning the coupling of uracil binding to the halting of replication. The importance of key amino acids, identified by the analysis of the structure and their conservation between archaeal polymerases, was confirmed by site-directed mutagenesis. The crystal structure of V93Q, a polymerase variant that no longer recognises uracil, is also reported, explaining the V93Q phenotype by the steric exclusion of uracil from the pocket.


Global patterns in the impact of marine herbivores on benthic primary producers.
Despite the importance of consumers in structuring communities, and the widespread assumption that consumption is strongest at low latitudes, empirical tests for global scale patterns in the magnitude of consumer impacts are limited. In marine systems, the long tradition of experimentally excluding herbivores in their natural environments allows consumer impacts to be quantified on global scales using consistent methodology. We present a quantitative synthesis of 613 marine herbivore exclusion experiments to test the influence of consumer traits, producer traits and the environment on the strength of herbivore impacts on benthic producers. Across the globe, marine herbivores profoundly reduced producer abundance (by 68% on average), with strongest effects in rocky intertidal habitats and the weakest effects on habitats dominated by vascular plants. Unexpectedly, we found little or no influence of latitude or mean annual water temperature. Instead, herbivore impacts differed most consistently among producer taxonomic and morphological groups. Our results show that grazing impacts on plant abundance are better predicted by producer traits than by large-scale variation in habitat or mean temperature, and that there is a previously unrecognised degree of phylogenetic conservatism in producer susceptibility to consumption.


Long-term independent evaluation after arthroscopic extra-articular Bankart repair with absorbable tacks. A clinical and radiographic study with a seven to ten-year follow-up.
Several arthroscopic methods have been developed to treat posttraumatic recurrent anterior shoulder instability in an attempt to match the results that can be achieved with open repair. The aim of this study was to perform an independent long-term clinical and radiographic evaluation after extra-articular arthroscopic Bankart repair with use of absorbable tacks (Suretac fixators). Eighty-one consecutive patients with posttraumatic recurrent anterior shoulder instability underwent an extra-articular arthroscopic Bankart procedure. Seventy-one (88%) of the patients were reexamined physically after a median duration of follow-up of 107 months by two independent examiners and constituted the study group. Their clinical and radiographic outcomes were documented. At the time of follow-up, twenty-seven (38%) of the seventy-one patients had experienced some kind of shoulder instability, although fifteen of them had had a new, clinically relevant shoulder injury. Eleven patients had had subluxation only, and sixteen had had redislocation. Fourteen of the twenty-seven patients had had a single episode of instability. Seven patients had undergone additional surgery to treat shoulder instability. The instability episodes occurred less than two years postoperatively in nine patients, between two and five years postoperatively in twelve, and more than five years postoperatively in six. At the time of final follow-up the median external rotation in abduction was 90 degrees (range, 0 degrees to 120 degrees) compared with 95 degrees (range, 70 degrees to 125 degrees) for the contralateral, uninjured shoulders (p<0.001). Before the injury, fifty-two patients (73%) participated in overhead or contact sports, whereas thirty-four patients (45%) participated in such activities at the time of follow-up. At the time of follow-up, the drill holes used to implant the absorbable tacks were invisible or hardly visible in fifty-eight (91%) of sixty-four patients for whom radiographs had been made. A marked increase in degenerative changes was noted when follow-up radiographs were compared with the preoperative radiographs. This long-term follow-up study of arthroscopic extra-articular Bankart repairs revealed an unexpectedly high number of patients with new episodes of instability. This finding led to a slight modification of the technique. Since most instability episodes occurred after two years, it is important to follow patients for a longer period of time after surgical treatment of recurrent anterior shoulder instability to identify the true recurrence rate.


Familial glomerular disease with asymptomatic proteinuria and nephrotic syndrome: a new clinical entity.
Seventy-three members of a 100-member kindred with asymptomatic proteinuria, nephrotic syndrome, and progressive renal failure were studied. Of those studied, 11 members had progressed to end-stage renal disease and seven had significant proteinuria (greater than 1 g/24 hours) with normal renal function. The genetic mode of inheritance was autosomal dominant with variable penetrance and expressivity. Histopathologic changes were variable but included focal segmental glomerulosclerosis and diffuse glomerulosclerosis. Renal failure usually occurred in the fifth decade of life. The most consistent clinical finding was proteinuria without microscopic hematuria or other significant urinary sediment elements. This disease differed from Alport's hereditary nephritis and congenital nephrotic syndrome in age of onset, urinary findings, and associated conditions, that is, nerve deafness. The hereditary proteinuria and nephrotic syndrome described in this kindred represents another facet in the spectrum of hereditary renal disease.


MDMA and learning: effects of acute and neurotoxic exposure in the rat.
In two experiments, the effects of MDMA on the acquisition of lever-press responding of rats were examined under procedures in which water delivery was delayed by 0, 10, or 20 s relative to the response that produced it. In the first study, experimentally naive, water-deprived rats received an intraperitoneal injection of MDMA (0, 1.0, 3.2, or 5.6 mg/kg) prior to one 8-h experimental session. Response acquisition was observed under all conditions at all drug doses. MDMA increased the total number of responses emitted and the total number of water deliveries earned in dose-dependent fashion, but only when reinforcement was immediate. Under conditions of delay, MDMA had no effect on either measure. Under all reinforcement conditions, higher doses of MDMA typically produced an initial reduction in lever pressing, and in that sense interfered with learning. In the second study, rats received an MDMA injection regimen previously shown to be neurotoxic. Control rats received saline solution according to the same injection schedule. Two weeks after completing the regimen, rats were water deprived and exposed to behavioral procedures as described for the first experiment. Although MDMA significantly reduced 5-HT and 5-HIAA levels in the striatum and prefrontal cortex, mean performance of rats exposed to MDMA did not differ from that of rats exposed to vehicle. Twenty-five percent of the rats exposed to MDMA and delayed reinforcement did fail to acquire responding, which suggests that further study of the effects of neurotoxic doses of MDMA on initial response acquisition is warranted.


Raffinose crystallization during freeze-drying and its impact on recovery of protein activity.
To study i) phase transitions in raffinose solution in the frozen state and during freeze-drying and ii) evaluate the impact of raffinose crystallization on the recovery of protein activity in reconstituted lyophiles. X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to study the frozen aqueous solutions of raffinose pentahydrate. Phase transitions during primary and secondary drying were monitored by simulating the entire freeze-drying process, in situ, in the sample chamber of the diffractometer. The activity of lactate dehydrogenase (LDH) in reconstituted lyophiles was determined spectrophotometrically. Raffinose formed a kinetically stable amorphous freeze-concentrated phase when aqueous solutions were frozen at different cooling rates. When these solutions were subjected to primary drying without annealing, raffinose remained amorphous. Raffinose crystallized as the pentahydrate when the solutions were annealed at a shelf temperature of -10 degrees C. Primary drying of these annealed systems resulted in the dehydration of raffinose pentahydrate to an amorphous phase. The phase separation of the protein from the amorphous raffinose in these two systems during freeze-drying resulted in a significant reduction in the recovery of LDH activity, even though the lyophile was amorphous. Annealing of frozen aqueous raffinose solutions can result in solute crystallization, possibly as the pentahydrate. The crystalline pentahydrate dehydrates during primary drying to yield an amorphous lyophile. Raffinose crystallization during freeze-drying is accompanied by a significant loss of protein activity.


Catalytic growth and characterization of gallium nitride nanowires.
The preparation of high-purity and -quality gallium nitride nanowires is accomplished by a catalytic growth using gallium and ammonium. A series of catalysts and different reaction parameters were applied to systematically optimize and control the vapor-liquid-solid (VLS) growth of the nanowires. The resulting nanowires show predominantly wurtzite phase; they were up to several micrometers in length, typically with diameters of 10-50 nm. A minimum nanowire diameter of 6 nm has been achieved. Temperature dependence of photoluminescence spectra of the nanowires revealed that the emission mainly comes from wurtzite GaN with little contribution from the cubic phase. Moreover, the thermal quenching of photoluminescence was much reduced in the GaN nanowires. The Raman spectra showed five first-order phonon modes. The frequencies of these peaks were close to those of the bulk GaN, but the modes were significantly broadened, which is indicative of the phonon confinement effects associated with the nanoscale dimensions of the system. Additional Raman modes, not observed in the bulk GaN, were found in the nanowires. The field emission study showing notable emission current with low turn-on field suggests potential of the GaN nanowires in field emission applications. This work opens a wide route toward detailed studies of the fundamental properties and potential applications of semiconductor nanowires.


Induction of protective immunity to Haemophilus ducreyi in the temperature-dependent rabbit model of experimental chancroid.
The temperature-dependent rabbit model for chancroid, a sexually transmitted disease caused by the fastidious Gram-negative bacterium Haemophilus ducreyi, was used to investigate the abilities of previous infection and immunization with an acellular preparation of H. ducreyi to induce protective immunity. In the first set of experiments, animals were infected intradermally with either the 35000 or Cha-1 strains of H. ducreyi and then rechallenged 30 days later with both the homologous and heterologous strains. In animals infected with the 35000 strain, statistically significant protective immunity occurred only against the homologous strain, whereas protection against both homologous and heterologous challenge was obtained in rabbits previously infected with strain Cha-1. In a separate series of experiments, rabbits were immunized with cell envelopes from either strain 35000 or strain Cha-1 and then challenged with both the homologous and heterologous strains. In rabbits immunized with strain 35000 cell envelopes, significant protective immunity was observed only against challenge with the homologous strain. In animals immunized with strain Cha-1 cell envelopes, protection was obtained against both homologous and heterologous challenge. Histopathologic analysis of sites inoculated with strain 35000 (10(5) CFU) demonstrated that the inflammatory response in control animals was predominantly suppurative (i.e., heterophilic), whereas that of immunized animals was predominantly mononuclear and, at later time points, largely histiocytic. ELISA and Western blot analyses revealed that immunization produced a better humoral immune response than did infection and provided evidence for antigenic cross-reactivity between these two strains. These results provide the experimental basis for continued efforts to identify potential H. ducreyi vaccinogens.


Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo.
The incidence of breast cancer is increasing in the Western world and there is an urgent need for studies of the mechanisms of sex steroids in order to develop novel preventive strategies. Diet modifications may be among the means for breast cancer prevention. Angiogenesis, key in tumor progression, is regulated by the balance between pro- and anti-angiogenic factors, which are controlled in the extracellular space. Sampling of these molecules at their bioactive compartment is therefore needed. The aims of this study were to explore if tamoxifen, one of the most used anti-estrogen treatments for breast cancer affected some of the most important endogenous angiogenesis regulators, vascular endothelial growth factor (VEGF), angiogenin, and endostatin in normal breast tissue in vivo and if a diet supplementation with flaxseed had similar effects as tamoxifen in the breast. Microdialysis was used for in situ sampling of extracellular proteins in normal breast tissue of women before and after six weeks of tamoxifen treatment or before and after addition of 25 g/day of ground flaxseed to the diet or in control women. We show significant correlations between estradiol and levels of VEGF, angiogenin, and endostatin in vivo, which was verified in ex vivo breast tissue culture. Moreover, tamoxifen decreased the levels of VEGF and angiogenin in the breast whereas endostatin increased significantly. Flaxseed did not alter VEGF or angiogenin levels but similar to tamoxifen the levels of endostatin increased significantly. We conclude that one of the mechanisms of tamoxifen in normal breast tissue include tipping of the angiogenic balance into an anti-angiogenic state and that flaxseed has limited effects on the pro-angiogenic factors whereas the anti-angiogenic endostatin may be modified by diet. Further studies of diet modifications for breast cancer prevention are warranted.


Accelerating structure-function mapping using the ViVa webtool to mine natural variation.
Thousands of sequenced genomes are now publicly available capturing a significant amount of natural variation within plant species; yet, much of these data remain inaccessible to researchers without significant bioinformatics experience. Here, we present a webtool called ViVa (Visualizing Variation) which aims to empower any researcher to take advantage of the amazing genetic resource collected in the Arabidopsis thaliana 1001 Genomes Project (http://1001genomes.org). ViVa facilitates data mining on the gene, gene family, or gene network level. To test the utility and accessibility of ViVa, we assembled a team with a range of expertise within biology and bioinformatics to analyze the natural variation within the well-studied nuclear auxin signaling pathway. Our analysis has provided further confirmation of existing knowledge and has also helped generate new hypotheses regarding this well-studied pathway. These results highlight how natural variation could be used to generate and test hypotheses about less-studied gene families and networks, especially when paired with biochemical and genetic characterization. ViVa is also readily extensible to databases of interspecific genetic variation in plants as well as other organisms, such as the 3,000 Rice Genomes Project ( http://snp-seek.irri.org/) and human genetic variation ( https://www.ncbi.nlm.nih.gov/clinvar/).


Aging alters verapamil elimination and dynamics: single dose and steady-state responses.
Verapamil elimination kinetics and pharmacodynamic effects were studied in 29 healthy individuals (23-81 years of age) after single i.v. doses (0.15-0.22 mg/kg) and during infusions to reach stable plasma verapamil concentrations of 28 +/- 11, 57 +/- 19 and 112 +/- 26 ng/ml (mean +/- S.D.). Aging prolonged verapamil elimination (P less than .008): elimination half-life of 218 +/- 91 min in young (ages 20-39), 280 +/- 78 min in middle-aged (40-59) and 288 +/- 73 min in elderly (greater than 60). After single verapamil doses. 1) heart rate increased with lesser increases in elderly subjects; 2) blood pressure decreased (P = .006) with greater decreases in elderly subjects; 3) spontaneous P-R intervals increased with lesser increases in elderly subjects but, 4) atrioventricular conduction times increased during transesophageal pacing without detectable age differences in responses. During steady-state infusions, 1) heart rate during sinus rhythm was unchanged but atrioventricular dissociation with junctional rhythms developed in elderly subjects (3/9); 2) blood pressure decreased with greater decreases in the elderly; 3) spontaneous P-R intervals increased with lesser increases in the elderly but no age differences in paced P-R interval changes were detected at equivalent verapamil concentrations; 4) heart rate variation (during sinus rhythm) decreased in an age-independent manner as measured by decreases in the S.D. of R-R intervals and decreased power spectral content with greatest changes seen in high frequency (respiratory) content; and 5) heart rate and blood pressure responses to cold pressor and handgrip testing were not attenuated by verapamil. In conclusion, aging prolongs verapamil elimination and alters dynamic responses to verapamil with greater sinus node depression and hypotensive effects in elderly vs. younger subjects. Although less spontaneous P-R interval prolongation was seen on ECG of the elderly vs. young, underlying atrioventricular conduction was prolonged by verapamil independent of age as shown by results when pacing was used to eliminate frequency-dependent effects caused by differing heart rate responses.


Physician characteristics and prescribing for elderly people in New Brunswick: relation to patient outcomes.
To examine the relation between physician characteristics, prescribing behaviour and patient outcomes. Descriptive study linking four provincial databases. New Brunswick. All 366 general practitioners (GPs) (accounting for 40% of all physicians with a general licence in New Brunswick) who ordered at least 200 prescriptions for elderly beneficiaries of the New Brunswick Prescription Drug Program and saw at least 20 elderly patients in an office setting between Apr. 1, 1990, and Mar. 31, 1991. Physicians with palliative care practices were excluded. GPs' personal, professional and practice characteristics, their prescribing patterns, and mortality, morbidity (number of days in hospital per patient) and hip-fracture rates among their elderly patients. Compared with the GPs who had a lower mortality rate, those with a higher mortality rate prescribed more drugs overall (p < 0.001), specifically antidepressants, bronchodilators, cholesterol-lowering agents, gastrointestinal drugs, neuroleptics and nonsteroidal anti-inflammatory drugs (NSAIDs). They also were more likely to be male (p < 0.01), had larger practices (p < 0.001), saw more patients per day (p < 0.05) and billed more per year (p < 0.001). Compared with the GPs who had a lower morbidity rate, those with a higher morbidity rate prescribed more drugs overall (p < 0.005), specifically bronchodilators, gastrointestinal drugs and NSAIDs. They also were more likely to be younger (p < 0.005) and male (p < 0.01), had fewer years in practice (p < 0.001), saw more patients per day (p < 0.05) and billed more per patient (p < 0.01). The GPs who had a higher hip-fracture rate prescribed more drugs overall (p < 0.001), notably antihypertensives, bronchodilators, cholesterol-lowering agents, gastrointestinal drugs and NSAIDs, than those who had a lower hip-fracture rate. They also had a larger practice (p < 0.001), practised more days per year (p < 0.005), had more patient visits per year (p < 0.05) and billed more per year (p < 0.001). Younger male GPs who practised with relatively more intensity and prescribed more drugs per patient had practices with higher morbidity, mortality and hip-fracture rates among their elderly patients than the other GPs. There is a significant relation between certain physician characteristics, their prescribing behaviour and patient outcomes. Further study is required to determine what physician characteristics and prescribing behaviours for specific illnesses contribute to patient outcomes. Regional differences should also be examined, as should incentives in this fee-for-service system. Linkage of these types of provincial databases may help in the evaluation of physicians' performance and in the development of strategic interventions and practice guidelines.


Coherent synthesis of genomic associations with phenotypes and home environments.
Local adaptation is often studied via (i) multiple common garden experiments comparing performance of genotypes in different environments and (ii) sequencing genotypes from multiple locations and characterizing geographic patterns in allele frequency. Both approaches aim to characterize the same pattern (local adaptation), yet the complementary information from each has not yet been coherently integrated. Here, we develop a genome-wide association model of genotype interactions with continuous environmental gradients (G × E), that is reaction norms. We present an approach to impute relative fitness, allowing us to coherently synthesize evidence from common garden and genome-environment associations. Our approach identifies loci exhibiting environmental clines where alleles are associated with higher fitness in home environments. Simulations show our approach can increase power to detect loci causing local adaptation. In a case study on Arabidopsis thaliana, most identified SNPs exhibited home allele advantage and fitness trade-offs along climate gradients, suggesting selective gradients can maintain allelic clines. SNPs exhibiting G × E associations with fitness were enriched in genic regions, putative partial selective sweeps and associations with an adaptive phenotype (flowering time plasticity). We discuss extensions for situations where only adaptive phenotypes other than fitness are available. Many types of data may point towards the loci underlying G × E and local adaptation; coherent models of diverse data provide a principled basis for synthesis.


A brain-actuated wheelchair: asynchronous and non-invasive Brain-computer interfaces for continuous control of robots.
To assess the feasibility and robustness of an asynchronous and non-invasive EEG-based Brain-Computer Interface (BCI) for continuous mental control of a wheelchair. In experiment 1 two subjects were asked to mentally drive both a real and a simulated wheelchair from a starting point to a goal along a pre-specified path. Here we only report experiments with the simulated wheelchair for which we have extensive data in a complex environment that allows a sound analysis. Each subject participated in five experimental sessions, each consisting of 10 trials. The time elapsed between two consecutive experimental sessions was variable (from 1h to 2months) to assess the system robustness over time. The pre-specified path was divided into seven stretches to assess the system robustness in different contexts. To further assess the performance of the brain-actuated wheelchair, subject 1 participated in a second experiment consisting of 10 trials where he was asked to drive the simulated wheelchair following 10 different complex and random paths never tried before. In experiment 1 the two subjects were able to reach 100% (subject 1) and 80% (subject 2) of the final goals along the pre-specified trajectory in their best sessions. Different performances were obtained over time and path stretches, what indicates that performance is time and context dependent. In experiment 2, subject 1 was able to reach the final goal in 80% of the trials. The results show that subjects can rapidly master our asynchronous EEG-based BCI to control a wheelchair. Also, they can autonomously operate the BCI over long periods of time without the need for adaptive algorithms externally tuned by a human operator to minimize the impact of EEG non-stationarities. This is possible because of two key components: first, the inclusion of a shared control system between the BCI system and the intelligent simulated wheelchair; second, the selection of stable user-specific EEG features that maximize the separability between the mental tasks. These results show the feasibility of continuously controlling complex robotics devices using an asynchronous and non-invasive BCI.


Three-dimensional structure in solution of the calcium channel blocker omega-conotoxin MVIIA.
The three-dimensional solution structure of omega-conotoxin MVIIA, a 25-mer peptide antagonist of N-type calcium channels, was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 13 converged structures of omega-conotoxin MVIIA were obtained on the basis of 273 experimental constraints, including 232 distance constraints obtained from nuclear Overhauser effect (NOE) connectivities, 22 torsion angle (phi, chi 1) constraints, and 19 constraints associated with hydrogen bonds and disulfide bonds. The atomic root mean square difference about the averaged coordinate positions is 0.47 +/- 0.08 A for the backbone atoms (N, C alpha, C) and 1.27 +/- 0.14 A for all heavy atoms of the entire peptide. The molecular structure of omega-conotoxin MVIIA is composed of a short triple-stranded antiparallel beta-sheet. The overall beta-sheet topology is +2x, -1, which is the same as that reported for omega-conotoxin GVIA, another N-type calcium channel blocker. The orientation of beta-stranded structure is similar to each other, suggesting that the conserved disulfide bond combination is essential for the molecular folding. We have recently determined by using alanine substitution analyses that Tyr 13 is essential for the activity of both toxins. On the basis of functional and structural analysis, it is shown that both omega-conotoxin MVIIA and GVIA retain a similar conformation to locate Tyr 13 in the appropriate position to allow binding to N-type calcium channels. These results provide a molecular basis for understanding the mechanism of calcium channel modulation through the toxin-channel interaction and insight into the discrimination of different subtypes of calcium channels.


Infections in solid-organ transplant recipients.
Solid-organ transplantation is a therapeutic option for many human diseases. Infections are a major complication of solid-organ transplantation. All candidates should undergo a thorough infectious-disease screening prior to transplantation. There are three time frames, influenced by surgical factors, the level of immunosuppression, and environmental exposures, during which infections of specific types most frequently occur posttransplantation. Most infections during the first month are related to surgical complications. Opportunistic infections typically occur from the second to the sixth month. During the late posttransplant period (beyond 6 months), transplantation recipients suffer from the same infections seen in the general community. Opportunistic bacterial infections seen in transplant recipients include those caused by Legionella spp., Nocardia spp., Salmonella spp., and Listeria monocytogenes. Cytomegalovirus is the most common cause of viral infections. Herpes simplex virus, varicella-zoster virus, Epstein-Barr virus and others are also significant pathogens. Fungal infections, caused by both yeasts and mycelial fungi, are associated with the highest mortality rates. Mycobacterial, pneumocystis, and parasitic diseases may also occur.


A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol.
Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs. We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000-5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m2) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ≤ 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months. A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs. ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.


Quantitation of immunocompetence in Hodgkin's disease.
In vitro cellular immunocompetence was investigated on 35 patients with Hodgkin's disease by studying their in vitro lymphocyte responsiveness to full range stimulation achieved by a spectrum of phytohemagglutinin concentrations. When compared to the normal lymphocyte profile elicited from 35 control subjects, the Hodgkin's patterns of response enabled the identification of a quantifiable lymphocyte defect present in most patients regardless of their clinical status. Increasing severity of this defect was found with progression of the disease and was most pronounced in patients with skin anergy and absolute lymphopenia. The marked abnormality observed in patients restudied after intensive therapy returned towards normal in patients achieving a long lasting, unmaintained complete remission. The data suggest the early presence of an intrinsic functional lymphocyte defect, increasing severity of which may lead to progressive immunoincompetence, reflected to vitro by imparied lymphocyte responsiveness and in vivo by skin anergy and ultimately lymphopenia.


Multiple functions of a glioblastoma fusion oncogene.
RNA sequencing facilitates the discovery of novel gene fusions in cancer. In this issue of the JCI, Parker et al. identify an FGFR3-TACC3 fusion oncogene in glioblastoma and demonstrate a novel mechanism of pathogenicity. A miR-99a binding site within the 3'-untranslated region (3'-UTR) of FGFR3 is lost, releasing FGFR3 signaling from miR-99a-dependent inhibition and greatly enhancing tumor progression relative to WT FGFR3. These results provide compelling insight into the pathogenicity of a novel fusion oncogene and suggest new therapeutic approaches for a subset of glioblastomas.


Plate-specific gain map correction for the improvement of detective quantum efficiency in computed radiography.
The purpose of this work is to improve the noise power spectrum (NPS), and thus the detective quantum efficiency (DQE), of computed radiography (CR) images by correcting for spatial gain variations specific to individual imaging plates. CR devices have not traditionally employed gain-map corrections, unlike the case with flat-panel detectors, because of the multiplicity of plates used with each reader. The lack of gain-map correction has limited the DQE(f) at higher exposures with CR. This current work describes a feasible solution to generating plate-specific gain maps. Ten high-exposure open field images were taken with an RQA5 spectrum, using a sixth generation CR plate suspended in air without a cassette. Image values were converted to exposure, the plates registered using fiducial dots on the plate, the ten images averaged, and then high-pass filtered to remove low frequency contributions from field inhomogeneity. A gain-map was then produced by converting all pixel values in the average into fractions with mean of one. The resultant gain-map of the plate was used to normalize subsequent single images to correct for spatial gain fluctuation. To validate performance, the normalized NPS (NNPS) for all images was calculated both with and without the gain-map correction. Variations in the quality of correction due to exposure levels, beam voltage/spectrum, CR reader used, and registration were investigated. The NNPS with plate-specific gain-map correction showed improvement over the noncorrected case over the range of frequencies from 0.15 to 2.5 mm(-1). At high exposure (40 mR), NNPS was 50%-90% better with gain-map correction than without. A small further improvement in NNPS was seen from carefully registering the gain-map with subsequent images using small fiducial dots, because of slight misregistration during scanning. Further improvement was seen in the NNPS from scaling the gain map about the mean to account for different beam spectra. This study demonstrates that a simple gain-map can be used to correct for the fixed-pattern noise in a given plate and thus improve the DQE of CR imaging. Such a method could easily be implemented by manufacturers because each plate has a unique bar code and the gain-map for all plates associated with a reader could be stored for future retrieval. These experiments indicated that an improvement in NPS (and hence, DQE) is possible, depending on exposure level, over a wide range of frequencies with this technique.


Changing attitudes: The impact of Expert by Experience involvement in Mental Health Nursing Education: An international survey study.
Reform to nursing education is essential to ensure future generations of nurses are strongly positioned to value, know, and deliver strength-based, recovery-oriented mental health practice. A promising pathway to effectively drive reform is the coproduction of curricula by nursing academics and people with lived experience of recovery from mental distress referred to as Experts by Experience. The Co-production in Mental Health Nursing Education (COMMUNE) project is an international collaboration for development and implementation of consumer coproduced curricula. This study evaluated the inclusion of Expert by Experience-led mental health nursing education on nursing students' attitudes to people labelled with mental illness, mental health nursing, and consumer participation. A repeated self-report measures design was implemented in Australia, Ireland, and Finland to ascertain level of generalizability of consumer involvement within undergraduate nursing programmes. Data were collected from nursing students (n = 194) immediately before and after the education module, using three self-report instruments on attitudes (Mental Health Nurse Education Survey, Consumer Participation Questionnaire, and Opening Minds Scale). Data were analysed using descriptive and inferential statistics. Eighty-nine per cent of the 27 points of change reflected more favourable and accepting attitudinal change. Of these, 41% were significant at Bonferroni adjusted alpha of 0.0025. There was a statistically significant increase in preparedness for practice in the mental health field in each of the three countries. The most pronounced change is related to the social and systemic inclusion of people with a diagnostic label and recovery-oriented care more broadly.


Coherent imaging of the cone mosaic in the living human eye.
A new system for the recording of high-resolution images of the cone mosaic in the living room fovea has been developed. The experimental method is inspired by stellar speckle interferometry, used in astronomy to resolve binary stars. Series of short-exposure images of small areas of the fovea are registered under coherent illumination. These images show speckle patterns that have some correlation with the topography of the cone mosaic and retain high-resolution information. Such correlation is better revealed in the power spectrum (square modulus of the Fourier transform). The signal-to-noise ratio is increased, without loss of high frequencies, by averaging the power spectra of a number of such speckle patterns. The average power spectra show, in most of the cases, an elliptical ring (or hexagon), whose mean radius corresponds to the characteristic spatial frequency of the cone mosaic (or the inverse of the mean row-to-row cone spacing) at a given retinal location. Good results are obtained in the five normal observers tested, at various retinal eccentricities, up to 1 visual degree, including the center of the fovea for two eyes. We find a decrease in the spatial frequency of the mosaic with the eccentricity and an important intersubject variability, in agreement with anatomical studies.


Using computational simulation to aid in the prediction of socket fit: a preliminary study.
This study illustrates the use of computational analysis to predict prosthetic socket fit. A simple indentation test is performed by applying force to the residual limb of a trans-tibial amputee through an indenter until the subject perceives the onset of pain. Computational finite element (FE) analysis is then applied to evaluate the magnitude of pressure underlying the indenter that initiates pain (pain threshold pressure), and the pressure at the prosthetic socket-residual limb interface. The assessment of socket fit is examined by studying whether or not the socket-limb interface pressure exceeds the pain threshold pressure of the limb. Based on the computer-aided assessment, a new prosthetic socket is then fabricated and fitted to the amputee subject. Successful socket fit is achieved at the end of this process. The approach of using computational analysis to aid in assessing socket fit allows a more efficient evaluation and re-design of the socket even before the actual fabrication and fitting of the prosthetic socket. However, more thorough investigations are required before this approach can be widely used. A subsequent part of this paper discusses the limitations and suggests future research directions in this area.


Epidemiology, pathophysiology, and classification of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) workshop.
In August 2013, the National Institutes of Health sponsored a conference to address major gaps in our understanding of the epidemiology, pathophysiology, and management of fecal incontinence (FI) and to identify topics for future clinical research. This article is the first of a two-part summary of those proceedings. FI is a common symptom, with a prevalence that ranges from 7 to 15% in community-dwelling men and women, but it is often underreported, as providers seldom screen for FI and patients do not volunteer the symptom, even though the symptoms can have a devastating impact on the quality of life. Rough estimates suggest that FI is associated with a substantial economic burden, particularly in patients who require surgical therapy. Bowel disturbances, particularly diarrhea, the symptom of rectal urgency, and burden of chronic illness are the strongest independent risk factors for FI in the community. Smoking, obesity, and inappropriate cholecystectomy are emerging, potentially modifiable risk factors. Other risk factors for FI include advanced age, female gender, disease burden (comorbidity count, diabetes), anal sphincter trauma (obstetrical injury, prior surgery), and decreased physical activity. Neurological disorders, inflammatory bowel disease, and pelvic floor anatomical disturbances (rectal prolapse) are also associated with FI. The pathophysiological mechanisms responsible for FI include diarrhea, anal and pelvic floor weakness, reduced rectal compliance, and reduced or increased rectal sensation; many patients have multifaceted anorectal dysfunctions. The type (urge, passive or combined), etiology (anorectal disturbance, bowel symptoms, or both), and severity of FI provide the basis for classifying FI; these domains can be integrated to comprehensively characterize the symptom. Several validated scales for classifying symptom severity and its impact on the quality of life are available. Symptom severity scales should incorporate the frequency, volume, consistency, and nature (urge or passive) of stool leakage. Despite the basic understanding of FI, there are still major knowledge gaps in disease epidemiology and pathogenesis, necessitating future clinical research in FI.


Convection-enhanced delivery in intact and lesioned peripheral nerve.
Although the use of multiple agents is efficacious in animal models of peripheral nerve injury, translation to clinical applications remains wanting. Previous agents used in trials in humans either engendered severe side effects or were ineffective. Because the blood-central nervous system barrier exists in nerves as it does in the brain, limited drug delivery poses a problem for translation of basic science advances into clinical applications. Convection-enhanced delivery (CED) is a promising adjunct to current therapies for peripheral nerve injury. In the present study the authors assessed the capacity of convection to ferry macromolecules across sites of nerve injury in rat and primate models, examined the functional effects of convection on the intact nerve, and investigated the possibility of delivering a macromolecule to the spinal cord via retrograde convection from a peripherally introduced catheter. The authors developed a rodent model of convective delivery to lesioned sciatic nerves (injury due to crush or laceration in 76 nerves) and compared the results to a smaller series of five primates with similar injuries. In the intact nerve, convective delivery of vehicle generated only a transient neurapraxic deficit. Early after injury (postinjury Days 1, 3, 7, and 10), infusion failed to cross the site of injury in crushed or lacerated nerves. Fourteen days after crush injury, CED of radioactively-labeled albumin resulted in perfusion through the site of injury to distal growing neurites. In primates, successful convection through the site of crush injury occurred by postinjury Day 28. In contrast, in laceration models there was complete occlusion of the extracellular space to convective distribution at the site of laceration and repair, and convective distribution in the extracellular space crossed the site of injury only after there was histological evidence of completion of nerve regeneration. Finally, in two primates, retrograde infusion into the spinal cord through a peripheral nerve was achieved. Convection provides a safe and effective means to deliver macromolecules to regenerating neurites in crush-injured peripheral nerves. Convection block in lacerated and suture-repaired nerves indicates a significant intraneural obstruction of the extracellular space. a disruption that suggests an anatomical obstruction to extracellular and, possibly, intraaxonal flow, which may impair nerve regeneration. Through peripheral retrograde infusion, convection can be used for delivery to spinal cord gray matter. Convection-enhanced delivery provides a promising approach to distribute therapeutic agents to targeted sites for treatment of disorders of the nerve and spinal cord.


Angiogenesis in transgenic models of multistep carcinogenesis.
The histopathology and the epidemiology of human cancers, as well as studies of animal models of tumorigenesis, have led to a widely accepted notion that multiple genetic and epigenetic changes have to accumulate for progression to malignancy. Formation of new blood vessels (tumor angiogenesis) has been recognized, in addition to proliferative capabilities and to the ability to down-modulate cell death (apoptosis), as essential for the progressive growth and expansion of solid tumors beyond microscopic sizes of about 1-2 mm in diameter. Mice overexpressing activated forms of oncogenes or carrying targeted mutations in tumor suppressor genes have proven extremely useful for to linking the function of these genes with specific tumor processes; the interbreeding of these mice let us study the extent of cooperativity between different genetic lesions in disease progression, leading to a greater understanding of multi-stage nature of tumorigenesis.


Modelling and analysis of influenza A (H1N1) on networks.
In April 2009, a new strain of H1N1 influenza virus, referred to as pandemic influenza A (H1N1) was first detected in humans in the United States, followed by an outbreak in the state of Veracruz, Mexico. Soon afterwards, this new virus kept spreading worldwide resulting in a global outbreak. In China, the second Circular of the Ministry of Health pointed out that as of December 31, 2009, the country's 31 provinces had reported 120,000 confirmed cases of H1N1. We formulate an epidemic model of influenza A based on networks. We calculate the basic reproduction number and study the effects of various immunization schemes. The final size relation is derived for the network epidemic model. The model parameters are estimated via least-squares fitting of the model solution to the observed data in China. For the network model, we prove that the disease-free equilibrium is globally asymptotically stable when the basic reproduction is less than one. The final size will depend on the vaccination starting time, T, the number of infective cases at time T and immunization schemes to follow. Our theoretical results are confirmed by numerical simulations. Using the parameter estimates based on the observation data of the cumulative number of hospital notifications, we estimate the basic reproduction number R0 to be 1.6809 in China. Network modelling supplies a useful tool for studying the transmission of H1N1 in China, capturing the main features of the spread of H1N1. While a uniform, mass-immunization strategy helps control the prevalence, a targeted immunization strategy focusing on specific groups with given connectivity may better control the endemic.


Exercise and Use of Enhancement Drugs at the Time of the COVID-19 Pandemic: A Multicultural Study on Coping Strategies During Self-Isolation and Related Risks.
Introduction: Little is known about the impact of restrictive measures during the COVID-19 pandemic on self-image and engagement in exercise and other coping strategies alongside the use of image and performance-enhancing drugs (IPEDs) to boost performance and appearance. Objectives: To assess the role of anxiety about appearance and self-compassion on the practice of physical exercise and use of IPEDs during lockdown. Methods: An international online questionnaire was carried out using the Exercise Addiction Inventory (EAI), the Appearance Anxiety Inventory (AAI), and the Self-Compassion Scale (SCS) in addition to questions on the use of IPEDs. Results: The sample consisted of 3,161 (65% female) adults from Italy (41.1%), Spain (15.7%), the United Kingdom (UK) (12.0%), Lithuania (11.6%), Portugal (10.5%), Japan (5.5%), and Hungary (3.5%). The mean age was 35.05 years (SD = 12.10). Overall, 4.3% of the participants were found to engage in excessive or problematic exercise with peaks registered in the UK (11.0%) and Spain (5.4%). The sample reported the use of a wide range of drugs and medicines to boost image and performance (28%) and maintained use during the lockdown, mostly in Hungary (56.6%), Japan (46.8%), and the UK (33.8%), with 6.4% who started to use a new drug. Significant appearance anxiety levels were found across the sample, with 18.1% in Italy, 16.9% in Japan, and 16.7% in Portugal. Logistic regression models revealed a strong association between physical exercise and IPED use. Anxiety about appearance also significantly increased the probability of using IPEDs. However, self-compassion did not significantly predict such behavior. Anxiety about appearance and self-compassion were non-significant predictors associated with engaging in physical exercise. Discussion and Conclusion: This study identified risks of problematic exercising and appearance anxiety among the general population during the COVID-19 lockdown period across all the participating countries with significant gender differences. Such behaviors were positively associated with the unsupervised use of IPEDs, although no interaction between physical exercise and appearance anxiety was observed. Further considerations are needed to explore the impact of socially restrictive measures among vulnerable groups, and the implementation of more targeted responses.


Colonization by Pseudomonas aeruginosa of dental unit waterlines and its relationship with other bacteria: suggestions for microbiological monitoring.
Pseudomonas aeruginosa is an environmental bacterium, ubiquitous in aquatic habitats and water distribution systems, including dental unit waterlines (DUWLs). We investigated the prevalence of P. aeruginosa in DUWLs from private dental settings. We also analyzed the relationship between P. aeruginosa contamination and the presence of Legionella spp. and total viable count (TVC) in order to suggest a simple and inexpensive protocol to test the quality of water from DUWLs. We detected and quantified P. aeruginosa both by culture and by a PMA (propidium monoazide)-qPCR method. Overall, we detected P. aeruginosa in 17 samples using the PMA-qPCR and in 11 samples using the culture. All culture-positive samples were positive with the PMA-qPCR too, with an agreement between the two methods of 93% and a Cohen's kappa coefficient of κ = 0.747 (good concordance). Comparing results with results of our previous study, we noted that (a) P. aeruginosa was isolated only from DUWLs with high TVC and (b) five out of six Legionella-positive samples were negative for Pseudomonas spp. Our final suggestion is that the cleanliness of DUWLs should be assessed by TVC because it is a good indicator of the presence of pathogens such as Legionella spp. and P. aeruginosa.


Fibers for low-temperature radiometric measurements.
Theoretical calculations are presented for the performance of a fiber-optic radiometer which makes use of infrared transmitting fibers to measure low temperatures (near room temperature). We calculate the radiometer spatial resolution, the dependence of the radiometer signal on the surface temperature, and the minimum resolvable temperature difference (MRDeltaAT) of the radiometer. The performance of the fiber-optic radiometer is compared with a conventional optical (thin lens) radiometer.


Non-Hodgkin's lymphoma in systemic lupus erythematosus.
Recent evidence supports an association between systemic lupus erythematosus (SLE) and non-Hodgkin's lymphoma (NHL). To describe demographic factors, subtypes, and survival of patients with SLE who develop NHL. A multi-site cohort of 9547 subjects with definite SLE was assembled. Subjects at each centre were linked to regional tumour registries to determine cancer cases occurring after SLE diagnosis. For the NHL cases ascertained, descriptive statistics were calculated, and NHL subtype frequency and median survival time of patients determined. 42 cases of NHL occurred in the patients with SLE during the 76,948 patient-years of observation. The median age of patients at NHL diagnosis was 57 years. Thirty six (86%) of the 42 patients developing NHL were women, reflecting the female predominance of the cohort. In the patients, aggressive histological subtypes appeared to predominate, with the most commonly identified NHL subtype being diffuse large B cell (11 out of 21 cases for which histological subtype was available). Twenty two of the patients had died a median of 1.2 years after lymphoma diagnosis. These data suggest aggressive disease in patients with SLE who develop NHL. Continuing work should provide further insight into the patterns of presentation, prognosis, and aetiology of NHL in SLE.


Renal responses and pharmacokinetics of piretanide in humans: effect of route of administration, state of hydration and probenecid pretreatment.
The influence of route of administration, state of hydration and transport inhibitor probenecid on the renal responses of a loop diuretic, piretanide, were investigated in 14 healthy volunteers. Maximally achieved plasma concentrations after i.v. and oral piretanide were higher in the nonhydrated state [+54% (i.v.); + 68% (oral)], accompanied by significant decreases in mean residence time, renal clearance and fraction of unchanged drug excreted with nonsignificant decreases in t1/2, steady-state volume of distribution and total clearance when compared with the hydrated state. Relative differences between the two hydrated states in maximal plasma concentrations of piretanide remained after probenecid [+26% (i.v.); +55% (oral)] but changes in kinetic parameters did not. Pretreatment with probenecid produced significant increases in absolute peak and plasma diuretic concentrations, t1/2 and mean residence time while decreasing steady-state volume of distribution, total clearance, renal clearance and fraction of unchanged drug excreted without affecting the bioavailability of piretanide. Urinary drug recovery was greater after i.v. than after oral piretanide, the recovery being consistently lower in nonhydrated state [iv: 2.78 (nonhydrated) versus 3.41 mg/24 h (hydrated); oral: 1.93 (nonhydrated) versus 2.76 mg/24 h (hydrated)]. Probenecid pretreatment reduced the overall urinary recovery of piretanide without altering the i.v./oral differences. Excretion of sodium paralleled piretanide excretion throughout the study except after i.v. dosing in the nonhydrated state where changes in drug excretion after probenecid (2.55 versus 1.63 mg/6 h) failed to influence sodium output (167 versus 152 mmol/6 h). These results demonstrate the importance of route of administration and state of hydration in determining the pharmacocological response of loop diuretics within the kidney.


Establishing the Key Outcomes for Pediatric Emergency Medical Services Research.
The evidence supporting best practices when treating children in the prehospital setting or even the effect emergency medical services (EMS) has on patient outcomes is limited. Standardizing the critical outcomes for EMS research will allow for focused and comparable effort among the small but growing group of pediatric EMS investigators on specific topics. Standardized outcomes will also provide the opportunity to collectively advance the science of EMS for children and demonstrate the effect of EMS on patient outcomes. This article describes a consensus process among stakeholders in the pediatric emergency medicine and EMS community that identified the critical outcomes for EMS care in five clinical areas (traumatic brain injury, general injury, respiratory disease/failure, sepsis, and seizures). These areas were selected based on both their known public health importance and their commonality in EMS encounters. Key research outcomes identified by participating stakeholders using a modified nominal group technique for consensus building, which included small group brainstorming and independent voting for ranking outcomes that were feasible and/or important for the field.


Early Life Exposure to Perfluoroalkyl Substances (PFAS) and ADHD: A Meta-Analysis of Nine European Population-Based Studies.
To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive. We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother-child pairs. Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis. A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education. We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444.


Risk of injury to child passengers in sport utility vehicles.
The popularity of sport utility vehicles (SUVs) is growing, and they are increasingly being used as family vehicles. Because of the large size of SUVs, relative to passenger cars, parents may perceive that they are safer family vehicles. However, little is known about the safety of children in SUVs, compared with passenger cars. The objective of this study was to determine the relative risk of injury to children involved in crashes in SUVs, compared with those in passenger cars. From an on-going motor vehicle crash surveillance system, a probability sample of 3922 child occupants 0 to 15 years of age, representing 72396 children in crashes of either SUVs or passenger cars (model year 1998 or newer), from 3 large US regions, was identified between March 1, 2000, and December 31, 2003. Injuries were defined as concussions and other brain injuries, spinal cord injuries, facial fractures and lacerations, internal organ injuries, extremity fractures, and scalp lacerations. Logistic regression modeling was used to compute the odds ratio (OR) of injury for children in SUVs versus passenger cars, both unadjusted and adjusted for several potential confounders, including differences in child seating position, restraint use, vehicle weight, exposure of the child to a passenger airbag, and whether the vehicle rolled over. A total of 38.2% of children were in SUVs and 61.8% were in passenger cars. The average weight of SUVs was 1317 lb greater than the average weight of passenger cars. Among all children in the study, those restrained appropriately were less likely to be injured (OR: 0.25; 95% confidence interval [CI]: 0.15-0.45) and those in the front seat were more likely to be injured (OR: 2.06; 95% CI: 1.33-3.21). In both vehicle types, children exposed to a passenger airbag were more likely to be injured than were those who were not (OR: 4.70; 95% CI: 2.36-9.37). Rollover crashes increased the risk of injury in both vehicle types (OR: 3.29; 95% CI: 1.88-5.76) and occurred more than twice as frequently with SUVs (2.9%, compared with 1.2% with passenger cars). There was a trend for increasing vehicle weight being a protective factor with both vehicle types (OR: 0.86; 95% CI: 0.73-1.01). After adjustment for all of the aforementioned factors, the risk of injury was not significantly different for children in SUVs versus passenger cars (adjusted OR: 1.50; 95% CI: 0.88-2.57). Especially detrimental for children in SUVs was being unrestrained versus restrained in a rollover crash (OR: 24.99; 95% CI: 6.68-93.53). Despite the greater vehicle weight of SUVs, the risk of injury for children in SUVs is similar to that for children in passenger cars. The potential advantage offered by heavier SUVs seems to be offset by other factors, including an increased tendency to roll over. Age-appropriate child restraint and rear seat positioning are important, particularly for children in SUVs, given the very high risk of injury for children restrained inappropriately in rollover crashes.


Streptococcal cysteine protease augments lung injury induced by products of group A streptococci.
Streptococcus pyogenes infections in humans may be associated with severe clinical manifestations, including adult respiratory distress syndrome and a toxic shock-like syndrome. These observations have led to the investigation of products of group A streptococci that may contribute to increased virulence. Streptococcal pyrogenic exotoxin B is a highly conserved precursor of an extracellular cysteine protease that is secreted by S. pyogenes. We investigated the ability of this streptococcal cysteine protease (SCP) to act synergistically with either streptococcal cell wall antigen (SCW) or streptolysin-O (SLO) to augment lung injury in rats. Intratracheal administration of either SCW or SLO alone caused lung injury, as measured by pulmonary vascular leak. Bronchoalveolar lavage (BAL) fluid analysis showed that SCW induced neutrophil accumulation and appearance of interleukin-1beta and tumor necrosis factor alpha. In contrast, SLO induced neither neutrophil influx nor significant cytokine elevations in BAL fluids. Intratracheal administration of SCP with either SCW or SLO resulted in synergistic augmentation of lung vascular permeability and accumulation of BAL neutrophils. The synergy was reduced when SCP was either heat inactivated or coinstilled with a peptide inhibitor of the protease. SCP in the presence of SCW resulted in a significant increase in BAL fluid tumor necrosis factor alpha content but not in immunoreactive interleukin-1beta. Moreover, the copresence of SAP with SAW resulted in increased BAL fluid nitrite-nitrate levels, indicative of nitric oxide production. These data demonstrate that SCP acts synergistically with other S. pyogenes products (SCW or SLO) to increase tissue injury and provide additional evidence that SCP may function as an important virulence factor in group A streptococcal infections.


Imaging of Human Neurolisteriosis: A Prospective Study of 71 Cases.
Neurolisteriosis ranks among the most severe neurological infections. Its radiological features have not been thoroughly studied. We describe here the neuroradiological features of neurolisteriosis and assess their prognostic value. Patients with microbiologically proven neurolisteriosis were enrolled from November 2009 to October 2013 in MONALISA study. Magnetic resonance and computed tomography images were studied by 2 independent neuroradiologists. Predictors of 3-month mortality were determined using logistic regression. Seventy-one patients were included; 42 were men (59%). Mean age was 64 years. Sixty patients (85%) reported signs of encephalitis, with clinical brainstem involvement in 16 (23%). Images were abnormal in 87% of cases (62/71). Main neuroradiological images were meningeal enhancement (25/71, 35%), abscess(es), or nodular image(s) evocative of abscess (10/71, 14%), hemorrhages (11/71, 15%), contrast-enhancing ventricles, or hydrocephalus (7/71, 10%). White-matter images (42/71, 59%), dilated Virchow-Robin spaces (22/71, 31%), and cerebral atrophy were also reported (34/71, 48%). Brainstem involvement (meningeal enhancement, abscess) was reported in only 7/71 cases (10%). Three-month survival was lower in patients with hydrocephalus or contrast-enhancing ventricles (1/7 [14%] than without [47/64, 73%], P = .005) and in patients with parenchymal images (abscess[es], nodule[s]\, or white matter images; 25/46 [54%] vs 23/25 without [92%], P = .004). Parenchymal images were associated with lower 3-month survival in the multivariable model (odds ratio 5.60, 95% confidence interval [1.42-29.6], P = .02). Neurolisteriosis presents as a combination of neuroradiological images, none being specific. Radiological signs of rhombencephalitis are uncommon, whereas, unexpectedly, hemorrhagic images are frequent. The negative prognostic value of parenchymal neuroradiological images was evidenced. NCT01520597.


Effects of intraovarian infusion of insulin-like growth factor-I on ovarian follicular function in cattle.
The objective of this study was to determine if increased secretion of intraovarian insulin-like growth factor-I (IGF-I), experimentally induced via minipumps, affects follicular function in cattle. Fourteen cycling Holstein cows were divided equally into two groups: Control, osmotic minipumps (containing vehicle) surgically inserted into each ovary, or IGF-I treated, osmotic minipumps as in Controls but pumping 2.0 microg of recombinant human IGF-I per hr for 7 days. All cows were synchronized with prostaglandin F(2alpha) 0.10) between Control and IGF-I-treated cows during Days 2 to 6 of treatment. IGF-I treatment increased (P<0.05) estradiol concentrations in follicular fluid of small follicles, but had no effect (P<0.10) on estradiol concentrations in follicular fluid of large follicles, or on progesterone, androstenedione, or IGF binding protein concentrations in small or large follicles. We conclude that a 7-day infusion of IGF-I directly into the stroma of the ovary altered follicular growth and follicular fluid estradiol concentrations.


Newly generated dentate granule cells from epileptic rats exhibit elongated hilar basal dendrites that align along GFAP-immunolabeled processes.
Previous studies showed that neurogenesis occurs in the dentate gyrus of the adult rodent. Recent evidence suggests that the resulting newly born neurons integrate into pre-existing hippocampal circuitry. Newly born neurons in the developing and adult dentate gyrus exhibit a transient basal dendrite. In adult pilocarpine-induced epileptic rats, basal dendrites persist and are ectopically located in the hilus where they receive synaptic input from mossy fiber axons. We hypothesize that these hilar basal dendrites are derived from newly born neurons that are born after the pilocarpine-induced seizures. To test this hypothesis, the length of basal dendrites from epileptic rats was compared with that from control rats using doublecortin immunocytochemistry, which labels newly born neurons and their processes for up to 3 weeks after their genesis. The data on hilar basal dendrites in pilocarpine animals indicate that those from newly born neurons are significantly longer than those found in the control rats. We also demonstrate that 20% of newly born neurons in the epileptic rat have a basal dendrite that enters the hilus at an angle greater than 30 degrees from its cell body as compared with <2% in the control rats. Lastly, we provide evidence that the hilar basal dendrites in the epileptic rats are adjacent to glial fibrillary acidic protein-labeled astrocytic processes in the hilus and suggest that an ectopic glial scaffold in the hilus is involved with the formation of hilar basal dendrites. In conclusion, the data show that newly born neurons from epileptic rats have longer hilar basal dendrites and their formation might relate to gliosis which occurs as a result of hilar neuronal cell loss after status epilepticus.


Factors affecting general practitioners' recruitment of patients into a prospective study.
Many research projects depend on general practitioners (GPs) to recruit patients into the study. As part of a study of patients' experiences of treatment for menorrhagia, completeness of recruitment and the extent of bias introduced by failure to recruit was assessed. Only 129 (41%) of 315 GPs who had agreed to recruit patients actually did so. A review of notes in six practices revealed that only 40 (20.4%) of 196 eligible patients had been recruited. There was some evidence that the recruited patients had more severe symptoms than those not recruited. There was no difference in recruitment rates between male and female doctors, but those who had received a practice visit from a member of the research team recruited more patients. A survey of participating GPs revealed that forgetfulness and time pressures were the main factors inhibiting recruitment.


Signal jamming mediates sexual conflict in a duetting bird.
Signal evolution in social animals has produced a wide variety of communal displays, many of them remarkable feats of complex coordination. The two main explanations for this temporal precision are: (1) it evolves as a cooperative signal of coalition quality or (2) it minimizes signal jamming (i.e., interference of one signal by another). However, support for the first hypothesis is inconclusive, and the role of jamming in communal signaling strategies remains unknown. Here, we use playback experiments to examine how social context influences the structure of duets in a pair-living antbird (Hypocnemis peruviana). The results show that, although resident pairs produced coordinated duets when responding to rival pairs, conflicts of interest caused duet coordination to break down. Specifically, females responded to unpaired sexual rivals by jamming the signals of their own mates, who in turn compensated by adjusting their signals to avoid interference. In demonstrating this interaction, we provide the first evidence that signal jamming occurs between mates and that strategies for reducing jamming can result in increased signal complexity. These findings highlight the importance of jamming avoidance in determining the structure of duets and suggest that conflict between signalers, rather than cooperation alone, may drive the evolution of sophisticated communal displays in social animals.


Experiences of health science students during clinical placements at the University of Zimbabwe.
Clinical placement is an essential component of training in health sciences because it is where theory and practice interface. To explore experiences of health sciences students during clinical placement in terms of supervision, challenges and coping strategies. It was a cross sectional survey. University ofZimbabwe, College of Health Sciences. 179 multidisciplinary health science students. A cross-sectional survey was conducted using a self-administered questionnaire. Ethical clearance was obtained. Descriptive statistics were used for analysis. These were perceptions of students with regard to supervision, challenges faced during clinical placement and coping strategies used. 179 participants responded to the questionnaires. Participants enjoyed linking theory to practice. Perceptions on supervision were both positive and negative. Inadequate supervision and inappropriate behaviours by supervisors were some of the challenges faced. Almost 89% used stress-relieving strategies such as focusing on why they were doing the clinical placement and the importance of successful completion. Ninety-one per cent had never used cannabis/mbanje but 41% had engaged in sexual activity to cope with challenges. This study found that the perceptions of health sciences students about supervision clinical placement, challenges faced and the coping strategies are almost the same as those found elsewhere. It is therefore important to plan clinical placement with the involvement of clinical educators. Supervisors' workshops should be held to create a forum to discuss clinical placement issues. Follow-up of students by academics is recommended. Students should be empowered to cope with challenges.


Prognostic Factors for Respiratory Dysfunction for Cervical Spinal Cord Injury and/or Cervical Fractures in Elderly Patients: A Multicenter Survey.
Retrospective Cohort Study. The purpose of this study was to investigate the prognosis of respiratory function in elderly patients with cervical spinal cord injury (SCI) and to identify predictive factors. We included 1353 cases of elderly cervical SCI patients collected from 78 institutions in Japan. Patients who required early tracheostomy and ventilator management and those who developed respiratory complications were defined as the respiratory disability group. Patients' background characteristics, injury mechanism, injury form, neurological disability, complications, and treatment methods were compared between the disability and non-disability groups. Multiple logistic regression analysis was used to examine the independent factors. Patients who required respiratory management for 6 months or longer after injury and those who died of respiratory complications were classified into the severe disability group and were compared with minor cases who were weaned off the respirator. A total of 104 patients (7.8%) had impaired respiratory function. Comparisons between the disabled and non-disabled groups and between the severe and mild injury groups yielded distinct trends. In multiple logistic regression analysis, age, blood glucose level, presence of ossification of posterior longitudinal ligament (OPLL), anterior vertebral hematoma, and critical paralysis were selected as independent risk factors. Age, OPLL, severe paralysis, anterior vertebral hematoma, hypoalbuminemia, and blood glucose level at the time of injury were independent factors for respiratory failure. Hyperglycemia may have a negative effect on respiratory function in this condition.


Splenic sarcoidosis mimicking neoplastic disease.
Sarcoidosis is a multisystem granulomatous disease of unknown cause that commonly involves the spleen. Sarcoid can produce either homogeneous splenomegaly or multiple splenic nodules. Although other organ system involvement usually occurs, this is not invariable. Herein, we report on the clinical, histological, and radiological features-including sonography and MRI-of an isolated splenic sarcoidosis that mimicked neoplastic disease in a 37-year-old female. Knowledge of this atypical sonographic presentation may prevent unnecessary splenectomy.


Antimicrobial, antioxidant and cytotoxic activities and phytochemical screening of some yemeni medicinal plants.
The traditional medicine still plays an important role in the primary health care in Yemen. The current study represents the investigation of 16 selected plants, which were collected from different localities of Yemen. The plants were dried and extracted with two different solvents (methanol and hot water) to yield 34 crude extracts. The obtained extracts were tested for their antimicrobial activity against three Gram-positive bacteria, two Gram-negative bacteria, one yeast species and three multiresistant Staphylococcus strains using agar diffusion method, for their antioxidant activity using scavenging activity of DPPH radical method and for their cytotoxic activity using the neutral red uptake assay. In addition, a phytochemical screening of the methanolic extracts was done. Antibacterial activity was shown only against Gram-positive bacteria, among them multiresistant bacteria. The highest antimicrobial activity was exhibited by the methanolic extracts of Acalypha fruticosa, Centaurea pseudosinaica, Dodonaea viscosa, Jatropha variegata, Lippia citriodora, Plectranthus hadiensis, Tragia pungens and Verbascum bottae. Six methanolic extracts especially those of A. fruticosa, Actiniopteris semiflabellata, D. viscosa, P. hadiensis, T. pungens and V. bottae showed high free radical scavenging activity. Moreover, remarkable cytotoxic activity against FL-cells was found for the methanolic extracts of A. fruticosa, Iris albicans, L. citriodora and T. pungens. The phytochemical screening demonstrated the presence of different types of compounds like flavonoids, terpenoids and others, which could be responsible for the obtained activities.


Cost Evaluation During Decision-Making in Patients at Early Stages of Psychosis.
Jumping to conclusions during probabilistic reasoning is a cognitive bias reliably observed in psychosis and linked to delusion formation. Although the reasons for this cognitive bias are unknown, one suggestion is that psychosis patients may view sampling information as more costly. However, previous computational modeling has provided evidence that patients with chronic schizophrenia jump to conclusions because of noisy decision-making. We developed a novel version of the classical beads task, systematically manipulating the cost of information gathering in four blocks. For 31 individuals with early symptoms of psychosis and 31 healthy volunteers, we examined the numbers of "draws to decision" when information sampling had no, a fixed, or an escalating cost. Computational modeling involved estimating a cost of information sampling parameter and a cognitive noise parameter. Overall, patients sampled less information than controls. However, group differences in numbers of draws became less prominent at higher cost trials, where less information was sampled. The attenuation of group difference was not due to floor effects, as in the most costly block, participants sampled more information than an ideal Bayesian agent. Computational modeling showed that, in the condition with no objective cost to information sampling, patients attributed higher costs to information sampling than controls did, Mann-Whitney U = 289, p = 0.007, with marginal evidence of differences in noise parameter estimates, t(60) = 1.86, p = 0.07. In patients, individual differences in severity of psychotic symptoms were statistically significantly associated with higher cost of information sampling, ρ = 0.6, p = 0.001, but not with more cognitive noise, ρ = 0.27, p = 0.14; in controls, cognitive noise predicted aspects of schizotypy (preoccupation and distress associated with delusion-like ideation on the Peters Delusion Inventory). Using a psychological manipulation and computational modeling, we provide evidence that early-psychosis patients jump to conclusions because of attributing higher costs to sampling information, not because of being primarily noisy decision makers.


Relationship between nanohardness and mineral content of artificial carious enamel lesions.
The aim of this study was to compare cross-sectional nanohardness, measured using an ultra-microindentation system, with mineral content, from transversal microradiography, of artificial enamel caries lesions. Sections (85 +/- 10 microm) from 16 bovine enamel samples with artificial caries were prepared. The mineral content and cross-sectional nanohardness at known depths from the surface were compared. Both methods showed lesion profiles with a surface layer. The determination of nanohardness seems limited to lesions with a mineral content >45 vol%. There was a moderate linear relationship between mineral content and the square root of nanohardness (R2 = 0.81). It was concluded that the conversion of cross-sectional hardness into mineral content remains questionable and cannot be recommended.


Cardiac receptors, vasopressin, and corticosteroid release during arterial hypotension in dogs.
The relative roles of cardiopulmonary and sinoaortic baroreceptors in the regulation of vasopressin and corticosteroid release were evaluated in conscious dogs. The dogs were prepared with inflatable cuffs around either the ascending aorta, proximal to the brachiocephalic trunk, or the pulmonary artery. Inflation of the cuffs was adjusted to cause a reduction of mean systemic arterial pressure (MAP) of 0, 5, 10, 20, or 30% of control for 1 h in separate experiments. In spite of the profound systemic hypotension caused by constriction of the ascending aorta, plasma vasopressin failed to increase and corticosteroids increased only in response to a 30% decrease in MAP. In contrast, a 5% reduction in MAP during pulmonary arterial constriction increased plasma vasopressin and corticosteroid concentrations significantly. The apparent paradox in these results is correlated with different effects of the two maneuvers on left atrial pressure. Left atrial pressure increased dose dependently during inflation of the ascending aortic cuff but decreased during inflation of the pulmonary arterial cuff. In contrast, graded inflation of the pulmonary arterial cuff caused dose-dependent increases in right atrial pressure, plasma vasopressin, and corticosteroids. Therefore, we conclude that powerful inhibitory signals, arising from the left heart, can inhibit vasopressin and hypotension release in response to systemic hypotension.


Integrated care for co-occurring disorders: psychiatric symptoms, social functioning, and service costs at 18 months.
Persons with severe mental illness have high rates of comorbid substance use disorders. These co-occurring disorders present a significant challenge to community mental health services, and few clinical trials are available to guide the development of effective services for this population. The study aimed to evaluate the effectiveness of a program for case managers that trained them to manage substance use disorders among persons with severe mental illness. A cluster-randomized controlled trial design was used in South London to allocate case managers either to training or to a waiting list control condition. Outcomes and service costs (health care and criminal justice) over 18 months of 127 patients treated by 40 case managers who received training were compared with those of 105 patients treated by 39 case managers in the control condition. Brief Psychiatric Rating Scale scores for the intervention group indicated significant improvements in psychotic and general psychopathology symptoms. Participants in the intervention group also reported fewer needs for care at follow-up. No significant differences were found between the two groups in levels of substance use at 18 months. At follow-up both groups reported increased satisfaction with care. Service costs were also similar for the two groups. Compared with standard care, integrated treatment for co-occurring disorders provided by nonspecialist mental health staff produced significant improvements in symptoms and level of met needs, but not in substance use or quality of life, at no additional cost.


Long-term outcomes of patients with 10 or more colorectal liver metastases.
Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients. The study population consisted of a multicentre cohort of patients with CLM (N=12 406) operated on, with intention to resect, from January 2005-June 2013 and whose data were prospectively collected in the LiverMetSurvey registry. Overall, the group ⩾10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26-0.48)). Other independent favourable factors were as follows: maximal tumour size <40 mm (HR 0.67 (0.49-0.92)); age <60 years (HR 0.66 (0.50-0.88)); preoperative MRI (HR 0.65 (0.47-0.89)); and adjuvant chemotherapy (HR 0.73 (0.55-0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor. Liver resection might provide long-term survival in patients with ⩾10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed.