Trends of Dispensed Opioids in Catalonia, Spain, 2007-19: A Population-Based Cohort Study of Over 5 Million Individuals.
Objective: To characterize the trend of opioid use (number of users, dispensations and oral morphine milligram equivalents) in Catalonia (Spain). Design, setting, and participants: This population-based cohort study included all individuals aged 18 years or older, registered in the Information System for Research in Primary Care (SIDIAP), which covers >75% of the population in Catalonia, Spain, from 1 January 2007, to 31 December 2019. Main exposure and outcomes: The exposures were all commercialized opioids and their combinations (ATC-codes): codeine, tramadol, oxycodone, tapentadol, fentanyl, morphine, and other opioids (dihydrocodeine, hydromorphone, dextropropoxyphene, buprenorphine, pethidine, pentazocine). The main outcomes were the annual figures per 1,000 individuals of 1) opioid users, 2) dispensations, and 3) oral morphine milligram equivalents (MME). Results were stratified separately by opioid types, age (5-year age groups), sex (male or female), living area (rural or urban), and socioeconomic status (from least, U1, to most deprived, U5). The overall trends were quantified using the percentage change (PC) between 2007 and 2019. Results: Among 4,656,197 and 4,798,114 residents from 2007 to 2019, the number of opioid users, dispensations and morphine milligram equivalents per 1,000 individuals increased 12% (percentage change: 95% confidence interval (CI) 11.9-12.3%), 105% (95% confidence interval 83%-126%) and 339% (95% CI 289%-390%) respectively. Tramadol represented the majority of opioid use in 2019 (61, 59, and 54% of opioid users, dispensations, and total MME, respectively). Individuals aged 80 years or over reported the sharpest increase regarding opioid users (PC: 162%), dispensations (PC: 424%), and MME (PC: 830%). Strong opioids were increasingly prescribed for non-cancer pains over the years. Conclusion: Despite the modest increase of opioid users, opioid dispensations and MME increased substantially, particularly in the older population. In addition, strong opioids were incrementally indicated for non-cancer pains over the years. These findings suggest a transition of opioid prescriptions from intermittent to chronic and weak to strong and call for more rigorous opioid stewardship.


Understanding the Uncanny: Both Atypical Features and Category Ambiguity Provoke Aversion toward Humanlike Robots.
Robots intended for social contexts are often designed with explicit humanlike attributes in order to facilitate their reception by (and communication with) people. However, observation of an "uncanny valley"-a phenomenon in which highly humanlike entities provoke aversion in human observers-has lead some to caution against this practice. Both of these contrasting perspectives on the anthropomorphic design of social robots find some support in empirical investigations to date. Yet, owing to outstanding empirical limitations and theoretical disputes, the uncanny valley and its implications for human-robot interaction remains poorly understood. We thus explored the relationship between human similarity and people's aversion toward humanlike robots via manipulation of the agents' appearances. To that end, we employed a picture-viewing task (Nagents = 60) to conduct an experimental test (Nparticipants = 72) of the uncanny valley's existence and the visual features that cause certain humanlike robots to be unnerving. Across the levels of human similarity, we further manipulated agent appearance on two dimensions, typicality (prototypic, atypical, and ambiguous) and agent identity (robot, person), and measured participants' aversion using both subjective and behavioral indices. Our findings were as follows: (1) Further substantiating its existence, the data show a clear and consistent uncanny valley in the current design space of humanoid robots. (2) Both category ambiguity, and more so, atypicalities provoke aversive responding, thus shedding light on the visual factors that drive people's discomfort. (3) Use of the Negative Attitudes toward Robots Scale did not reveal any significant relationships between people's pre-existing attitudes toward humanlike robots and their aversive responding-suggesting positive exposure and/or additional experience with robots is unlikely to affect the occurrence of an uncanny valley effect in humanoid robotics. This work furthers our understanding of both the uncanny valley, as well as the visual factors that contribute to an agent's uncanniness.


Production of an enterotoxin by a gastro-enteritis-associated Aeromonas strain.
The potential of motile Aeromonas species to cause human gastrointestinal infections has been recognised recently. Considerable worldwide epidemiological, microbiological and clinical investigations have shown that some strains of the different motile aeromonads are of increasing enteropathogenic significance, especially in children, the elderly and in immunocompromised individuals. Some of the diarrhoeal symptoms of Aeromonas-associated gastro-enteritis have been attributed to enterotoxins. In this study, 15 Aeromonas isolates from clinical and non-clinical sources, representing the three motile aeromonads commonly associated with gastro-enteritis (A. caviae, A. hydrophila and A. veronii biovar sobria), were tested for their ability to cause fluid accumulation in infant mice by the suckling mouse technique. Eight isolates were found to produce enterotoxin. Of these, an A. veronii biovar sobria strain (AS15), isolated from lamb kidney, was found to produce the highest enterotoxin score. An enterotoxin of c. 40 kDa produced by A. veronii biovar sobria AS15 was purified by Sephacryl S-100 gel filtration and high-performance liquid chromatography. This enterotoxin caused marked fluid accumulation in infant mice by the suckling mouse technique. The purified enterotoxin cross-reacted with cholera toxin antibodies and was readily inactivated by heating at 56 degrees C for 10 min. The production of a 'cholera-like' enterotoxin by Aeromonas isolates from samples of animal origin suggests that these organisms could be of public health significance in food products.


A mutant T7 RNA polymerase as a DNA polymerase.
We have identified a T7 RNA polymerase (RNAP) mutant that efficiently utilizes deoxyribonucleoside triphosphates. In vitro this mutant will synthesize RNA, DNA or 'transcripts' of mixed dNMP/rNMP composition depending on the mix of NTPs present in the synthesis reaction. The mutation is conservative, changes Tyr639 within the active site to phenylalanine and does not affect promoter specificity or overall activity. Non-conservative mutations of this tyrosine also reduce discrimination between deoxyribo- and ribonucleoside triphosphates, but these mutations also cause large activity reductions. Of 26 mutations of other residues in and around the active site examined none showed marked effects on rNTP/dNTP discrimination. Mutations of the corresponding tyrosine in DNA polymerase (DNAP) I increase miscoding, though effects on dNTP/rNTP discrimination for the DNAP I mutations have not been reported. This conserved tyrosine may therefore play a similar role in many polymerases by sensing incorrect geometry in the structure of the substrate/template/product due to inappropriate substrate structure or mismatches. T7 RNAP can use RNA templates as well as DNA templates and is capable of both primer extension and de novo initiation. The Y639F mutant retains the ability to use RNA or DNA templates. Thus this mutant can display de novo initiated or primed DNA-directed DNA polymerase, reverse transcriptase, RNA-directed RNA polymerase or DNA-directed RNA polymerase activities depending simply on the templates and substrates presented to it in the synthesis reaction.


Is long-axis view superior to short-axis view in ultrasound-guided central venous catheterization?
To evaluate whether using long-axis or short-axis view during ultrasound-guided internal jugular and subclavian central venous catheterization results in fewer skin breaks, decreased time to cannulation, and fewer posterior wall penetrations. Prospective, randomized crossover study. Urban emergency department with approximate annual census of 60,000. Emergency medicine resident physicians at the Denver Health Residency in Emergency Medicine, a postgraduate year 1-4 training program. Resident physicians blinded to the study hypothesis used ultrasound guidance to cannulate the internal jugular and subclavian of a human torso mannequin using the long-axis and short-axis views at each site. An ultrasound fellow recorded skin breaks, redirections, and time to cannulation. An experienced ultrasound fellow or attending used a convex 8-4 MHz transducer during cannulation to monitor the needle path and determine posterior wall penetration. Generalized linear mixed models with a random subject effect were used to compare time to cannulation, number of skin breaks and redirections, and posterior wall penetration of the long axis and short axis at each cannulation site. Twenty-eight resident physicians participated: eight postgraduate year 1, eight postgraduate year 2, five postgraduate year 3, and seven postgraduate year 4. The median (interquartile range) number of total internal jugular central venous catheters placed was 27 (interquartile range, 9-42) and subclavian was six catheters (interquartile range, 2-20). The median number of previous ultrasound-guided internal jugular catheters was 25 (interquartile range, 9-40), and ultrasound-guided subclavian catheters were three (interquartile range, 0-5). The long-axis view was associated with a significant decrease in the number of redirections at the internal jugular and subclavian sites, relative risk 0.4 (95% CI, 0.2-0.9) and relative risk 0.5 (95% CI, 0.3-0.7), respectively. There was no significant difference in the number of skin breaks between the long axis and short axis at the subclavian and internal jugular sites. The long-axis view for subclavian was associated with decreased time to cannulation; there was no significant difference in time between the short-axis and long-axis views at the internal jugular site. The prevalence of posterior wall penetration was internal jugular short axis 25%, internal jugular long axis 21%, subclavian short axis 64%, and subclavian long axis 39%. The odds of posterior wall penetration were significantly less in the subclavian long axis (odds ratio, 0.3; 95% CI, 0.1-0.9). The long-axis view for the internal jugular was more efficient than the short-axis view with fewer redirections. The long-axis view for subclavian central venous catheterization was also more efficient with decreased time to cannulation and fewer redirections. The long-axis approach to subclavian central venous catheterization is also associated with fewer posterior wall penetrations. Using the long-axis view for subclavian central venous catheterization and avoiding posterior wall penetrations may result in fewer central venous catheter-related complications.


[Randomized controlled study on ear-electroacupuncture treatment of endometriosis-induced dysmenorrhea in patients].
To observe the therapeutic effect of ear-electroacupuncture (Ear-EA) on dysmenorrhea in patients with endometriosis and to explore its underlying mechanism. A total of 80 endometriosis patients were randomly and equally divided into ear-EA group and body-EA group. EA (50 Hz, 0.5-0.8 mA) was applied to auricular points (Uterus, Subcortex, Shenmen, Endocrine, etc.) and body acupoints [Tianshu (ST 25), Qihai (CV 6), Guanyuan (CV 4), Sanyinjiao (SP 6), Diji (SP 8), Uterus (EX-CA 1), etc.] respectively for 30 min, once every other day for 3 months. Dysmenorrhea severity score (DSS) was assessed and plasma prostaglandin (PGE2) and 6-Keto-PGF1alpha levels detected by radioimmunoassay. Compared with pre-treatment, DSS lowered significantly during the 1st and 2nd menstrual cycle in body-EA group, and during the 1st, 2nd and 3rd menstruation in ear-EA group; and the DSS of ear-EA group during the 3rd menstruation was evidently lower than that of body-EA group (P < 0.05). During the 3rd menstrual onset after the treatment, plasma PGE2 contents in both groups decreased obviously (P < 0.01), and plasma 6-Keto-PGF1alpha, levels increased considerably in comparison with pre-treatment (P < 0.01). Comparison between two groups during the 3rd menstruation showed that plasma PGE2 level of ear-EA group was markedly lower than that of body-EA group, and 6-Keto-PGF1alpha, level of ear-EA group was significantly higher than that of body-EA group (P < 0.05). No significant difference was found between two groups in clinical therapeutic effect (P > 0.05). Both ear-EA and body-EA can effectively relieve endometriosis-induced dysmenorrhea, and the former is superior to the later in reducing pain severity, which may be closely related to their effects in reducing plasma PGE2 and raising 6-Keto-PGF1alpha level.


Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.
Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12.


Nerve growth factor triggers microfilament assembly and paxillin phosphorylation in human B lymphocytes.
Increasing evidence suggests that the nervous system is involved in allergic inflammation. One of the potential regulatory molecules of the neuroimmune system is nerve growth factor (NGF). Recent studies from our group demonstrated the presence of a functional NGF receptor (NGFR) on human B lymphocytes. Moreover, we showed that gp140trk tyrosine kinase, which serves as an NGFR, was involved in transduction of early signaling events in human B lymphocytes. The mechanisms by which NGF initiates the signaling cascade and the link between the neuroimmune systems are unknown. We have focused on the role of the cytoskeleton as a possible mediator for transduction of signals induced by NGF. Polymerized actin (F-actin) content was determined by fluorescent staining and immunoblotting with antiactin antibody. Addition of NGF caused a time- and concentration-dependent increase in F-actin content, and maximum effects were noted after 1 min. These increases in F-actin content and NGF-induced thymidine incorporation could be blocked by incubating the cells with cytochalasin D and botulinum C2 toxin before the addition of NGF. Incubation of human B lymphocytes with 10 nM K252a, an inhibitor of Trk kinase, decreased NGF-induced microfilament assembly by 75%. In immunoprecipitation experiments, addition of NGF to B cells induced a rapid increase in the tyrosine phosphorylation of paxillin, one of a group of focal adhesion proteins involved in linking actin filaments to the plasma membrane. Coimmunoprecipitation studies demonstrated the association between gp140trk kinase and paxillin. Together, these observations suggest that actin assembly is involved in NGF signaling in human B cells, and that paxillin may be essential in this pathway after phosphorylation by gp140trk kinase.


Growth hormone is protective against acute methadone-induced toxicity by modulating the NMDA receptor complex.
Human growth hormone (GH) displays promising protective effects in the central nervous system after damage caused by various insults. Current evidence suggests that these effects may involve N-methyl-d-aspartate (NMDA) receptor function, a receptor that also is believed to play a role in opioid-induced neurotoxicity. The aims of the present study were to examine the acute toxic effects of methadone, an opioid receptor agonist and NMDA receptor antagonist, as well as to evaluate the protective properties of recombinant human GH (rhGH) on methadone-induced toxicity. Primary cortical cell cultures from embryonic day 17 rats were grown for 7days in vitro. Cells were treated with methadone for 24h and the 50% lethal dose was calculated and later used for protection studies with rhGH. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase release, and caspase activation. Furthermore, the mRNA expression levels of NMDA receptor subunits were investigated following methadone and rhGH treatment using quantitative PCR (qPCR) analysis. A significant protective effect was observed with rhGH treatment on methadone-induced mitochondrial dysfunction and in methadone-induced LDH release. Furthermore, methadone significantly increased caspase-3 and -7 activation but rhGH was unable to inhibit this effect. The mRNA expression of the NMDA receptor subunit GluN1, GluN2a, and GluN2b increased following methadone treatment, as assessed by qPCR, and rhGH treatment effectively normalized this expression to control levels. We have demonstrated that rhGH can rescue cells from methadone-induced toxicity by maintaining mitochondrial function, cellular integrity, and NMDA receptor complex expression.


Presaturation Power Adjusted Pulsed CEST: A Method to Increase Independence of Target CEST Signals.
Chemical exchange saturation transfer (CEST) imaging has been demonstrated to discuss the concentration changes of amide proton, glutamate, creatine, or glucose measured at 3.5, 3.0, 2.0, and 1.0-1.2 ppm. However, these peaks in z-spectra are quite broad and overlap with each other, and thus, the independence of a CEST signal on any specific metabolite is still open to question. Here, we described whether there was interference among the CEST signals and how these CEST signals behave when the power of the presaturation pulse was changed. Based on these results, further experiments were designed to investigate a method to increase the independence of the CEST signal in both phantoms and animals. The result illustrates a clear interference among CEST signals. A presaturation power adjusted pulsed- (PPAP-) CEST method which was designed based on the exchange rates of the metabolites can be used to remove contributions from other exchanging species in the same sample. Further, the method was shown to improve the independence of the glutamate signal in vivo in the renal medulla in mice. The PPAP-CEST method has the potential to increase the independence of any target CEST signals in vivo by choosing the appropriate combination of pulse amplitudes and durations.


Coordinate regulation of G protein signaling via dynamic interactions of receptor and GAP.
Signal output from receptor-G-protein-effector modules is a dynamic function of the nucleotide exchange activity of the receptor, the GTPase-accelerating activity of GTPase-activating proteins (GAPs), and their interactions. GAPs may inhibit steady-state signaling but may also accelerate deactivation upon removal of stimulus without significantly inhibiting output when the receptor is active. Further, some effectors (e.g., phospholipase C-beta) are themselves GAPs, and it is unclear how such effectors can be stimulated by G proteins at the same time as they accelerate G protein deactivation. The multiple combinations of protein-protein associations and interacting regulatory effects that allow such complex behaviors in this system do not permit the usual simplifying assumptions of traditional enzyme kinetics and are uniquely subject to systems-level analysis. We developed a kinetic model for G protein signaling that permits analysis of both interactive and independent G protein binding and regulation by receptor and GAP. We evaluated parameters of the model (all forward and reverse rate constants) by global least-squares fitting to a diverse set of steady-state GTPase measurements in an m1 muscarinic receptor-G(q)-phospholipase C-beta1 module in which GTPase activities were varied by approximately 10(4)-fold. We provide multiple tests to validate the fitted parameter set, which is consistent with results from the few previous pre-steady-state kinetic measurements. Results indicate that (1) GAP potentiates the GDP/GTP exchange activity of the receptor, an activity never before reported; (2) exchange activity of the receptor is biased toward replacement of GDP by GTP; (3) receptor and GAP bind G protein with negative cooperativity when G protein is bound to either GTP or GDP, promoting rapid GAP binding and dissociation; (4) GAP indirectly stabilizes the continuous binding of receptor to G protein during steady-state GTPase hydrolysis, thus further enhancing receptor activity; and (5) receptor accelerates GDP/GTP exchange primarily by opening an otherwise closed nucleotide binding site on the G protein but has minimal effect on affinity (K(assoc) = k(assoc)/k(dissoc)) of G protein for nucleotide. Model-based simulation explains how GAP activity can accelerate deactivation >10-fold upon removal of agonist but still allow high signal output while the receptor is active. Analysis of GTPase flux through distinct reaction pathways and consequent accumulation of specific GTPase cycle intermediates indicate that, in the presence of a GAP, the receptor remains bound to G protein throughout the GTPase cycle and that GAP binds primarily during the GTP-bound phase. The analysis explains these behaviors and relates them to the specific regulatory phenomena described above. The work also demonstrates the applicability of appropriately data-constrained system-level analysis to signaling networks of this scale.


Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade.
Immune-checkpoint inhibitors (ICI) are highly effective in reinvigorating T cells to attack cancer. Nevertheless, a large subset of patients fails to benefit from ICI, partly due to lack of the cancer neoepitopes necessary to trigger an immune response. In this study, we used the thiopurine 6-thioguanine (6TG) to induce random mutations and thus increase the level of neoepitopes presented by tumor cells. Thiopurines are prodrugs which are converted into thioguanine nucleotides that are incorporated into DNA (DNA-TG), where they can induce mutation through single nucleotide mismatching. In a pre-clinical mouse model of a mutation-low melanoma cell line, we demonstrated that 6TG induced clinical-grade DNA-TG integration resulting in an improved tumor control that was strongly T cell dependent. 6TG exposure increased the tumor mutational burden, without affecting tumor cell proliferation and cell death. Moreover, 6TG treatment re-shaped the tumor microenvironment by increasing T and NK immune cells, making the tumors more responsive to immune-checkpoint blockade. We further validated that 6TG exposure improved tumor control in additional mouse models of melanoma. These findings have paved the way for a phase I/II clinical trial that explores whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy (NCT05276284).


Incidence of maternal near-miss in Kenya in 2018: findings from a nationally representative cross-sectional study in 54 referral hospitals.
Although the Kenyan government has made efforts to invest in maternal health over the past 15 years, there is no evidence of decline in maternal mortality. To provide necessary evidence to inform maternal health care provision, we conducted a nationally representative study to describe the incidence and causes of maternal near-miss (MNM), and the quality of obstetric care in referral hospitals in Kenya. We collected data from 54 referral hospitals in 27 counties. Individuals admitted with potentially life-threatening conditions (using World Health Organization criteria) in pregnancy, childbirth or puerperium over a three month study period were eligible for inclusion in our study. All cases of severe maternal outcome (SMO, MNM cases and deaths) were prospectively identified, and after consent, included in the study. The national annual incidence of MNM was 7.2 per 1,000 live births and the intra-hospital maternal mortality ratio was 36.2 per 100,000 live births. The major causes of SMOs were postpartum haemorrhage and severe pre-eclampsia/eclampsia. However, only 77% of women with severe preeclampsia/eclampsia received magnesium sulphate and 67% with antepartum haemorrhage who needed blood received it. To reduce the burden of SMOs in Kenya, there is need for timely management of complications and improved access to essential emergency obstetric care interventions.


[A 4-year-old girl with double vision following trauma].
BACKGROUND Due to its long intracranial course, the abducens nerve is vulnerable in case of acceleration injury of the head. In rare cases, this may lead to posttraumatic paralysis of this cranial nerve. CASE DESCRIPTION A 4-year-old girl visited the emergency department after sustaining a head trauma. Neurological examination revealed no focal abnormalities at first. Three days later, she experienced diplopia, the consequence of isolated abducens nerve paralysis. CT and MRI brain imaging revealed no abnormalities. We treated her with an eye patch for a short time. At examination after 1 year, she was no longer experiencing any symptoms and the paralysis had almost completely disappeared. CONCLUSION Isolated paralysis of the abducens nerve may occur until up to 6 days after a trauma, without any visible intracranial abnormalities revealed by imaging. Even though only few children with this condition have been described, prognosis seems to be favourable and symptoms disappear in the majority of patients. Frequent follow-up by the ophthalmologist and the orthoptist is recommended, possibly with symptomatic treatment of the diplopia.


Sprint vs. interval training in football.
The aim of this study was to compare the effects of high-intensity aerobic interval and repeated-sprint ability (RSA) training on aerobic and anaerobic physiological variables in male football players. Forty-two participants were randomly assigned to either the interval training group (ITG, 4 x 4 min running at 90 - 95 % of HRmax; n = 21) or repeated-sprint training group (RSG, 3 x 6 maximal shuttle sprints of 40 m; n = 21). The following outcomes were measured at baseline and after 7 weeks of training: maximum oxygen uptake, respiratory compensation point, football-specific endurance (Yo-Yo Intermittent Recovery Test, YYIRT), 10-m sprint time, jump height and power, and RSA. Significant group x time interaction was found for YYIRT (p = 0.003) with RSG showing greater improvement (from 1917 +/- 439 to 2455 +/- 488 m) than ITG (from 1846 +/- 329 to 2077 +/- 300 m). Similarly, a significant interaction was found in RSA mean time (p = 0.006) with only the RSG group showing an improvement after training (from 7.53 +/- 0.21 to 7.37 +/- 0.17 s). No other group x time interactions were found. Significant pre-post changes were found for absolute and relative maximum oxygen uptake and respiratory compensation point (p < 0.05). These findings suggest that the RSA training protocol used in this study can be an effective training strategy for inducing aerobic and football-specific training adaptations.


Impact of the COVID-19 Pandemic on Teacher Quality of Life: A Longitudinal Study from before and during the Health Crisis.
Prior to the COVID-19 pandemic, teachers were already reporting a low quality of life (QoL) perception, with a significant impact on mental and physical health due to various stress factors associated with work overload. The objective of this study was to evaluate the QoL impact on Chilean teachers before and during the COVID-19 pandemic. The analysis was performed following a longitudinal design on a sample of 63 Chilean teachers in pre-pandemic and COVID-19 pandemic timeframes. QoL perception, along with teachers' sociodemographic data, was evaluated via the Short-Form 36 Health Survey (SF-36) questionnaire. Sociodemographic variables presented no significant variations in pre-pandemic and pandemic comparisons. QoL, however, showed a significant decrease during the pandemic compared to the pre-pandemic measurement (p < 0.01). In each gender, there were significant differences between pre-pandemic and pandemic timeframes, with a greater impact among women in the mental and physical component summary variables and seven of the eight QoL scales (p < 0.01). Between age categories, people under 45 presented significant differences (p < 0.05) between pre-pandemic and pandemic timeframes in all summary dimensions and measurements. In conclusion, Chilean teachers' QoL perception has been affected by the COVID-19 pandemic. These findings could be related to work overload due to teleworking or feelings of uncertainty, loneliness, and fear that the pandemic and its associated confinements will worsen.


Susceptibility of Neisseria meningitidis to 16 antimicrobial agents and characterization of resistance mechanisms affecting some agents.
Neisseria meningitidis represents a pathogen of great public health importance in both developed and developing countries. Resistance to some antimicrobial agents used either for therapy of invasive infections or for prophylaxis of case contacts has long been recognized, although specific guidelines for susceptibility testing have not been fully developed. We have examined the susceptibilities of a collection of 442 meningococcal clinical isolates from 15 countries to 16 antimicrobial agents. These included isolates recovered between 1917 and 2004, with representatives of all major serogroups. All isolates were tested by the Clinical and Laboratory Standards Institute (formerly NCCLS) broth microdilution method using Mueller-Hinton lysed horse blood broth, while a subset of 102 isolates was tested by agar dilution using Mueller-Hinton sheep blood agar. Most isolates provided adequate growth for MIC determinations by both broth and agar methods. Growth in broth was enhanced by CO(2) incubation and was required for two strains (1.7%). MICs of the study drugs compared favorably between the broth and agar methods (79 to 100% essential agreement), and MICs also generally agreed closely (92 to 100% essential agreement, excluding azithromycin) between broth tests incubated in the two different atmospheres. Elevated penicillin and ampicillin MICs (> or =0.12 microg/ml and > or =0.25 microg/ml, respectively) occurred in 14.3% and 8.6% of strains and were associated with polymorphisms of the penA gene encoding a modified penicillin-binding protein 2. None of the 442 isolates produced beta-lactamase. Elevated tetracycline and doxycycline (but not minocycline) MICs were associated with efflux-mediated resistance encoded by tet(B) in 13 strains. Resistance to sulfisoxazole in 21.7% of strains and to trimethoprim-sulfamethoxazole in 21.0% resulted from polymorphisms of folP encoding a modified dihydropteroate synthetase. Seven strains were resistant to rifampin due to mutations in the rpoB gene, and two strains were resistant to chloramphenicol due to production of chloramphenicol acetyltransferase mediated by catP. Two strains had reduced quinolone susceptibility due to mutations of gyrA. The determination of the susceptibilities of a large group of meningococcal strains (including strains with characterized resistance mechanisms) to 16 antimicrobial agents has served as the essential first step in defining susceptibility testing breakpoints specific for this organism.


Effect of soluble P55 tumour-necrosis factor binding fusion protein on the local Shwartzman and Arthus reactions.
1. In this study, the effects of a protein synthesis inhibitor, cycloheximide, and a soluble tumour necrosis factor (TNF) binding/IgG fusion protein, p55-sf2, on the priming and challenge stages of the local Shwartzman reaction (LSR) were assessed and compared with their effects on the acute inflammatory response induced by recombinant human tumour necrosis factor-alpha (rhTNF), lipopolysaccharide (LPS) and a reversed passive Arthus (RPA) reaction in rabbit skin. 2. The LSR was induced in skin by giving an intradermal (i.d.) priming injection of LPS followed by two i.v. challenge injections 20 h and 22 h later. Accumulation of 51-Cr-labelled red blood cells and [125I]-albumin were measured at 24 h as markers of haemorrhage and oedema formation, respectively. 3. The RPA reaction was induced in the rabbit by giving i.d. injections of Arthus anti-serum (anti-bovine-gamma-globulin, BGG) followed 5 min later by an i.v. injection of the antigen (BGG). Oedema formation and the accumulation of 111In-labelled neutrophils produced in the RPA reaction and in response to i.d. injection of rhTNF and LPS were measured over the 4 h period after inducing the responses. 4. A single local injection of cycloheximide (10 micrograms/site) did not inhibit neutrophil accumulation or oedema formation produced by 100% Arthus anti-sera. Although LPS injected i.d. induced a marked dose-dependent neutrophil accumulation, there was little associated plasma leakage. Cycloheximide (10 micrograms/site) did not significantly inhibit the neutrophil accumulation induced by LPS (0.1 microgram/site). In the LSR, priming i.d. injections of LPS caused a dose-dependent increase in haemorrhage and plasma leakage at skin sites after challenge with LPS (two injections of 100 micrograms, i.v.). Co-injection of a single dose of cycloheximide (10 micrograms/site) with LPS (30 micrograms/site) caused a marked reduction in the amount of haemorrhage. Local cycloheximide (10 micrograms/site) administered immediately before LSR challenge did not affect the responses produced in the LSR. 5. Neutrophil accumulation induced by TNF (0.17 micrograms/site) was abolished by co-administration of p55-sf2 (3 micrograms/site) whereas neutrophil accumulation induced by i.d. LPS and produced in the RPA reaction was not affected. In the LSR, haemorrhage and oedema formation were inhibited by p55-sf2 (3 micrograms/site) when it was administered i.d. with the LPS priming injection, but not when given i.d. immediately before LSR challenge. 6. These data suggest that the acute neutrophil accumulation produced in the RPA reaction and in response to i.d. LPS may not be dependent on local protein synthesis or TNF production. On the other hand, haemorrhage appears to be dependent on local protein synthesis during the priming phase but not during the challenge stage of the LSR. Importantly, haemorrhage and plasma leakage appear to be dependent on local TNF generation during the priming phase but not during the challenge stage of the LSR. Thus TNF appears to play a key role in the LSR in rabbit skin.


Predictors for outcome of failure of balloon dilatation in patients with achalasia.
Pneumatic balloon dilatation (PD) is a regular treatment modality for achalasia. The reported success rates of PD vary. Recurrent symptoms often require repeated PD or surgery. To identify predicting factors for symptom recurrence requiring repeated treatment. Between 1974 and 2006, 336 patients were treated with PD and included in this longitudinal cohort study. The median follow-up was 129 months (range 1-378). Recurrence of achalasia was defined as symptom recurrence in combination with increased lower oesophageal sphincter (LOS) pressure on manometry, requiring repeated treatment. Patient characteristics, results of timed barium oesophagram and manometry as well as baseline PD characteristics were evaluated as predictors of disease recurrence with Kaplan-Meier curves and Cox regression analysis. 111 patients had symptom recurrence requiring repeated treatment. Symptoms recurred after a mean follow-up of 51 months (range 1-348). High recurrence percentages were found in patients younger than 21 years in whom the 5 and 10-year risks of recurrence were 64% and 72%, respectively. These risks were respectively 28% and 36% in patients with classic achalasia, respectively 48% and 60% in patients without complete obliteration of the balloon's waist during PD and respectively 25% and 33% in patients with a LOS pressure greater than 10 mm Hg at 3 months post-dilatation. These four predictors remained statistically significant in a multivariable Cox analysis. Although PD is an effective primary treatment in patients with primary achalasia, patients are at risk of recurrent disease, with this risk increasing during long-term follow-up. Young age at presentation, classic achalasia, high LOS pressure 3 months after PD and incomplete obliteration of the balloon's waist during PD are the most important predicting factors for the need for repeated treatment during follow-up. Patients who meet one or more of these characteristics may be considered earlier for alternative treatment, such as surgery.


Chaotic neural response during conflicting Stroop task reflects the level of serum cortisol in patients with unipolar depression.
According to recent findings detecting a cognitive conflict is related to activation of anterior cingulate cortex (ACC) and central autonomic network. Several recent findings also suggest the hypothesis that the cognitive conflict is related to specific nonlinear chaotic changes of the neural signal. This conflict related activation elicits autonomic responses which can be assessed by psychophysiological measures such as heart rate variability calculated as beat to beat R-R intervals (RRI). The present study used Stroop word-colour test as an experimental approach to psychophysiological study of cognitive conflict in connection with RRI measurement, assessment of serum cortisol and calculation of largest Lyapunov exponents in nonlinear data analysis of RRI time series in 30 patients with unipolar depression. Significant correlation -0.45 (p<0.01) between largest Lyapunov exponents during conflicting Stroop task and serum cortisol levels has been found. The study indicates that a defect of neural inhibition during conflicting Stroop task is closely related to decreased serum cortisol levels which probably reflect defense psychological mechanisms.


The antiangiogenic properties of sulfated β-cyclodextrins in anticancer formulations incorporating 5-fluorouracil.
Sulfated β-cyclodextrins (S-β-CDs) are useful excipients for improving the solubility of drugs. One such formulation incorporating 5-fluorouracil (5-FU), termed FD(S), showed improved efficacy over 5-FU alone in orthotopic carcinoma xenograft models. S-β-CDs have heparin-like anticoagulant properties, which may have contributed toward the improved antitumor effect of FD(S). S-β-CDs have also been reported to modify a number of processes involved in angiogenesis. Although the anticoagulant nature of S-β-CDs was established, the antiangiogenic properties of S-β-CDs within FD(S) were unknown. The effect of S-β-CD and FD(S) on the proliferation and migration of endothelial cells in live-cell kinetic assays, and the reorganization of human umbilical vein endothelial cells into tubule structures in vitro was assessed. The effects of S-β-CD on angiogenesis in vitro were validated ex vivo using the rat aorta ring assay and the chick embryo chorioallantoic membrane assay. S-β-CD does not alter proliferative endothelial cell sensitivity to 5-FU cytotoxicity. S-β-CD alone and within FD(S) significantly inhibited angiogenesis by impeding endothelial cell migration, resulting in the inhibition of tubule formation and hence new vasculature. In addition to the cytotoxic action of the drug 5-FU, therapeutic inhibition of angiogenesis by S-β-CDs within FD(S) could potentially limit local invasion and metastases. This has important implications for the exploitation of S-β-CDs for drug formulation improvements or for drug delivery of anticancer biologics.


An experimental and theoretical study of core-valence double ionisation of acetaldehyde (ethanal).
Core-valence double ionisation spectra of acetaldehyde (ethanal) are presented at photon energies above the carbon and oxygen 1s ionisation edges, measured by a versatile multi-electron coincidence spectroscopy technique. We use this molecule as a testbed for analyzing core-valence spectra by means of quantum chemical calculations of transition energies. These theoretical approaches range from two simple models, one based on orbital energies corrected by core valence interaction and one based on the equivalent core approximation, to a systematic series of quantum chemical electronic structure methods of increasing sophistication. The two simple models are found to provide a fast orbital interpretation of the spectra, in particular in the low energy parts, while the coverage of the full spectrum is best fulfilled by correlated models. CASPT2 is the most sophisticated model applied, but considering precision as well as computational costs, the single and double excitation configuration interaction model seems to provide the best option to analyze core-valence double hole spectra.


The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat.
The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg kg-1, = 3-5). Alosetron administered via the duodenum also inhibited this reflex, with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.


Varicella Zoster Virus Necrotizing Retinitis in Two Patients with Idiopathic CD4 Lymphocytopenia.
Progressive outer retinal necrosis (PORN) associated with varicella zoster virus (VZV) is usually diagnosed in HIV positive or immunosuppressed patients. We report two cases of immunocompetent patients with necrotizing viral retinitis found to have idiopathic CD4 lymphocytopenia. Clinical presentation, examination, imaging, and laboratory testing of two patients with VZV retinitis are presented. An HIV negative patient with history of herpes zoster presented with rapid loss of vision and examination consistent with PORN. PCR testing confirmed VZV. Lymphocytopenia was noted with a CD4 count of 25/mm(3). A second HIV negative patient presented with blurred vision and lid swelling and was found to have peripheral VZV retinitis confirmed by PCR. Laboratory workup revealed lymphocytopenia with a CD4 count of 133/mm(3). VZV necrotizing retinitis classic for PORN can occur in HIV negative patients. Idiopathic CD4 lymphocytopenia should be considered healthy patients who develop ocular infections seen in the immunocompromised.


The dynamic changes of dominant clones of Staphylococcus aureus causing bloodstream infections in the European region: results of a second structured survey.
Staphylococcus aureus is one of the most important human pathogens and meticillin-resistant S. aureus (MRSA) presents a major cause of healthcare- and community-acquired infections. This study investigated the spatial and temporal changes of S. aureus causing bacteraemia in Europe over a five-year interval and explored the possibility of integrating pathogen-based typing data with epidemiological and clinical information at a European level. Between January 2011 and July 2011, 350 laboratories serving 453 hospitals in 25 countries collected 3,753 isolates (meticillin-sensitive S. aureus (MSSA) and MRSA) from patients with S. aureus bloodstream infections. All isolates were sent to the national staphylococcal reference laboratories and characterised by quality-controlled spa typing. Data were uploaded to an interactive web-based mapping tool. A wide geographical distribution of spa types was found, with some prevalent in all European countries. MSSA was more diverse than MRSA. MRSA differed considerably between countries with major international clones expanding or receding when compared to a 2006 survey. We provide evidence that a network approach of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of S. aureus populations such as early signalling of emerging strains, cross-border spread and importation by travel.


An alternative manoeuvre for posterior canal BPPV treatment.
The aim of this study is to evaluate the effectiveness of a new manoeuvre in the treatment of posterior canal benign paroxysmal positional vertigo (p-BPPV) based on the idea that highly accelerated endolymphatic flow may lead a mass of otoconia to collide with the walls of the posterior semicircular canal, resulting in its disintegration and/or in the expulsion of the free particles from the posterior semicircular canal. Our study group included 146 patients with a diagnosis of p-BPPV. All patients underwent the new manoeuvre, which consisted of several high-acceleration successive head movements in the horizontal plane performed by the same physician. The results of the study group were compared with those of a sham control group of 30 patients with p-BPPV undergoing placebo treatment. The patients of both groups were reviewed in a follow-up appointment 1 month and 1 year after the initial treatment. Complete resolution of symptoms immediately after the manoeuvre was observed in 92% of patients. At 1-month and 1-year follow-up assessment, all the patients in the study group reported complete relief from their symptoms compared with only 13% and 43% of control patients respectively. Recurrence of symptoms was reported in 12 patients (8%) from the study group, who responded successfully to one additional session. This study establishes the efficacy of the new manoeuvre in the short- and long-term management of p-BPPV. It is a quick office procedure, usually resolving this disorder with a single session, although there some limitations in patients with underlying cervical spine pathology.


Effects of spatial coherence in diffraction phase microscopy.
Quantitative phase imaging systems using white light illumination can exhibit lower noise figures than laser-based systems. However, they can also suffer from object-dependent artifacts, such as halos, which prevent accurate reconstruction of the surface topography. In this work, we show that white light diffraction phase microscopy using a standard halogen lamp can produce accurate height maps of even the most challenging structures provided that there is proper spatial filtering at: 1) the condenser to ensure adequate spatial coherence and 2) the output Fourier plane to produce a uniform reference beam. We explain that these object-dependent artifacts are a high-pass filtering phenomenon, establish design guidelines to reduce the artifacts, and then apply these guidelines to eliminate the halo effect. Since a spatially incoherent source requires significant spatial filtering, the irradiance is lower and proportionally longer exposure times are needed. To circumvent this tradeoff, we demonstrate that a supercontinuum laser, due to its high radiance, can provide accurate measurements with reduced exposure times, allowing for fast dynamic measurements.


Skin sympathetic nerve activity and the temporal clustering of cardiac arrhythmias.
Simultaneous noninvasively recorded skin sympathetic nerve activity (SKNA) and electrocardiogram (neuECG) can be used to estimate cardiac sympathetic tone. We tested the hypothesis that large and prolonged SKNA bursts are associated with temporal clustering arrhythmias. We recorded neuECG in 10 patients (69 ± 10 years old) with atrial fibrillation (AF) episodes and in 6 patients (50 ± 13 years old) with ventricular tachycardia (VT) or fibrillation (VF) episodes. Clustering was defined by an arrhythmic episode followed within 1 minute by spontaneous recurrences of the same arrhythmia. The neuECG signals were bandpass filtered between 500-1000 Hz to display SKNA. There were 22 AF clusters, including 231 AF episodes from 6 patients, and 9 VT/VF clusters, including 99 VT/VF episodes from 3 patients. A total duration of SKNA bursts associated with AF was longer than that during sinus rhythm (78.9 min/hour [interquartile range (IQR) 17.5-201.3] vs. 16.3 min/hour [IQR 14.5-18.5], P = 0.022). The burst amplitude associated with AF in clustering patients was significantly higher than that in nonclustering patients (1.54 μV [IQR 1.35-1.89], n = 114, vs. 1.20 μV [IQR 1.05-1.42], n = 21, P < 0.001). The SKNA bursts associated with VT/VF clusters lasted 9.3 ± 3.1 minutes, with peaks that averaged 1.13 ± 0.38 μV as compared with 0.79 ± 0.11 μV at baseline (P = 0.041). Large and sustained sympathetic nerve activities are associated with the temporal clustering of AF and VT/VF. This study was supported in part by NIH grants R42DA043391 (THE), R56 HL71140, TR002208-01, R01 HL139829 (PSC), a Charles Fisch Cardiovascular Research Award endowed by Suzanne B. Knoebel of the Krannert Institute of Cardiology (TK and THE), a Medtronic-Zipes Endowment, and the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (PSC).


Spot the difference-development of a syndrome based protein microarray for specific serological detection of multiple flavivirus infections in travelers.
The family Flaviviridae, genus Flavivirus, holds many of the world's most prevalent arboviral diseases that are also considered the most important travel related arboviral infections. In most cases, flavivirus diagnosis in travelers is primarily based on serology as viremia is often low and typically has already been reduced to undetectable levels when symptoms set in and patients seek medical attention. Serological differentiation between flaviviruses and the false-positive results caused by vaccination and cross-reactivity among the different species, are problematic for surveillance and diagnostics of flaviviruses. Their partially overlapping geographic distribution and symptoms, combined with increase in travel, and preexisting antibodies due to flavivirus vaccinations, expand the need for rapid and reliable multiplex diagnostic tests to supplement currently used methods. We describe the development of a multiplex serological protein microarray using recombinant NS1 proteins for detection of medically important viruses within the genus Flavivirus. Sera from clinical flavivirus patients were used for primary development of the protein microarray. Results show a high IgG and IgM sensitivity and specificity for individual NS1 antigens, and limited cross reactivity, even within serocomplexes. In addition, the serology based on this array allows for discrimination between infection and vaccination response for JEV vaccine, and no cross-reactivity with TBEV and YFV vaccine induced antibodies when testing for antibodies to other flaviviruses. Based on these data, multiplex NS1-based protein microarray is a promising tool for surveillance and diagnosis of flaviviruses.


West Nile virus-associated encephalitis in recipients of renal and pancreas transplants: case series and literature review.
Although West Nile fever is mild in the vast majority of infected persons, there is growing evidence that the disease may be more severe in the immunocompromised population. We describe 3 recipients of kidney or pancreas transplants who developed West Nile fever, 2 of whom had meningoencephalitis. As is the norm when treating serious infections in transplant recipients, a reduction of immunosuppression was pursued for these patients. Despite the severe nature of the disease in 2 patients, all recovered from the disease. The time course of neurologic recovery in the 2 patients with meningoencephalitis is highlighted. We also review the literature on West Nile fever in organ transplant recipients. In areas where West Nile virus is endemic, one must have a high index of suspicion for the illness when dealing with fever in transplant recipients.


The Mitochondrial Genomes of a Myxozoan Genus Kudoa Are Extremely Divergent in Metazoa.
The Myxozoa are oligo-cellular parasites with alternate hosts--fish and annelid worms--and some myxozoan species harm farmed fish. The phylum Myxozoa, comprising 2,100 species, was difficult to position in the tree of life, due to its fast evolutionary rate. Recent phylogenomic studies utilizing an extensive number of nuclear-encoded genes have confirmed that Myxozoans belong to Cnidaria. Nevertheless, the evolution of parasitism and extreme body simplification in Myxozoa is not well understood, and no myxozoan mitochondrial DNA sequence has been reported to date. To further elucidate the evolution of Myxozoa, we sequenced the mitochondrial genomes of the myxozoan species Kudoa septempunctata, K. hexapunctata and K. iwatai and compared them with those of other metazoans. The Kudoa mitochondrial genomes code for ribosomal RNAs, transfer RNAs, eight proteins for oxidative phosphorylation and three proteins of unknown function, and they are among the metazoan mitochondrial genomes coding the fewest proteins. The mitochondrial-encoded proteins were extremely divergent, exhibiting the fastest evolutionary rate in Metazoa. Nevertheless, the dN/dS ratios of the protein genes in genus Kudoa were approximately 0.1 and similar to other cnidarians, indicating that the genes are under negative selection. Despite the divergent genetic content, active oxidative phosphorylation was indicated by the transcriptome, metabolism and structure of mitochondria in K. septempunctata. As possible causes, we attributed the divergence to the population genetic characteristics shared between the two most divergent clades, Ctenophora and Myxozoa, and to the parasitic lifestyle of Myxozoa. The fast-evolving, functional mitochondria of the genus Kudoa expanded our understanding of metazoan mitochondrial evolution.


Carbon dots as analytical tools for sensing of thioredoxin reductase and screening of cancer cells.
Thioredoxin Reductase (TrxR) is a redox regulating enzyme which is predestined for the maintenance of redox homeostasis of mammalian cells. However, the elevated level of TrxR is associated with the progress of various types of tumors and therefore, this is a significant target for the detection of cancer cells. Herein, an easily engineered 'Turn ON' fluorescent sensor probe has been synthesized for the detection of TrxR and cell imaging using carbon dots. The emission intensity of fCDs on complexation with Cu2+ ions was drastically quenched. Subsequently, the addition of TrxR to the solution of the fCDs-Cu2+ complex leads to the cleavage of the disulfide bond of the fCDs, which acclaim the release of 3-mercaptopropionic acid. 3-Mercaptopropionic acid, being a strong bi-dentate chelating agent for Cu2+ ions, extracted Cu2+ from the coordination sphere of fCDs and restored the original fluorescence intensity of fCDs. Thus, the probe is operating with a simple process of "ON-OFF" emission switching due to Cu2+ and "OFF-ON" switching with TrxR. The probe has been successfully used for real-time application to monitor TrxR activities in the complex biological system. The fluorescence images of MCF-7 and HeLa cells after incubation with the fCDs-Cu2+ complex were recorded under a confocal laser scanning microscope (CLSM) as a function of time. Enhancement in the emission intensity of cancer cells after 2 h of treatment demonstrates the potential application of the sensor probe for the bioimaging of endogenous TrxR in living cells and screening of cancer cells. Such fluorescent probes will open the door for the development of promising clinical devices for the diagnosis of cancer cells.


Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypes.
No data exist on angiogenic patterns and their prognostic impact in human glioblastoma. Such data are relevant for translation of antiangiogenic therapies into clinical applications. Using immunohistochemistry for CD34, we assessed vascular patterns in 114 primary glioblastomas. Vascular patterns comprised unevenly distributed glomeruloid/garland-like/clustered bizarre vascular formations and evenly distributed delicate capillary-like microvessels ("classic" vascular pattern). The combination of low content of bizarre vascular formations and prominent classic vascular pattern (n=29) was an independent factor for longer survival (p=0.006, Cox regression), as well as postoperative high Karnofsky performance status (p=0.005). In patients with a prominent classic vascular pattern, there was no difference of MIB1 labeling index whereas microvessel density and apoptotic index (TUNEL) were significantly higher as compared to all other patients (p<0.05). In addition, diffuse expression of hypoxia-inducible factor (HIF)-1alpha and strong expression of vascular endothelial growth factor were more common (p<0.05, Chi-square test). FISH revealed loss of chromosomes 1p and 19q only in 1/7 long-time survivors with classic pattern. We conclude that vascular patterns in primary glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins. Our findings denote for the first time distinct angiogenic subtypes of human glioblastoma which may prove relevant for anti-angiogenic therapy approaches.


Prognostic value of gated SPECT in patients with left bundle branch block.
The aim of this study was to assess the prognostic value of quantitative gated technetium 99m tetrofosmin single photon emission computed tomography (SPECT) imaging in patients with left bundle branch block (LBBB). We followed up 101 consecutive patients with LBBB using Tc-99m tetrofosmin gated SPECT imaging. The mean follow-up was 1.24 years (maximum, 2.48 years). Hard endpoints were all-cause death and acute myocardial infarction. Event-free survival curves were obtained. Optimal cutoff points for left ventricular (LV) volumes and LV ejection fraction (EF) to predict outcome were determined by receiver operating characteristic curve analysis. Of the patients, 94 had an abnormal study. Fifteen hard events occurred (thirteen deaths). Perfusion abnormalities were similar for patients with or without events. For LV function parameters, the survival curves were maximally separated when we used cutoff values of 160 mL or greater for end-diastolic volume (P = .019 and hazard ratio [HR] of 1.04 for hard events, P = .024 and HR of 1.04 for all-cause death), 100 mL or greater for end-systolic volume (P = .043 and HR of 1.04 for hard events, P = .062 and HR of 1.04 for all-cause death), and lower than 35% for LVEF (P = .013 and HR of 0.81 for hard events, P = .047 and HR of 0.81 for all-cause death). By use of quantitative gated SPECT imaging, LBBB patients with an end-diastolic volume of 160 mL or greater, end-systolic volume of 100 mL or greater, or LVEF lower than 35% are at increased risk for subsequent cardiac events.


The role of cost-consequence analysis in healthcare decision-making.
A greater understanding of value associated with new pharmaceutical products should lead to better decision-making. Most commonly cost-effectiveness ratios (CERs) are used to indicate value; however, researchers have recently shown that CER estimates are rarely used by decision-makers in making formulary decisions. In this article, a cost-consequence approach to estimating the value for money of a new treatment for a specific disease is described. Using a cost-consequence approach, the impact of the new treatment on lifetime resource use and costs (including specific healthcare service use and costs, and productivity losses) and health outcomes (including disease symptoms, life expectancy and quality of life) for an individual or group of individuals is estimated and presented in a tabular format. The cost-consequence format is more likely to be approachable, readily understandable and applied by healthcare decision-makers than a simple CER. The decision-maker may use selected items from the cost-consequence analysis to compute composite measures of drug value, such as cost per life-year gained or cost per quality-adjusted life-year (QALY) gained. In general, the cost-consequence approach, by making the impact of the new treatment as comprehensive and transparent as possible, will enable decision-makers to select the components most relevant to their perspective and will also give them confidence that the data are credible to use as the basis for resource allocation decisions.


The effect of community-based health management on the health of the elderly: a randomized controlled trial from China.
An aging population poses significant challenges to health care in China. Health management has been implemented to reduce the costs of care, raise health service utilization, increase health knowledge and improve quality of life. Several studies have tried to verify the effectiveness of health management in achieving these goals worldwide. However, there have been insufficient randomized control trials (RCTs) to draw reliable conclusions. The few small-scale studies conducted in China include mostly the general population rather than the elderly. Our study is designed to evaluate the impact of community-based health management on the health of the elderly through an RCT in Nanjing, China. Two thousand four hundred participants, aged 60 or older and who gave informed consent, were randomly allocated 1:1 into management and control groups, the randomization schedule was concealed from community health service center staff until allocation. Community-based health management was applied in the former while the latter was only given usual care. After 18 months, three categories of variables (subjective grading health indices, objective health indices and health service utilization) were measured based on a questionnaire, clinical monitoring and diagnostic measurements. Differences between the two groups were assessed before and after the intervention and analyzed with t-test, χ2-test, and multiple regression analysis. Compared with the control group, the management group demonstrated improvement on the following variables (P<0.01): health knowledge score, self-evaluated psychological conditions, overall self-evaluated health conditions, diet score, physical activity duration per week, regular blood pressure monitoring, waist-to-hip ratio, systolic blood pressure and fasting blood sugar. The number of outpatient clinic visits did not differ significantly (P=0.60) between the two groups before intervention, while after intervention it was smaller in the management group than in the control group (P<0.01). However, the number of hospital admissions in the preceding 6 months was not different between the two groups even after intervention (P=0.36). Multiple regression analysis showed that gender, age, education level, chronic disease status and self-evaluated psychological conditions were important factors affecting health knowledge score, BMI, and waist-to-hip ratio. Community-based health management improved both subjective grading health indices, objective health indices and decreased the number of outpatient clinic visits, demonstrating effectiveness in improving elderly health. ChiCTR-OCH-11001716.


Evidence for the Rare Decay Σ^{+}→pμ^{+}μ^{-}.
A search for the rare decay Σ^{+}→pμ^{+}μ^{-} is performed using pp collision data recorded by the LHCb experiment at center-of-mass energies sqrt[s]=7 and 8 TeV, corresponding to an integrated luminosity of 3 fb^{-1}. An excess of events is observed with respect to the background expectation, with a signal significance of 4.1 standard deviations. No significant structure is observed in the dimuon invariant mass distribution, in contrast with a previous result from the HyperCP experiment. The measured Σ^{+}→pμ^{+}μ^{-} branching fraction is (2.2_{-1.3}^{+1.8})×10^{-8}, where statistical and systematic uncertainties are included, which is consistent with the standard model prediction.


BASILIScan: a tool for high-throughput analysis of intrinsic disorder patterns in homologous proteins.
Intrinsic structural disorder is a common property of many proteins, especially in eukaryotic and virus proteomes. The tendency of some proteins or protein regions to exist in a disordered state usually precludes their structural characterisation and renders them especially difficult for experimental handling after recombinant expression. A new intuitive, publicly-available computational resource, called BASILIScan, is presented here. It provides a BLAST-based search for close homologues of the protein of interest, integrated with a simultaneous prediction of intrinsic disorder together with a robust data viewer and interpreter. This allows for a quick, high-throughput screening, scoring and selection of closely-related yet highly structured homologues of the protein of interest. Comparative parallel analysis of the conservation of extended regions of disorder in multiple sequences is also offered. The use of BASILIScan and its capacity for yielding biologically applicable predictions is demonstrated. Using a high-throughput BASILIScan screen it is also shown that a large proportion of the human proteome displays homologous sequences of superior intrinsic structural order in many related species. Through the swift identification of intrinsically stable homologues and poorly conserved disordered regions by the BASILIScan software, the chances of successful recombinant protein expression and compatibility with downstream applications such as crystallisation can be greatly increased.


Assessing the potential for sea-based macroalgae cultivation and its application for nutrient removal in the Baltic Sea.
Marine eutrophication is a pervasive and growing threat to global sustainability. Macroalgal cultivation is a promising circular economy solution to achieve nutrient reduction and food security. However, the location of production hotspots is not well known. In this paper the production potential of macroalgae of high commercial value was predicted across the Baltic Sea region. In addition, the nutrient limitation within and adjacent to macroalgal farms was investigated to suggest optimal site-specific configuration of farms. The production potential of Saccharina latissima was largely driven by salinity and the highest production yields are expected in the westernmost Baltic Sea areas where salinity is >23. The direct and interactive effects of light availability, temperature, salinity and nutrient concentrations regulated the predicted changes in the production of Ulva intestinalis and Fucus vesiculosus. The western and southern Baltic Sea exhibited the highest farming potential for these species, with promising areas also in the eastern Baltic Sea. Macroalgal farming did not induce significant nutrient limitation. The expected spatial propagation of nutrient limitation caused by macroalgal farming was less than 100-250 m. Higher propagation distances were found in areas of low nutrient and low water exchange (e.g. offshore areas in the Baltic Proper) and smaller distances in areas of high nutrient and high water exchange (e.g. western Baltic Sea and Gulf of Riga). The generated maps provide the most sought-after input to support blue growth initiatives that foster the sustainable development of macroalgal cultivation and reduction of in situ nutrient loads in the Baltic Sea.


Genetic variation in nicotine metabolism predicts the efficacy of extended-duration transdermal nicotine therapy.
In a placebo-controlled trial, we examined the efficacy of a 6-month ("extended") transdermal nicotine therapy vs. the 8-week ("standard") therapy in 471 Caucasian smokers with either normal or reduced rates of nicotine metabolism as determined at pretreatment. Extended therapy was superior to standard therapy in genotypic or phenotypic reduced metabolizers (RMs) of nicotine but not in normal metabolizers (NMs). RMs of nicotine are candidates for extended transdermal nicotine therapy, whereas an alternative therapeutic approach may be needed for those with normal rates of nicotine metabolism.


Epidemiology of lacrosse injuries in high school-aged girls and boys: a 3-year prospective study.
To report the types, mechanisms, and circumstances of lacrosse injuries incurred by high school-aged girls and boys during organized interscholastic and summer camp games. Descriptive epidemiology study. For 3 years, the authors gathered data on girls' and boys' lacrosse injuries for 359 040 high school and 28 318 summer camp athletic exposures using a lacrosse-specific computerized injury surveillance system. The most prevalent injuries were organized into multifactorial injury scenarios. In high school play, the injury rate for adolescent boys (2.89 per 1000 athletic exposures) was slightly higher than that for girls (2.54 per 1000 athletic exposures) (incidence rate ratio = 1.14; 95% confidence interval, 1.00-1.30). The most prevalent injuries for adolescent girls and boys were knee and ankle sprains resulting from noncontact mechanisms. Male players had significantly higher rates of shoulder, neck, trunk, and back injuries and higher game-to-practice injury ratios. In addition, they had higher rates of concussive events from player-to-player contact. Female players had higher rates of overall head injuries, many involving contusions and abrasions from stick and ball contact. The overall injury rates for boys' and girls' high school lacrosse were significantly lower than those for collegiate play. Significant differences existed between adolescent boys and girls with respect to injury mechanisms, body parts injured, and player and team activity at the time of injury.


Relationships between the front crawl stroke parameters of competitive unilateral arm amputee swimmers, with selected anthropometric characteristics.
The purpose of this study was to determine the relationships between swimming speed (SS), stroke length (SL), and stroke frequency (SF) for competitive single-arm amputee front crawl swimmers and assess their relationships with anthropometric characteristics. Thirteen highly trained swimmers (3 male, 10 female) were filmed underwater from a lateral view during seven increasingly faster 25-m front crawl trials. Increases in SS (above 75% of maximum SS) were achieved by a 5% increase in SF, which coincided with a 2% decrease in SL. At SSmax, interswimmer correlations showed that SF was significantly related to SS (r = .72; p < .01) whereas SL was not. Moderate but nonsignificant correlations suggested that faster swimmers did not necessarily use longer and slower strokes to swim at a common submaximal speed when compared with their slower counterparts. No correlations existed between SL and any anthropometric characteristics. Biacromial breadth, shoulder girth, and upper-arm length all significantly correlated with the SF used at SSmax. These findings imply that as a consequence of being deprived of an important propelling limb, at fast swimming speeds SF is more important than SL in influencing the performance outcome of these single-arm amputee swimmers.


Postcoital finesse.
Mating changes female reproductive behavior in profound ways. In Drosophila, the trigger for this behavioral switch is a small peptide called sex peptide (SP), which is transferred with the male seminal fluid during insemination. Two papers in this issue of Neuron (Häsemayer et al. and Yang et al.) show that SP inhibits a small set of internal sensory neurons in the female genital tract. These neurons project to the CNS to control the female's reproductive behavior.


Physiological niche and geographical range in European diving beetles (Coleoptera: Dytiscidae).
Geographical ranges vary greatly in size and position, even within recent clades, but the factors driving this remain poorly understood. In aquatic beetles, thermal niche has been shown to be related to both the relative range size and position of congeners but whether other physiological parameters play a role is unknown. Metabolic plasticity may be critical for species occupying more variable thermal environments and maintaining this plasticity may trade-off against other physiological processes such as immunocompetence. Here we combine data on thermal physiology with measures of metabolic plasticity and immunocompetence to explore these relationships in Deronectes (Dytiscidae). While variation in latitudinal range extent and position was explained in part by thermal physiology, aspects of metabolic plasticity and immunocompetence also appeared important. Northerly distributed, wide-ranging species apparently used different energy reserves under thermal stress from southern endemic congeners and differed in their antibacterial defences. This is the first indication that these processes may be related to geographical range, and suggests parameters that may be worthy of exploration in other taxa.


Emergence of alcohol expectancies in childhood: a possible critical period.
Previous investigations with adolescents (aged 12-19) have shown alcohol-related expectancies to develop in childhood prior to significant drinking experience and to covary directly with drinking behavior. To chart the development of alcohol expectancies in children as young as age 6, a procedure was developed to be as independent as possible of age-related variation in reading and language development. This instrument was administered to 114 elementary school children of both genders, distributed across grades 1 to 5. Psychometric analysis provided evidence of the test's reliability and validity. Evaluation of the developmental pattern produced two primary findings: (1) there was an overall trend of increasingly positive expectancies with age; and (2) strikingly, the bulk of the increase was observed in the third and fourth grades. Children's expectancies may be less differentiated than adolescent or adult expectancies. These findings suggest that the precursors for later alcohol use and abuse are formed in childhood and that prevention efforts may need to begin as early as third grade.


Age and health-related quality of life, general self-efficacy, and functional level 12 months following dysvascular major lower limb amputation: a prospective longitudinal study.
Aim: This study investigates the effect of time and age on health-related quality of life, general self-efficacy, and functional level 12 months following dysvascular major lower limb amputation (LLA).Methods: A prospective cohort study design with assessments at baseline and follow-up 3, 6, and 12 months post-amputation. Data were collected via in-person interviews using Short Form 36, the General Self-efficacy scale and Barthel Index 100. Out of a consecutive sample of 103 patients having dysvascular major LLA (tibia, knee, or femoral), 38 patients completed the study. Outcome at follow-up was compared with baseline and analyzed in age groups.Results: All SF36 subscale scores were below population norms at baseline. At 12 months, two out of eight scores-physical function and role-physical-had not improved. Different patterns of change over the 12 months were detected among the subscales, and psychosocial problems persisted and fluctuated throughout the 12 months in all age groups. Large differences were identified between age groups in physical function with the loss of physical function almost solely evident among the oldest (aged 75+ years) patients.Conclusions: Special attention should be given to the oldest patients need for rehabilitation so that they gain higher quality of life.Implications for rehabilitationPsychosocial problems persist and fluctuate throughout the first 12 months after major LLAs in all age groups and rehabilitation services should include psychosocial support throughout the first year to all patients independent of age.Waiting for an unnecessarily long period of time for a prosthesis can negatively impact both physical and psychosocial aspects of health-related QOL, and interventions to reduce waiting time are warranted.Differences between age groups in functional level after 12 months exist, with the loss of function almost solely evident among the oldest patients (aged 75+ years). A special focus should be given to the oldest patients' need of everyday rehabilitation to regain basic physical functions.


Pros and cons of using biomarkers versus clinical decisions in start and stop decisions for antibiotics in the critical care setting.
Patients in the intensive care unit (ICU) frequently receive prolonged or even unnecessary antibiotic therapy, which selects for antibiotic-resistant bacteria. Over the last decade there has been great interest in biomarkers, particularly procalcitonin, to reduce antibiotic exposure. In this narrative review, we discuss the value of biomarkers and provide additional information beyond clinical evaluation in order to be clinically useful and review the literature on sepsis biomarkers outside the neonatal period. Both benefits and limitations of biomarkers for clinical decision-making are reviewed. Several randomized controlled trials (RCTs) have shown the safety and efficacy of procalcitonin to discontinue antibiotic therapy in patients with severe sepsis or septic shock. In contrast, there is limited utility of procalcitonin for treatment initiation or withholding therapy initially. In addition, an algorithm using procalcitonin for treatment escalation has been ineffective and is probably associated with poorer outcomes. Little data from interventional studies are available for other biomarkers for antibiotic stewardship, except for C-reactive protein (CRP), which was recently found to be similarly effective and safe as procalcitonin in a randomized controlled trial. We finally briefly discuss biomarker-unrelated approaches to reduce antibiotic duration in the ICU, which have shown that even without biomarker guidance, most patients with sepsis can be treated with relatively short antibiotic courses of approximately 7 days. In summary, there is an ongoing unmet need for biomarkers which can reliably and early on identify patients who require antibiotic therapy, distinguish between responders and non-responders and help to optimize antibiotic treatment decisions among critically ill patients. Available evidence needs to be better incorporated in clinical decision-making.


Strain variation and geographic endemism in Streptococcus iniae.
Twenty-six Israeli isolates of Streptococcus iniae from both marine and fresh/brackish water sources were compared with each other and with 9 foreign isolates. All the isolates were tentatively identified according to their biochemical profile. Direct sequencing of approximately 600 bp PCR products of the 16S rDNA confirmed their identification as S. iniae at the molecular level and revealed a new (one-nucleotide) variant among Israeli isolates, in addition to 2 variants that had been previously reported. Strain variation was further examined by subjecting the isolates to randomly amplified polymorphic DNA (RAPD) and amplified fragment length polymorphism (AFLP) analyses. The RAPD method allowed separation of the isolates into only 2 groups, one including 5 Israeli fresh/brackish water isolates and one including all the other isolates. The AFLP method grouped the Israeli marine isolates into one homogeneous cluster, although they had been obtained in different years (1995 to 2001) from different species of fish, and from wild (Red Sea) as well as cultured (both Mediterranean and Red Sea) sources. The Israeli fresh/brackish water isolates and foreign isolates separated into distinct entities that clustered at generally high degrees of similarity. The distance between the clusters of the Israeli marine and fresh/brackish water isolates indicates that the S. iniae streptococcosis that has been afflicting the aquaculture industries in the 2 environments in recent years was caused by distinct strains. AFLP showed superior discriminative properties over RAPD in detecting intraspecific variation and proved to be an important tool for the characterization of S. iniae. A correlation between strain variation and geographic endemism was established.


Hypergraph-based anomaly detection of high-dimensional co-occurrences.
This paper addresses the problem of detecting anomalous multivariate co-occurrences using a limited number of unlabeled training observations. A novel method based on using a hypergraph representation of the data is proposed to deal with this very high-dimensional problem. Hypergraphs constitute an important extension of graphs which allow edges to connect more than two vertices simultaneously. A variational Expectation-Maximization algorithm for detecting anomalies directly on the hypergraph domain without any feature selection or dimensionality reduction is presented. The resulting estimate can be used to calculate a measure of anomalousness based on the False Discovery Rate. The algorithm has O(np) computational complexity, where n is the number of training observations and p is the number of potential participants in each co-occurrence event. This efficiency makes the method ideally suited for very high-dimensional settings, and requires no tuning, bandwidth or regularization parameters. The proposed approach is validated on both high-dimensional synthetic data and the Enron email database, where p > 75,000, and it is shown that it can outperform other state-of-the-art methods.


Effect of gold subsurface layer on the surface activity and segregation in Pt/Au/Pt3M (where M = 3d transition metals) alloy catalyst from first-principles.
The effect of a subsurface hetero layer (thin gold) on the activity and stability of Pt skin surface in Pt3M system (M = 3d transition metals) is investigated using the spin-polarized density functional theory calculation. First, we find that the heterometallic interaction between the Pt skin surface and the gold subsurface in Pt/Au/Pt3M system can significantly modify the electronic structure of the Pt skin surface. In particular, the local density of states projected onto the d states of Pt skin surface near the Fermi level is drastically decreased compared to the Pt/Pt/Pt3M case, leading to the reduction of the oxygen binding strength of the Pt skin surface. This modification is related to the increase of surface charge polarization of outmost Pt skin atoms by the electron transfer from the gold subsurface atoms. Furthermore, a subsurface gold layer is found to cast the energetic barrier to the segregation loss of metal atoms from the bulk (inside) region, which can enhance the durability of Pt3M based catalytic system in oxygen reduction condition at fuel cell devices. This study highlights that a gold subsurface hetero layer can provide an additional mean to tune the surface activity toward oxygen species and in turn the oxygen reduction reaction, where the utilization of geometric strain already reaches its practical limit.


Adipose-Derived Stem Cells Accelerate Diabetic Wound Healing Through the Induction of Autocrine and Paracrine Effects.
Cell-based therapy is an attractive approach for the treatment of chronic nonhealing wounds. This study investigated whether adipose-derived stem cells (ASCs) can accelerate diabetic wound healing and traffic in the engraftment of ASCs. Dorsal full-thickness skin wound defects (6 × 5 cm) were created in a streptozotocin (STZ)-induced diabetes rodent model. Group I served as a nondiabetic normal control, group II served as a diabetic control without ASCs, and group III included rats that were injected subcutaneously in the wound margin twice with nondiabetic ASCs (1 × 10(7) ASCs/dose). The wound healing was assessed clinically. Histological examination and immunohistochemical analyses of periwound tissue were performed. Green fluorescence protein (GFP)(+)-ASCs were used to examine the engraftment of these cells after injection. XenoLight DiR-labeled ASCs were implanted to detect migration ability using an IVIS imaging system. Results revealed that complete wound healing time statistically decreased in the ASC-treated group compared to the controls (p < 0.001). Histological examination revealed the ASC-treated group showed a significant reduction in the proinflammatory reaction, with significantly increased levels of EGF, VEGF, rPH, and Ki-67 expression compared to the controls. The populations of GFP(+)-ASCs in circulating blood significantly increased after ASC injection compared to those of controls. Immunofluorescence staining showed GFP(+)-ASCs significantly accumulated in the subdermal layer of the wound margin and increased angiogenesis via vWF and VEGF expression after injection. IVIS analysis revealed ASCs could exist and home into the periwound area up to 8 weeks postimplantation. In conclusion, ASCs significantly enhanced diabetic wound healing, engrafted into the local wound tissue, and implanted into circulating blood. ASC treatment stimulated neoangiogenesis and increased tissue regeneration through paracrine and autocrine mechanisms.


Follow-up study after intracranial percutaneous transluminal cerebral balloon angioplasty.
Our objective was to find the specific angiographic characteristics of atherosclerotic lesions that indicate suitability for intracranial percutaneous transluminal cerebral balloon angioplasty (PTCBA). Forty-two clinically symptomatic patients with 42 hemodynamically significant intracranial lesions (>70% stenosis) were treated by PTCBA between January 1992 and May 1996. Before treatment, the patients were assigned to three groups according to the angiographic characteristics of the lesions, as follows: type A, short (5 mm or less in length) concentric or moderately eccentric lesions less than totally occlusive; type B, tubular (5 to 10 mm in length), extremely eccentric or totally occluded lesions, less than 3 months old; and type C, diffuse (more than 10 mm in length), extremely angulated (>90 degrees) lesions with excessive tortuosity of the proximal segment, or totally occluded lesions, and 3 months old or older. The patients were followed up for a period of 1 month to 6 years to compare the results of PTCBA treatment among the three groups. Primary end points were death, stroke, or bypass surgery. The clinical success rates for the type A, B, and C groups were 92%, 86%, and 33%, respectively. Cumulative risks of fatal or nonfatal ischemic stroke or ipsilateral bypass surgery in type A, B, and C groups were 8%, 26%, and 87%, respectively. The cumulative risk of 8% among patients in the type A group appeared to be smaller than in studies reported in the literature. PTCBA for intracranial simple (type A) lesions yields a favorable clinical outcome for symptomatic patients.


Clinical factors associated with rape victims' ability to testify in court: a records-based study of final psychiatric recommendation to court.
A rape victim may encounter professionals in both the health and the legal systems. Unanswered questions remain about clinical factors associated with a rape victim's ability to testify in court, and the quality of care offered to rape victims. The objectives of this study were thus to determine the clinical factors that are associated with a rape victim's ability to testify in court, as well as to undertake a preliminary exploration of the referral system between the court and the mental health services. A retrospective study was conducted of rape victims referred by the court (n=70) to be assessed psycho-legally by psychiatrists. Rape victims who were recommended as able and those recommended as unable to testify in court were compared with regard to their clinical characteristics. Thirty-seven (53.6%) victims were recommended as able to testify and 32 (46.4%) victims as unable to testify in court. Victims from rural areas and victims with severe mental retardation were statistically significantly more often found to be unable to testify in court. Almost half (49.2%) of the victims were referred by court for first assessment within six months of being raped. Most (63.5%) victims were assessed for the first time within one month of being referred. The decision about a victim's ability to testify should not be based solely on the two statistically significant variables but, rather, individualised. Optimal mental health and legal services should be offered to rape victims. Further studies are required in assessing the collaboration between the health and legal systems.


Spatial clustering by disease severity among reported Rocky Mountain spotted fever cases in the United States, 2001-2005.
Rocky Mountain spotted fever (RMSF) occurs throughout much of the United States, ranging in clinical severity from moderate to fatal infection. Yet, little is known about possible differences among severity levels across geographic locations. To identify significant spatial clusters of severe and non-severe disease, RMSF cases reported to Centers for Disease Control and Prevention (CDC) were geocoded by county and classified by severity level. The statistical software program SaTScan was used to detect significant spatial clusters. Of 4,533 RMSF cases reported, 1,089 hospitalizations (168 with complications) and 23 deaths occurred. Significant clusters of 6 deaths (P = 0.05, RR = 11.4) and 19 hospitalizations with complications (P = 0.02, RR = 3.45) were detected in southwestern Tennessee. Two geographic areas were identified in north-central North Carolina with unusually low rates of severity (P = 0.001, RR = 0.62 and P = 0.001, RR = 0.45, respectively). Of all hospitalizations, 20% were clustered in central Oklahoma (P = 0.02, RR = 1.43). Significant geographic differences in severity were observed, suggesting that biologic and/or anthropogenic factors may be impacting RMSF epidemiology in the United States.


The ACTTION-APS-AAPM Pain Taxonomy (AAAPT) Multidimensional Approach to Classifying Acute Pain Conditions.
With the increasing societal awareness of the prevalence and impact of acute pain, there is a need to develop an acute pain classification system that both reflects contemporary mechanistic insights and helps guide future research and treatment. Existing classifications of acute pain conditions are limiting, with a predominant focus on the sensory experience (eg, pain intensity) and pharmacologic consumption. Consequently, there is a need to more broadly characterize and classify the multidimensional experience of acute pain. Consensus report following expert panel involving the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), American Pain Society (APS), and American Academy of Pain Medicine (AAPM). As a complement to a taxonomy recently developed for chronic pain, the ACTTION public-private partnership with the US Food and Drug Administration, the APS, and the AAPM convened a consensus meeting of experts to develop an acute pain taxonomy using prevailing evidence. Key issues pertaining to the distinct nature of acute pain are presented followed by the agreed-upon taxonomy. The ACTTION-APS-AAPM Acute Pain Taxonomy will include the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Future efforts will consist of working groups utilizing this taxonomy to develop diagnostic criteria for a comprehensive set of acute pain conditions. The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) is a multidimensional acute pain classification system designed to classify acute pain along the following dimensions: 1) core criteria, 2) common features, 3) modulating factors, 4) impact/functional consequences, and 5) putative pathophysiologic pain mechanisms. Significant numbers of patients still suffer from significant acute pain, despite the advent of modern multimodal analgesic strategies. Mismanaged acute pain has a broad societal impact as significant numbers of patients may progress to suffer from chronic pain. An acute pain taxonomy provides a much-needed standardization of clinical diagnostic criteria, which benefits clinical care, research, education, and public policy. For the purposes of the present taxonomy, acute pain is considered to last up to seven days, with prolongation to 30 days being common. The current understanding of acute pain mechanisms poorly differentiates between acute and chronic pain and is often insufficient to distinguish among many types of acute pain conditions. Given the usefulness of the AAPT multidimensional framework, the AAAPT undertook a similar approach to organizing various acute pain conditions.


Resveratrol attenuates high-fat diet-induced disruption of the blood-brain barrier and protects brain neurons from apoptotic insults.
The blood-brain barrier (BBB) maintains brain microenvironment. Our previous study showed that oxidized low-density lipoprotein (oxLDL) can damage the BBB by inducing apoptosis of cerebrovascular endothelial cells. This study was aimed at evaluating the effects of resveratrol on high-fat diet-induced insults to the BBB and brain neurons. Exposure of mice to a high-fat diet for 8 weeks increased levels of serum total cholesterol (146 ± 13) and LDL (68 ± 8), but resveratrol decreased such augmentations (119 ± 6; 45 ± 8). Permeability assays showed that a high-fat diet induced breakage of the BBB (88 ± 21). Meanwhile, resveratrol alleviated this interruption (16 ± 6). Neither resveratrol nor a high-fat diet caused the death of cerebrovascular endothelial cells. Instead, exposure to a high-fat diet disrupted the polymerization of occludin and zonula occludens (ZO)-1, but resveratrol significantly attenuated those injuries. Neither a high-fat diet nor resveratrol changed the levels of occludin or ZO-1 in brain tissues. Resveratrol protected brain neurons against high-fat diet-induced caspase-3 activation and genomic DNA fragmentation. This study shows that resveratrol can attenuate the high-fat diet-induced disruption of the BBB via interfering with occludin and ZO-1 tight junctions, and protects against apoptotic insults to brain neurons.


EMG activity of upper limb on spinal cord injury individuals during whole-body vibration.
Whole-body vibration (WBV) has shown positive results increasing electromyographic (EMG) activity and strength in a healthy population when applied to upper and lower limbs. The aim of this study was to verify if WBV increases the EMG signal of the upper limb muscles in patients with spinal cord injury (SCI). For this study, 15 patients with SCI were selected and one single session of WBV was applied to the upper limb. Five sessions of 30 s at 30 Hz were applied and EMG of anterior deltoid and forearm muscles was measured. The results show that EMG activity had a significant increase during WBV session compared with baseline muscle activity. These results support WBV as an efficient tool to increase the upper body EMG in individuals with SCI.


The subthalamic nucleus modulates the early phase of probabilistic classification learning.
Previous models proposed that the subthalamic nucleus (STN) is critical in the early phase of skill acquisition. We hypothesized that subthalamic deep brain stimulation modulates the learning curve in early classification learning. Thirteen idiopathic Parkinson's disease patients (iPD) with subthalamic deep brain stimulation (STN-DBS), 9 medically treated iPD, and 21 age-matched healthy controls were tested with a probabilistic classification task. STN-DBS patients were tested with stimulation OFF and ON, and medically treated patients with medication OFF and ON, respectively. Performance and reaction time were analyzed on the first 100 consecutive trials as early learning phase. Moreover, data were separated for low and high-probability patterns, and more differentiated strategy analyses were used. The major finding was a significant modulation of the learning curve in DBS patients with stimulation ON: although overall learning was similar to healthy controls, only the stimulation ON group showed a transient significant performance dip from trials '41-60' that rapidly recovered. Further analysis indicated that this might be paralleled by a modulation of the learning strategy, particularly on the high-probability patterns. The reaction time was unchanged during the dip. Our study supports that the STN serves as a relay in early classification learning and directs attention toward unacquainted content. The STN might play a role in balancing the short-term success against strategy optimization for improved long-term outcome.