Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition.
Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs. The ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process. Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as "strongly agree" or "somewhat agree" (68-88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications. A provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment.


First Report of Sclerotinia Stem and Twig Blight Caused by Sclerotinia sclerotiorum on Citrus volkameriana Rootstock in Italy.
Volkamer lemon (Citrus volkameriana Ten. & Pasq., Rutaceae family) is the most commonly used rootstock for some ornamental citrus (oval kumquat and calamondin), improving the aesthetic quality of the plants and their marketable value. During the winter of 2011, symptoms of stem blight were observed on approximately 10% of 12,000 1-year-old potted C. volkameriana seedlings grown in different blocks in a commercial nursery near Catania (eastern Sicily, Italy). In the same nursery, only 1% of 15,000 older seedlings (2-year-old) showed disease symptoms. Initial symptoms included gray lesions on stems and occasionally on twigs. Later, buff lesions and gum exude appeared. Symptomatic stems and twigs were usually girdled and killed. In the lesions, irregular, dark gray sclerotia (1.0 to 5 × 1.0 to 7.0 mm, average 2.5 × 3.9 mm) were produced. In high relative humidity, cottony, white mycelia on the bark surface of infected tissues were also observed. Isolations were performed by transferring approximately 300 fragments of symptomatic tissues from 15 C volkameriana seedlings, surface-sterilized with 1% NaClO for 1 min, on potato dextrose agar (PDA) amended with 100 mg/liter of streptomycin sulfate. Sclerotinia sclerotiorum (Lib.) de Bary was recovered from all infected plants. Colony type, morphology, and dimensions of sclerotia were examined on PDA at 22 ± 1°C after 10 days in the dark. Sclerotia produced on PDA measured 2.0 to 7.0 × 1.5 to 4.0 mm (average 5.6 × 2.6 mm). DNA isolation was performed with the DNA Purification Kit (Puragene-Gentra, Minneapolis, MN) following the manufacturer's instructions. Amplification and sequencing of the internal transcribed spacer (ITS) region of rDNA was performed with primers ITS1/ITS4 (2). BLAST analysis of the 550-bp segment showed a 98% homology with S. sclerotiorum strain ms85 (GenBank Accession No HQ833450.1), thus confirming identification based on morphology. Koch's postulates were fulfilled by pathogenicity tests carried out on 20 1-year-old potted C. volkameriana seedlings. Each seedling was inoculated with five mycelial agar plugs (6 mm in diameter) and five sclerotia from the edge of 10-day-old colonies on PDA and placed in wounds made with a sterile blade in the bark of stem and twigs. Inoculated wounds (10 for each plant) were wrapped with Parafilm. The same number of control plants were wounded and inoculated with sterile PDA plugs. All inoculated plants were incubated in a growth chamber at 22°C with 80 to 90% relative humidity for 14 days. Blight symptoms and lesions on the stem and twigs identical to those observed in the nursery developed on all plants with both types of inoculum. Noninoculated control plants remained symptomless. S. sclerotiorum was reisolated from all symptomatic tissues and identified by morphology as previously described, completing Koch's postulates. To our knowledge, this is the first report of S. sclerotiorum stem and twig blight on C. volkameriana. Worldwide, Sclerotinia stem and twig blight is considered a minor disease on citrus (1), but this evidence suggests that in eastern Sicily, S. sclerotiorum may be an important pathogen of young C. volkameriana seedlings in nurseries. References: (1) J. A. Menge. Page 35 in: Compendium of Citrus Diseases. 2nd ed. The American Phytopathological Society, St. Paul, MN, 2000. (2) T. J.White et al. Page 315in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, 1990.


Identifying candidate sites for crop biofortification in Latin America: case studies in Colombia, Nicaragua and Bolivia.
Agricultural science can address a population's vitamin, amino acid and mineral malnutrition through biofortification - agronomy, plant breeding and biotechnology to develop crops with high nutrient contents. Biofortified crop varieties should be grown in areas with populations at risk of nutrient deficiency and in areas where the same crop is already grown and consumed. Information on the population at risk of nutrient deficiency is rarely available for sub-national administrative units, such as provinces, districts, and municipalities. Nor is this type of information commonly analyzed with data on agricultural production. This project developed a method to identify populations at risk of nutrient deficiency in zones with high crop production, places where biofortification interventions could be targeted. Nutrient deficiency risk data were combined with crop production and socioeconomic data to assess the suitability of establishing an intervention. Our analysis developed maps of candidate sites for biofortification interventions for nine countries in Latin America and the Caribbean. Results for Colombia, Nicaragua, and Bolivia are presented in this paper. Interventions in northern Colombia appear promising for all crops, while sites for bean biofortification are widely scattered throughout the country. The most promising sites in Nicaragua are found in the center-north region. Candidate sites for biofortification in Bolivia are found in the central part of the country, in the Andes Mountains. The availability and resolution of data limits the analysis. Some areas show opportunities for biofortification of several crops, taking advantage of their spatial coincidence. Results from this analysis should be confirmed by experts or through field visits. This study demonstrates a method for identifying candidate sites for biofortification interventions. The method evaluates populations at risk of nutrient deficiencies for sub-national administrative regions, and provides a reasonable alternative to more costly, information-intensive approaches.


Report of the Canadian Cardiovascular Society's consensus conference on the Management of the Postmyocardial Infarction Patient.
In October 1989, the Canadian Cardiovascular Society announced a program to achieve consensus on important issues in the care of patients with cardiovascular disease. This report on the management of the postmyocardial infarction patient represents the first in a series of these consensus conferences. The process for establishing consensus recommendations involved several steps. A primary panel of 11 experts from various fields was selected to review the available clinical evidence and to make a list of recommendations about management decisions in the postmyocardial infarction period. The initial report was distributed to a secondary panel of 16 reviewers* representing allied health care constituencies from across Canada. On the basis of the critical reviews and feedback from these reviewers, a revised report was distributed to all members (over 800) of the Canadian Cardiovascular Society for further review and feedback. This iterative approach resulted in a penultimate report that was presented at a plenary session of the annual scientific meeting of the Canadian Cardiovascular Society on Oct. 18, 1990, in Halifax, NS. On the basis of discussion and feedback from this symposium, the consensus review was completed.


Surviving sepsis campaign: research priorities for sepsis and septic shock.
To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic-based discussion. The entire committee iteratively developed the entire document and recommendations. Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction? While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock.


An efficient record linkage scheme using graphical analysis for identifier error detection.
Integration of information on individuals (record linkage) is a key problem in healthcare delivery, epidemiology, and "business intelligence" applications. It is now common to be required to link very large numbers of records, often containing various combinations of theoretically unique identifiers, such as NHS numbers, which are both incomplete and error-prone. We describe a two-step record linkage algorithm in which identifiers with high cardinality are identified or generated, and used to perform an initial exact match based linkage. Subsequently, the resulting clusters are studied and, if appropriate, partitioned using a graph based algorithm detecting erroneous identifiers. The system was used to cluster over 250 million health records from five data sources within a large UK hospital group. Linkage, which was completed in about 30 minutes, yielded 3.6 million clusters of which about 99.8% contain, with high likelihood, records from one patient. Although computationally efficient, the algorithm's requirement for exact matching of at least one identifier of each record to another for cluster formation may be a limitation in some databases containing records of low identifier quality. The technique described offers a simple, fast and highly efficient two-step method for large scale initial linkage for records commonly found in the UK's National Health Service.


Expectations for methodology and translation of animal research: a survey of health care workers.
Health care workers (HCW) often perform, promote, and advocate use of public funds for animal research (AR); therefore, an awareness of the empirical costs and benefits of animal research is an important issue for HCW. We aim to determine what health-care-workers consider should be acceptable standards of AR methodology and translation rate to humans. After development and validation, an e-mail survey was sent to all pediatricians and pediatric intensive care unit nurses and respiratory-therapists (RTs) affiliated with a Canadian University. We presented questions about demographics, methodology of AR, and expectations from AR. Responses of pediatricians and nurses/RTs were compared using Chi-square, with P < .05 considered significant. Response rate was 44/114(39%) (pediatricians), and 69/120 (58%) (nurses/RTs). Asked about methodological quality, most respondents expect that: AR is done to high quality; costs and difficulty are not acceptable justifications for low quality; findings should be reproducible between laboratories and strains of the same species; and guidelines for AR funded with public money should be consistent with these expectations. Asked about benefits of AR, most thought that there are sometimes/often large benefits to humans from AR, and disagreed that "AR rarely produces benefit to humans." Asked about expectations of translation to humans (of toxicity, carcinogenicity, teratogenicity, and treatment findings), most: expect translation >40% of the time; thought that misleading AR results should occur <21% of the time; and that if translation was to occur <20% of the time, they would be less supportive of AR. There were few differences between pediatricians and nurses/RTs. HCW have high expectations for the methodological quality of, and the translation rate to humans of findings from AR. These expectations are higher than the empirical data show having been achieved. Unless these areas of AR significantly improve, HCW support of AR may be tenuous.


Fitness cost of resistance to Bt cotton linked with increased gossypol content in pink bollworm larvae.
Fitness costs of resistance to Bacillus thuringiensis (Bt) crops occur in the absence of Bt toxins, when individuals with resistance alleles are less fit than individuals without resistance alleles. As costs of Bt resistance are common, refuges of non-Bt host plants can delay resistance not only by providing susceptible individuals to mate with resistant individuals, but also by selecting against resistance. Because costs typically vary across host plants, refuges with host plants that magnify costs or make them less recessive could enhance resistance management. Limited understanding of the physiological mechanisms causing fitness costs, however, hampers attempts to increase costs. In several major cotton pests including pink bollworm (Pectinophora gossypiella), resistance to Cry1Ac cotton is associated with mutations altering cadherin proteins that bind this toxin in susceptible larvae. Here we report that the concentration of gossypol, a cotton defensive chemical, was higher in pink bollworm larvae with cadherin resistance alleles than in larvae lacking such alleles. Adding gossypol to the larval diet decreased larval weight and survival, and increased the fitness cost affecting larval growth, but not survival. Across cadherin genotypes, the cost affecting larval growth increased as the gossypol concentration of larvae increased. These results suggest that increased accumulation of plant defensive chemicals may contribute to fitness costs associated with resistance to Bt toxins.


No evidence of cardiotoxicity during antimalarial treatment with artemether-lumefantrine.
Artemether-lumefantrine is a new fixed antimalarial combination effective against multidrug-resistant falciparum malaria. A prospective electrocardiographic study was conducted in 150 patients receiving artemetherlumefantrine and 50 treated with artesunate-mefloquine. There was no evidence for clinically significant changes in the electrocardiographic intervals and in particular no relationship between plasma concentrations of lumefantrine and QTc prolongation. Artemether-lumefantrine does not have significant cardiac effects at therapeutic doses.


Regional brain perfusion in epileptic dogs evaluated by technetium-99m-ethyl cysteinate dimer SPECT.
We evaluated the feasibility of interictal single photon emission computed tomography (SPECT) to detect alterations in regional cerebral blood flow and neuronal activity in dogs with idiopathic epilepsy. Twelve dogs with idiopathic epilepsy underwent interictal technetium-99m-ethyl cysteinate dimer SPECT of the brain. Different cortical regions of interest (ROIs), 1 ROI at the cerebellum and 1 ROI at the subcortical area were evaluated by semiquantitative analysis and compared with a control group (18 dogs). Significant hypoperfusion (P = 0.02) was present in the subcortical area of epileptic dogs. This hypoperfusion was not associated with seizure frequency, age at onset of seizures, duration of epilepsy, or time since the last seizure. Interictal SPECT did not reveal cortical or cerebellar perfusion alterations. The subcortical area may play an important role in the pathophysiology of canine idiopathic epilepsy.


Cardiac autonomic functions derived from short-term heart rate variability recordings associated with heart rate recovery after treadmill exercise test in young individuals.
Analysis of short-term heart rate variability (HRV) may provide useful information about autonomic nervous control of heart rate recovery. We studied 495 individuals (273 men), age range 19-85 years, submitted to treadmill exercise tests and short-term HRV evaluations over time (standard deviation of the normal-to-normal interval [SDNN], the square root of the mean squared differences of successive normal-to-normal intervals [RMSSD], the number of interval differences of successive normal-to-normal intervals greater than 50 ms [NN50 count], the proportion derived by dividing NN50 count by the total number of normal-to-normal intervals [pNN50]) and frequency (low-frequency power [LF], high-frequency power [HF], total power) domains. Among 495 patients, 106 patients (68 men) were elderly (age ≥ 65 years). Male gender and hypertension were significantly higher in elderly patients. The young patients had higher HRR after exercise. HRR at 4 min (54 ± 13 vs 60 ± 12 beats/min; P = 0.003) was the most significant predictor for positive exercise test result. In the young group, both time domain measures (SDNN: correlation coefficient 0.34, P < 0.001; RMSSD: correlation coefficient 0.37, P < 0.001) and frequency domain measures (LF: correlation coefficient 0.21, P < 0.001; HF: correlation coefficient 0.13, P = 0.01; total power: correlation coefficient 0.22, P < 0.001) were significantly associated with HRR at 4 min. HRR at 4 min was significantly associated with short-term HRV of time and frequency domains in young individuals, but not elderly ones, receiving treadmill exercise test.


Magnetic properties experiments on the Mars exploration Rover Spirit at Gusev Crater.
The magnetic properties experiments are designed to help identify the magnetic minerals in the dust and rocks on Mars-and to determine whether liquid water was involved in the formation and alteration of these magnetic minerals. Almost all of the dust particles suspended in the martian atmosphere must contain ferrimagnetic minerals (such as maghemite or magnetite) in an amount of approximately 2% by weight. The most magnetic fraction of the dust appears darker than the average dust. Magnetite was detected in the first two rocks ground by Spirit.


Public idiotopes and/or internal images in the anti-poly(Glu60Ala30Tyr10) response: analysis by monoclonal antibodies.
From BALB/c mice immunized with BALB/c polyclonal anti-GAT antibodies, we have obtained monoclonal antiidiotypic antibodies directed against public idiotopes expressed following GAT (Glu60Ala30Tyr10) immunization in all individuals of all mouse strains tested. Nine monoclonal anti-Id antibodies were studied in detail. One of these monoclonals recognizes only polyclonal anti-GAT antibodies; the other eight recognize polyclonal anti-GAT antibodies and monoclonal anti-GAT antibodies. The distribution of the structures recognized by the different monoclonal anti-Id on a battery of twenty monoclonal anti-GAT antibodies allows a definition of two families of public idiotopes. The significance of the existence of these two families is discussed in light of the hypothesis recently proposed by Jerne et al. (EMBO J., 1982, 1, 243-247) who consider that the induction of internal images of antigen during immunization leading to the production of antiidiotypic reagents is responsible for the existence of public idiotopes. Our present results may be interpreted to indicate that even though certain monoclonal anti-Id reagents could be internal images of the antigen, the others do, in fact, recognize public idiotopes. Therefore, the notion of internal image does not exclude the existence of public idiotypic specificities.


The New England Journal of Medicine: commercial conflict of interest and revisiting the Vioxx scandal.
At a recent cardiology conference in New Delhi, the cardiologist Deepak Natarajan raised the concern that commercial conflicts of interest (COIs) were corrupting medical journals. Natarajan cited "manipulated" publications in The New England Journal of Medicine (NEJM) as one example to support his view. His comments were met with silence and an air of indignation. Natarajan's medical colleagues were stunned, disbelieving, and then, angry.


Family matters! - The caregivers' perspective of Mental Healthcare Act 2017.
Mental health continues to fight for acceptance in health care all over the world. The need for a separate act for mental illnesses proves this fact even more. The very nature of the mental illness has necessitated legislation to aid the service providers and service users. The Mental Healthcare Act 2017 has taken great initiatives in terms of protection of human rights for people with mental illness such as the inclusion of mental illness in health insurance, stress on informed consent, decriminalization of suicide, and introduction of advance directives (ADs) and punishment to those who violate the law. However, in a country like India where the family as a unit has more significance than personal autonomy, the new act emphasizes the patient's rights and, in doing so, may make the doctors more defensive and fearful in making clinical decisions, thus shifting the burden to the shoulders of the family members. There is a need for suitable amendments to include the family's concerns as well; otherwise, the present act would stand as an alien Western law enforced on Indian cohesive family dynamics. Qualitative studies are required from the family's perspective to illustrate the hindrances that the patients' families are facing. In the context of Indian family structure and dynamics and working in the Indian community, we feel that without suitable amendments to include the family's concerns, the present act would stand as an alien Western law enforced on Indian cohesive family dynamics.


Random number generation deficit in early schizophrenia.
Random number generation with a written response mode provides a potentially appealing marker for executive processes. Impaired performance on written random number generation tasks has been reported in chronic schizophrenic patients. However, no study has investigated whether such a deficit occurs in early schizophrenia and whether its profile and severity are similar to those in patients with chronic illness. This study investigated the ability to generate random numbers in patients with early schizophrenia (n = 44) and a healthy control group (n = 48). Patients were less able to maintain several production strategies and generated more stereotyped response sequences, whereas their abilities to identify randomness with an even-handed treatment of digits and to monitor the equality of occurrence of single digits appeared to remain intact. These results provide evidence that some aspects of the deficits in random number generation among chronic schizophrenic patients are also present at early psychotic episode, while some other aspects are relatively less affected in the early years.


Variation in activity rates may explain sex-specific dorsal color patterns in Habronattus jumping spiders.
In many animals, color pattern and behavior interact to deceive predators. For mimics, such deception can range from precise (near-perfect mimicry) to only subtle resemblance (imperfect mimicry) and such strategies often differ by sex because of differing ecological selection pressures. In this field study, we examine variation in behavior and ecology that may be linked with sex differences in dorsal color pattern in three sympatric species of Habronattus jumping spiders (H. clypeatus, H. hallani, H. pyrrithrix). Males of these species have conspicuous dorsal patterning that is subtly reminiscent of the general color patterns of wasps and bees, while females are cryptic. We show that, compared with females, these conspicuous males exhibited increased leg-waving behavior outside of the context of courtship; such behavior is common in jumping spiders that mimic wasps and bees presumably because a mimic's waving legs resemble antennae. Males of a fourth sympatric species (H. hirsutus) without conspicuous dorsal patterning did not exhibit increased leg-waving. These results are consistent with and offer preliminary support for the idea that male color and behavior may work together to deceive predators. We also examined whether higher movement rates of males (who must wander to find females) and/or different use of the microhabitat by the sexes could explain sexual dichromatism. We found that microhabitat use was similar for males and females, but males of all three conspicuously-colored species spent more time actively moving than females. To our knowledge, this is the first study to speculate that conspicuous male dorsal coloration in Habronattus may have a deceptive function, and to explore why dorsal coloration differs between the sexes.


Group Contribution Method to Predict the Mass Transfer Coefficients of Organics through Various RO Membranes.
Reverse osmosis (RO) is a membrane technology that separates dissolved species from water. RO has been applied for the removal of chemical contaminants from water for potable reuse applications. The presence of a wide variety of influent chemical contaminants and the insufficient rejection of low-molecular-weight neutral organics by RO calls for the need to develop a model that predicts the rejection of various organics. In this study, we develop a group contribution method (GCM) to predict the mass transfer coefficients by fragmenting the structure of low-molecular-weight neutral organics into small parts that interact with the RO membrane. Overall, 54 organics including 26 halogenated and oxygenated alkanes, 8 alkenes, and 20 alkyl and halobenzenes were used to determine 39 parameters to calibrate for 6 different RO membranes, including 4 brackish water and 2 seawater membranes. Through six membranes, approximately 80% of calculated rejection was within an error goal (i.e., ±5%) from the experimental observation. To extend the GCM for a reference RO membrane, ESPA2-LD, 14 additional organics were included from the literature to calibrate nitrogen-containing functional groups of nitrosamine, nitriles, and amide compounds. Overall, 49 organics (72% of 68 compounds) from calibration and 7 compounds (87.5% of 8 compounds) from prediction were within the error goal.


Effectiveness of prolotherapy in the treatment of chronic rotator cuff lesions.
Rotator cuff lesions are one of the major causes of shoulder pain and dysfunction. Numerous non-surgical treatment modalities have been described for chronic rotator cuff lesions, but the debate continues over the optimal procedure. The aim of this report is to present the results of prolotherapy in the treatment of chronic refractory rotator cuff lesions. Dextrose prolotherapy will reduce pain and improve shoulder function and patient satisfaction. We recruited 120 patients with chronic rotator cuff lesions and symptoms that persisted for longer than 6 months. Patients were divided into two groups: one treated with exercise (control group; n=60) and the other treated with prolotherapy injection (prolotherapy group; n=60). In the latter, ultrasound-guided prolotherapy injections were applied under aseptic conditions. In the former, patients received a physiotherapy protocol three sessions weekly for 12 weeks. Both groups were instructed to carry out a home exercise program. Clinical assessment of shoulder function was performed using a visual analog scale (VAS) for pain, Shoulder Pain and Disability Index (SPADI), Western Ontario Rotatory Cuff (WORC) Index, patient satisfaction, and shoulder range of motion. Patients were examined at baseline, weeks 3, 6, and 12, and last follow-up (minimum of one year). A total of 101 patients (44 controls and 57 in the prolotherapy group) completed all study protocols and were included in the study. Using a within-group comparison, both groups achieved significant improvements over baseline, as measured by the VAS, SPADI, WORC index, and shoulder range of motion (P<0.001). Using a between-group comparison, a significant difference was found in the VAS scores at baseline, weeks 3, 6, and 12, and last follow-up. In addition, significant differences were found in the SPADIs and WORC indices at weeks 6 and 12 and the last follow-up. Significant differences were found in shoulder abduction and flexion at week 12 and last follow-up, and in internal rotation at last follow-up. However, no significant was found in external rotation at any follow-up period. In the prolotherapy group, 53 patients (92.9%) reported excellent or good outcomes; in the control group, 25 patients (56.8%) reported excellent or good outcomes. Prolotherapy is an easily applicable and satisfying auxiliary method in the treatment of chronic rotatory cuff lesions. Randomized prospective comparative trial. Level of evidence 1.


Misoprostol for prevention and treatment of postpartum haemorrhage: A systematic review.
Postpartum haemorrhage (PPH) is a leading cause of maternal mortality especially in the developing world. Misoprostol, a highly effective drug is highly effective in inducing uterine contractions and has been proposed as a low-cost, easy-to-use intervention for PPH. This study assessed evidence of the effectiveness of misoprostol for the prevention and treatment of PPH. Databases searched included MEDLINE, PUBMED, CINHAL, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE. Reference lists and conference proceedings were also searched for more studies. Three studies included in the meta-analysis were limited to randomised controlled trials (RCT). Two reviewers independently screened all articles for methodological quality using a standardised instrument adapted from the Cochrane Collaboration website. Data were entered in Review Manager 5.1 software for analysis. Three trials (n=2346) compared misoprostol to a placebo. Misoprostol was shown not to be effective in reducing PPH (risk ratios [RR] 0.65; 95% confidence interval [CI] 0.40-1.06). Only one trial reported on the need for a blood transfusion (RR 0.14; 95% CI 0.02-1.15). Shivering (RR 2.75; 95% CI 2.26-3.34) and pyrexia (RR 5.34; 95% CI 2.86-9.96) were significantly more common with misoprostol than with a placebo. The use of misoprostol was not associated with any significant reduction in the incidence of PPH. Therefore, in order to verify the efficacious use of misoprostol in the treatment of PPH, specialised investigations of its dose and routes of administration for clinically significant effects and acceptable side effects are warranted.


Role of sevoflurane in organ protection during cardiac surgery in children: a randomized controlled trial.
The protective effects of volatile anaesthetics against ischaemia-reperfusion injury have been shown in vitro, but clinical studies have yielded variable results. We hypothesized that, in children, sevoflurane provides superior cardioprotection after cardiac surgery on cardiopulmonary bypass (CPB) compared with totally intravenous anaesthesia (TIVA). In this randomized controlled, single-centre study, 60 children with cyanotic and acyanotic heart defects undergoing elective cardiac surgery under CPB (RACHS-1 1-3) were randomized to sevoflurane or TIVA (midazolam <6 months of age, propofol >6 months of age). The primary end-point was the postoperative peak cardiac troponin I/T (cTnI/T). Perioperative cardiac function (as determined by brain-type natriuretic peptide, echocardiography and postoperative vasopressor/inotrope requirements), short-term clinical outcomes (duration of intubation, intensive care unit and hospital length of stay), postoperative inflammatory profile, and pulmonary, renal and liver function were defined as secondary end-points. Analysis of variance was used for statistical analysis. There was no statistically significant difference in postoperative peak troponin values or any of the secondary end-points. In the subgroup of acyanotic patients under 6 months, sevoflurane led to significantly lower postoperative troponin levels compared with midazolam [reduction of 54% (95% confidence interval 29-71%, P = 0.002)], without any differences in secondary outcome parameters. Sevoflurane did not provide superior myocardial protection in our general paediatric cardiac surgical population. In children under 6 months, however, sevoflurane might be beneficial in comparison with midazolam. The conditioning effects of sevoflurane in specific paediatric subgroups need to be further investigated.


Consistent gene expression profiles in MexTAg transgenic mouse and wild type mouse asbestos-induced mesothelioma.
The MexTAg transgenic mouse model of mesothelioma replicates many aspects of human mesothelioma, including induction by asbestos, pathogenicity and response to cytotoxic chemotherapy, despite high levels of the SV40 large T Antigen (TAg) in the mesothelial compartment. This model enables analysis of the molecular events associated with asbestos induced mesothelioma and is utilised here to investigate the molecular dynamics of tumours induced in these mice, using gene expression patterns as a read out. Gene expression of MexTAg mesothelioma cell lines bearing a high or low number of copies of the TAg transgene were compared to wild type mouse mesotheliomas and normal mouse mesothelial cells using Affymetrix microarray. These data were then compared to a similar published human microarray study using the same platform. The main expression differences between transgenic mouse and wild type mouse mesotheliomas occurred for genes involved in cell cycle regulation and DNA replication, as would be expected from overexpression of the TAg oncogene. Quantitative PCR confirmed that E2F and E2F regulated genes were significantly more upregulated in MexTAg mesotheliomas and MexTAg mesothelial cells compared to wild type mesotheliomas. Like human mesothelioma, both MexTAg and wild type mesotheliomas had more genes underexpressed than overexpressed compared to normal mouse mesothelial cells. Most notably, the cdkn2 locus was deleted in the wild type mouse mesotheliomas, consistent with 80 % human mesotheliomas, however, this region was not deleted in MexTAg mesotheliomas. Regardless of the presence of TAg, all mouse mesotheliomas had a highly concordant set of deregulated genes compared to normal mesothelial cells that overlapped with the deregulated genes between human mesotheliomas and mesothelial cells. This investigation demonstrates that the MexTAg mesotheliomas are comparable with wild type mouse mesotheliomas in their representation of human mesothelioma at the molecular level, with some key gene expression differences that are attributable to the TAg transgene expression. Of particular note, MexTAg mesothelioma development was not dependent on cdkn2 deletion.


HCaRG accelerates tubular repair after ischemic kidney injury.
The repair of the kidney after ischemia/reperfusion injury involves proliferation of proximal tubular epithelial cells as well as cell migration and differentiation. Immediately after reperfusion, expression of hypertension-related calcium-regulated gene (HCaRG/COMMD5) decreases, but its expression increases even higher than baseline during repair. HCaRG inhibits proliferation and accelerates wound healing and differentiation in cultured cells, but whether HCaRG can stimulate renal repair after ischemia/reperfusion injury is unknown. Here, transgenic mice overexpressing human HCaRG survived longer and recovered renal function faster than littermate controls after ischemia/reperfusion (64% versus 25% survival at 7 days). Proliferation of proximal tubular epithelial cells stopped earlier after ischemia/reperfusion injury, E-cadherin levels recovered more rapidly, and vimentin induction abated faster in transgenic mice. HCaRG overexpression also reduced macrophage infiltration and inflammation after injury. Taken together, these data suggest that HCaRG accelerates repair of renal proximal tubules by modulating cell proliferation of resident tubular epithelial cells and by facilitating redifferentiation.


Electrowetting-based control of droplet transition and morphology on artificially microstructured surfaces.
Electrowetting (EW) has recently been demonstrated as a powerful tool for controlling droplet morphology on smooth and artificially structured surfaces. The present work involves a systematic experimental investigation of the influence of electrowetting in determining and altering the state of a static droplet resting on an artificially microstructured surface. Extensive experimentation is carried out to benchmark a previously developed energy-minimization-based model that analyzed the influence of interfacial energies, surface roughness parameters, and electric fields in determining the apparent contact angle of a droplet in the Cassie and Wenzel states under the influence of an EW voltage. The EW voltage required to trigger a transition from the Cassie state to the Wenzel state is experimentally determined for surfaces having a wide range of surface parameters (surface roughness and fraction of surface area covered with pillars). The reversibility of the Cassie-Wenzel transition upon the removal of the EW voltage is also quantified and analyzed. The experimental results from the present work form the basis for the design of surfaces that enable dynamic control of droplet morphology. A significant finding from the present work is that nonconservative dissipative forces have a significant influence in opposing fluid flow inside the microstructured surface that inhibits reversibility of the Cassie-Wenzel transition. The artificially structured surfaces considered in this work have microscale roughness feature sizes that permits direct visual observation of EW-induced Cassie-Wenzel droplet transition; this is the first reported visual confirmation of EW-induced droplet state transition.


Femtosecond-laser pumped CdSiP₂ optical parametric oscillator producing 100 MHz pulses centered at 6.2 μm.
We report the first, to the best of our knowledge, femtosecond-laser-pumped optical parametric oscillator (OPO) based on the newly developed nonlinear crystal, CdSiP₂. The OPO was synchronously pumped by a mode-locked Yb:KYW/Yb:fiber master-oscillator power amplifier, providing 1.053 μm pump pulses with durations of 130 fs at a repetition rate of 100 MHz. The 0.5-mm-thick CdSiP₂ crystal was cut for a type-I noncritical interaction, providing a broad phase-matching bandwidth and ensuring excellent temporal overlap among the pump, signal, and idler pulses. The OPO generated signal pulses with a spectral coverage over 1260-1310 nm and mid-infrared idler pulses with a broad spectral coverage at 5.8-6.6 μm (6.2 THz). With a 2% output coupler (OC), the threshold pump power was 600 mW. At the maximum pump power of 1.6 W, 0.55 W was absorbed due to two-photon absorption and residual linear absorption in the CdSiP₂ crystal, 0.75 W was transmitted, and 53 mW signal power was extracted through the OC. We estimate that the generated idler power was 24 mW.


Comparison of species sensitivity distribution modeling approaches for environmental risk assessment of nanomaterials - A case study for silver and titanium dioxide representative materials.
Species sensitivity distributions (SSDs) are used in chemical safety assessments to derive predicted-no-effect-concentrations (PNECs) for substances with a sufficient amount of relevant and reliable ecotoxicity data available. For engineered nanomaterials (ENMs), ecotoxicity data are often compromised by poor reproducibility and the lack of nano-specific characterization needed describe an ENM under test exposure conditions. This may influence the outcome of SSD modelling and hence the regulatory decision-making. This study investigates how the outcome of SSD modelling is influenced by: 1) Selecting input data based on the nano-specific "nanoCRED" reliability criteria, 2) Direct SSD modelling avoiding extrapolation of data by including long-term/chronic NOECs only, and 3) Weighting data according to their nano-specific quality, the number of data available for each species, and the trophic level abundance in the ecosystem. Endpoints from freshwater ecotoxicity studies were collected for the representative nanomaterials NM-300 K (silver) and NM-105 (titanium dioxide), evaluated for regulatory reliability and scored according to the level of nano-specific characterization conducted. The compiled datasets are unique in exclusively dealing with representative ENMs showing minimal batch-to-batch variation. The majority of studies were evaluated as regulatory reliable, while the degree of nano-specific characterization varied greatly. The datasets for NM-300 K and NM-105 were used as input to the nano-weighted n-SSWD model, the probabilistic PSSD+, and the conventional SSD Generator by the US EPA. The conventional SSD generally yielded the most conservative, but least precise HC5 values, with 95 % confidence intervals up to 100-fold wider than the other models. The inclusion of regulatory reliable data only, had little effect on the HC5 generated by the conventional SSD and the PSSD+, whereas the n-SSWD estimated different HC5 values based on data segregated according to reliability, especially for NM-105. The n-SSWD weighting of data significantly affected the estimated HC5 values, however in different ways for the sub-datasets of NM-300 K and NM-105. For NM-300 K, the inclusion of NOECs only in the weighted n-SSWD yielded the most conservative HC5 of all datasets and models (a HC5 based on NOECs only could not be estimated for NM-105, due to limited number of data). Overall, the estimated HC5 values of all models are within a relatively limited concentration range of 25-100 ng Ag/L for NM-300 K and 1-15 μgTiO2/L for NM-105.


Investigating light-use efficiency across a jack pine chronosequence during dry and wet years.
Light-use efficiency (LUE) is the ability of vegetated canopies to use light for photosynthesis. Together with remote sensing estimates of canopy cover and meteorological inputs, LUE provides a physical basis for scaling carbon uptake processes from the stand to the global scale. A better understanding of the factors that control LUE will result in improved global estimates of carbon uptake from the terrestrial biosphere. To examine factors that control variability in LUE in stands of different ages during dry and wet conditions, we measured LUE in a chronosequence of four jack pine stands (recent clearcut (age 1-3), regenerating (age 8-9), immature (age 29-30) and mature (approximately 90 years old)) during one normal (2002), one very dry (2003) and two very wet (2004, 2005) growing seasons in Saskatchewan, Canada. Cumulative CO(2) fluxes decreased significantly at all sites during the drought year of 2003, as did mean LUE. Canopy foliage at the recently regenerating jack pine site increased by 19% between 2002 and 2003. Foliage growth rate was reduced by 6% between 2003 and 2004, and foliage biomass decreased by 6% from 2004 to 2005. Over the four years studied, LUE was greatest at the mature jack pine site and lower, but similar, at the other three sites. Mean growing-season LUE varied with mean soil water content at each site, except at that of the newly regenerating stand where soil water had little influence. Mean daily vapor pressure deficit typically had the greatest influence on variability in LUE at all sites. Diffuse versus direct radiation also had significant but varying effects on LUE in jack pine stands of different ages.


Terrestrial locomotion in the black-billed magpie: kinematic analysis of walking, running and out-of-phase hopping.
The inter-limb kinematic patterns of walking, running and out-of-phase hopping in black-billed magpies (Pica pica) were studied using high-speed video recordings. The flexion/extension patterns of the joints were similar between the gait types, suggesting that the within-leg control of the angular excursions is similar. This result is further supported by the fact that running and hopping are alternative gaits at speeds higher than walking; however, magpies show a preference for hopping. Moreover, only small differences occur between the kinematic patterns of the two limbs during out-of-phase hopping, during which the legs are believed to have different functions. The hindlimb kinematic patterns of magpies are like those of other flying and more terrestrial bird species; however, striking differences are found in comparison with humans at the level of the internal angles. This is probably due to the differences in the morphology and configuration of their legs.


Effects of curcumin in an orthotopic murine bladder tumor model.
Cigarette smoking (CS) is the main risk factor for bladder cancer development. There are more than 100 carcinogens present in cigarette smoke. Among the potential mediators of CS-induced alterations is nuclear factor-kappa (NF-kappaB), which is responsible for the transcription of genes related to cell transformation, tumor promotion, angiogenesis, invasion and metastasis. Curcumin is a polyphenol compound derived from Curcuma longa that suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis by down regulating NF-kappaB and its regulated genes. The aim of our study was to assess the effects of curcumin in bladder urothelial carcinoma. We studied the effects of curcumin in vitro and in vivo using the orthotropic syngeneic bladder tumor animal model MB49. Curcumin promotes apoptosis of bladder tumor cells in vitro. In vivo tumors of animals treated with curcumin were significantly smaller as compared to controls. Using immunohistochemistry, we demonstrated a decrease in the expression of Cox-2 by 8% and Cyclin D1 by 13% in the animals treated with curcumin; both genes regulated by NF-kappaB and related to cell proliferation. In this study, we showed that curcumin acts in bladder urothelial cancer, possibly dowregulating NF-kappaB-related genes, and could be an option in the treatment of urothelial neoplasms. The results of our study suggest that further research is warranted to confirm our findings.


Near-infrared light triggered photothermal therapy and enhanced photodynamic therapy with a tumor-targeting hydrogen peroxide shuttle.
Hypoxia, defined as inadequate oxygen supply at the tissue level, is a common pathological condition in the tumor microenvironment of certain solid tumors, leading to the limited efficiency of oxygen-dependent photodynamic therapy (PDT). To overcome this problem, tumor-targeting oxygen self-carrying nanoparticles are developed for photothermal therapy (PTT) and enhanced PDT to completely eradicate solid tumors. Hydrogen peroxide (H2O2) is a strong oxidant that can release oxygen in the presence of a catalyst or when being heated. The core-shell poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) are obtained by a double emulsion method: the hydrophilic H2O2/poly(vinylpyrrolidone) complex as an oxygen source and hydrophobic IR780 as a PTT/PDT agent are encapsulated into the core and shell of the NPs respectively. The tumor binding molecule, folic acid, is conjugated onto the surface of obtained PLGA NPs to enabling efficient cell uptake and tumor targeting. Once the PLGA-FA/IR780-H2O2 NPs are ingested by HepG2 cells, they can induce the photothermal effect and reactive oxygen species (ROS) are released to kill cancer cells under an 808 nm laser irradiation. The encapsulated H2O2 can supply additional oxygen and in turn significantly enhance the PDT effect. This innovative nanoplatform has exhibited excellent antitumor efficiency, verified vividly by the in vitro and in vivo assays, and may serve as a versatile platform for future cancer therapy.


Decreasing educational differences in mortality over 40 years: evidence from the Turin Longitudinal Study (Italy).
Recent studies suggest that inequalities in premature mortality have continued to rise over the last decade in most European countries, but not in southern European countries. In this study, we assess long-term trends (1971-2011) in absolute and relative educational inequalities in all-cause and cause-specific mortality in the Turin Longitudinal Study (Turin, Italy), a record-linkage study including all individuals resident in Turin in the 1971, 1981, 1991 and 2001 censuses, and aged 30-99 years (more than 2 million people). We examined mortality for all causes, cardiovascular disease (CVD), all cancers and specific cancers (lung, breast), as well as smoking and alcohol-related mortality. Overall mortality substantially decreased in all educational groups over the study period, although cancer rates only slightly declined. Absolute inequalities decreased for both genders (SII=962/694 in men/women in 1972-1976 and SII=531/259 in 2007-2011, p<0.01). Among men, absolute inequalities for CVD and alcohol-related causes declined (p<0.05), while remaining stable for other causes of death. Among women, declines in absolute inequalities were observed for CVD, smoking and alcohol-related causes and lung cancer (p<0.05). Relative inequalities in all-cause mortality remained stable for men and decreased for women (RII=1.92/2.03 in men/women in 1972-1976 and RII=2.15/1.32 in 2007-2011). Among men, relative inequalities increased for smoking-related causes, while among women they decreased for all cancers, CVD, smoking-related causes and lung cancer (p<0.05). Absolute inequalities in mortality strongly declined over the study period in both genders. Relative educational inequalities in mortality were generally stable among men; while they tended to narrow among women. In general, this study supports the hypothesis that educational inequalities in mortality have decreased in southern European countries.


Phomopsis amaranthicola and Microsphaeropsis amaranthi Symptoms on Amaranthus spp. Under South Texas Conditions.
Temperature, humidity, weed species and age, and inducible responses in the host are factors that could limit the efficacy of fungal bioherbicides. The influences of these factors on the efficacy of the fungal bioherbicides Phomopsis amaranthicola and Microsphaeropsis amaranthi against Palmer amaranth (Amaranthus palmeri), smooth pigweed (Amaranthus hybridus), and redroot pigweed (Amaranthus retroflexus) were investigated in greenhouse and field studies under south Texas conditions. Despite plants being given an initial dew period, the bioherbicides, applied individually or in combination, did not cause mortality on any pigweed species in greenhouse or field environments. In greenhouse experiments, fewer than 5% of the leaves in six- to eight-leaf A. palmeri plants developed necrotic lesions within 2 weeks after bioherbicide treatment and only 8% or fewer of the plants developed stem lesions. Disease incidence was significantly higher in A. hybridus and A. retroflexus, with as much as 94% of leaves developing necrosis and 95% of the plants having stem lesions. New leaf production was reduced by biobherbicide treatment in A. hybridus. Combined-pathogen inoculation caused leaf and stem lesions on mature (13 to 36 leaves per plant) A. hybridus and A. retroflexus. Summer and fall field inoculations with M. amaranthi on A. hybridus and A. palmeri produced disease incidence levels similar to or higher than those in greenhouse tests. Infection of A. palmeri by P. amaranthicola increased the peroxidase activity level nearly twofold compared with the controls. Neither pathogen influenced leaf free amino acid content. The high temperatures and low humidity of south Texas and interspecific variation in resistance, possibly linked to peroxidase induction, limited the efficacy of these bioherbicides.


Interferon gamma replacement as salvage therapy in chronic pulmonary aspergillosis: effects on frequency of acute exacerbation and all-cause hospital admission.
Chronic pulmonary aspergillosis (CPA) is often poorly responsive to antifungal treatment; secondary infections increase morbidity/mortality, particularly in progressive cases. Interferon gamma (IFNγ) has been implicated in not only Aspergillus control but also bacterial clearance. Clinical notes of patients with CPA treated with IFNγ (2011-2018) were retrospectively hand-searched. In patients treated for >12 months (n=20), the frequency of acute exacerbation reduced from 3.1 to 1.4 episodes/year (p=0.006) in the 12 months after treatment initiation compared with the 12 months before. A significant reduction in the frequency of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). These findings support further prospective studies.


Oncology Clinicians and the Minnesota Medical Cannabis Program: A Survey on Medical Cannabis Practice Patterns, Barriers to Enrollment, and Educational Needs.
Background: Medical cannabis has been available in the State of Minnesota since July 2015 through the Minnesota Medical Cannabis Program (MMCP). Objectives: Our study aimed to delineate oncology providers' views on medical cannabis, identify barriers to patient enrollment, and assess clinicians' interest in a clinical trial of medical cannabis in patients with stage IV cancer. Methods: From June to August 2017, we distributed a 14-question survey to Minnesota oncology physicians, advanced practice nurses, and physician assistants who care for adults and children with cancer. Descriptive analyses for each question were provided for all survey respondents. Results: Of the 529 eligible survey participants, 153 (29%) responded to our survey; 68 respondents were registered with the MMCP. Most identified themselves as a medical oncologist or medical oncology nurse practitioner/physician assistant (n=125, 82%), and most practiced in a community setting (n=102, 67%). Overall, 65% of respondents supported the use of medical cannabis. Perceived cost and inadequate research were the highest barriers to MMCP patient enrollment. The lowest barriers included lack of health group support for allowing certification of patients and risk of social stigma. Of all respondents, 36% lacked confidence in discussing the risks and benefits of medical cannabis, and 85% wanted more education. Conclusions: Although support for cannabis use in the cancer setting is growing, significant barriers remain. This study illustrates a clear need to give clinicians both data and education to guide their discussions about the benefits, risks, and cost considerations of using medical cannabis for cancer-related symptoms.


Quantitative histomorphometric description of implant anchorage for three types of dental implants following 3 months of healing in baboons.
Important to the understanding of the dynamics associated with dental implant anchorage over time is a knowledge of the supporting anatomy for common endosseous implants prior to being placed into function. This study followed 20 screw-shaped dental implants placed in edentulated (2 months' healing time) posterior jaws of five adult female baboons. Implants made of three biomaterials were placed and allowed to heal for 3 months prior to processing for evaluation. Percentage integration and bone area data from six horizontal sections along the entire length of each implant were collected and analyzed for differences between jaws, implant biomaterials, jaw/biomaterial, and sections of the implants (ANOVA, pairwise comparison using LSM with Bonferroni adjustment). The results indicated that overall mean percentage integration was 46.5 and mean percentage bone area was 39.9. Maxillary and mandibular differences for both parameters were statistically different (integration: maxillary = 38.1%, mandibular = 56.7%; bone area: maxillary = 35.8%, mandibular = 44.9%; both were significant at the P < .05 level). The biomaterial analyses revealed significant differences for percentage integration between the metal implants and the hydroxyapatite-coated implant (commercially pure titanium = 39.1%, titanium-aluminum-vanadium = 40.0%, hydroxyapatite-coated = 61.5%), but no such difference was noted for percentage bone area (commercially pure titanium = 38.8%, titanium-aluminum-vanadium = 38.9%, hydroxyapatite-coated = 42.3%). Discussion of the relative importance of the two parameters highlights the fact that resistance to functional loads requires establishing and then maintaining an adequate volume of bone, which may have a functionally specific structure based on the mechanical properties of the local jaw environment.


Enhancing social ability by stimulating right temporoparietal junction.
The temporoparietal junction (TPJ) is a key node within the "social brain". Several studies suggest that the TPJ controls representations of the self or another individual across a variety of low-level (agency discrimination, visual perspective taking, control of imitation) and high-level (mentalizing, empathy) sociocognitive processes. We explored whether sociocognitive abilities relying on on-line control of self and other representations could be modulated with transcranial direct current stimulation (tDCS) of TPJ. Participants received excitatory (anodal), inhibitory (cathodal), or sham stimulation before completing three sociocognitive tasks. Anodal stimulation improved the on-line control of self-other representations elicited by the imitation and perspective-taking tasks while not affecting attribution of mental states during a self-referential task devoid of such a requirement. Our findings demonstrate the efficacy of tDCS to improve social cognition and highlight the potential for tDCS to be used as a tool to aid self-other processing in clinical populations.


Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis.
Tendinopathy is a known adverse reaction associated to fluoroquinolones, but a meta-analysis was not yet published. The aim of this study was to conduct a systematic review and a meta-analysis of the scientific evidence evaluating the risk of tendon injury associated with fluoroquinolones. A literature search was conducted to identify observational studies which reported results on the risk of Achilles tendon rupture (ATR), risk of Achilles tendinitis (AT), or risk of any tendon disorders (ATD). A meta-analysis was performed by pooling odds ratios (ORs) with their 95% confidence intervals (CIs). Fifteen studies were included in the meta-analysis. Treatment with fluoroquinolones was associated with an increased risk of ATR (OR 2.52 (95% CI 1.81-3.52), p < 0.001, I2 = 76.7%), an increased risk of AT (OR 3.95 (95% CI 3.11-5.01), p < 0.001, I2 = 0%), and increased risk of ATD (OR 1.98 (95% CI 1.62-2.43), p < 0.001, I2 = 84.5%). The initial risk estimates remained statistically significant among patients aged ≥ 60 years old. Risk estimates did not significantly change after depending on the concomitant use of corticosteroids or studies methodological quality assessment. The analysis according to the type of fluoroquinolones was only possible for ATR, which were ofloxacin and norfloxacin were found to increase the risk of this outcome, but not ciprofloxacin and levofloxacin. The results of this meta-analysis confirm the risk of tendon injuries associated with fluoroquinolones. Older age and concomitant use of corticosteroids seem to be additional risk factors for tendinopathy.


Organisational factors and occupational balance in working parents in Sweden.
Parents with small children constitute a vulnerable group as they have an increased risk of sick leave due to stress-related disorders compared to adults without children. It has been shown that mothers and fathers to small children together spend more time in paid work than any other group, which could create negative stress and an experience of low occupational balance. The aim of this study was to examine associations between organisational factors and occupational balance among parents with small children in Sweden. Data were collected by a survey including questions about occupational balance, organisational factors and age, sex, employment rate, work position, monthly household income, number of children at home, separation/divorce last five years and overtime. The total number of parents included in this study was 718 (490 mothers and 228 fathers). Logistic regression models were applied to examine the odds ratios for occupational balance in relation to organisational factors. Parents who experienced positive attitudes towards parenthood and parental leave among colleagues and managers were more likely to experience high occupational balance than parents who experienced negative or neutral attitudes. Having a clear structure for handover when absent from work was also strongly associated with high occupational balance. The result of the present study indicates that some organisational factors could be important for the occupational balance of parents with small children.


Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3.
Current surveillance strategies for hepatocellular carcinoma (HCC) are applied uniformly in patients with cirrhosis, regardless of their cancer risk. The aim of this study was to compare the performance characteristics of the biomarkers alpha-fetoprotein (AFP), des-gamma carboxyprothrombin (DCP), and lectin-bound AFP (AFP-L3) in the diagnosis of HCC, and to determine the effect of risk factors for HCC on test performance. Eighty-four patients with HCC and 169 patients with cirrhosis were enrolled and their serum analyzed for total AFP, AFP-L3 and DCP. Receiver-operating characteristic (ROC) curves were constructed to determine the performance characteristics. DCP was significantly better than total AFP or AFP-L3 in differentiating HCC from cirrhosis, with a sensitivity of 86% and specificity of 93%. When subjects were divided into two groups by their risk for HCC, all 3 markers had a lower sensitivity and area under the ROC curve in the high-risk group compared to the low-risk group. In conclusion, DCP has the best performance characteristics of all 3 serum markers for the diagnosis of HCC. Serum biomarkers may be less sensitive and specific in the highest risk patients.


Missed Opportunities for HIV Prophylaxis Among Emergency Department Patients With Occupational and Nonoccupational Body Fluid Exposures.
Exposures to HIV are frequently managed in the emergency department (ED) for assessment and potential initiation of HIV postexposure prophylaxis. Despite established guidelines, it is unclear whether patients with a nonoccupational exposure are managed similarly to patients with an occupational exposure. This retrospective study used an administrative database to identify consecutive patients at a single ED with a discharge diagnosis of "blood or body fluid exposure" without sexual assault from April 1, 2007 to June 30, 2013. Patient exposure details and physician management were ascertained according to predefined guidelines. The primary outcome was the proportion of patients with high-risk exposures who were correctly given HIV prophylaxis; the secondary outcome was the proportion of patients with low-risk exposures who were correctly not given HIV prophylaxis. Other outcomes included the proportion of patients who had a baseline HIV test in the ED, the proportion who followed up with an HIV test within 6 months, and the number of seroconversions in this group. All outcomes were compared between nonoccupational and occupational exposure. Of 1,972 encounters, 1,358 patients (68.9%) had an occupational exposure and 614 (31.1%) had a nonoccupational exposure. In the occupational exposure group, 190 patients (14.0%) were deemed high risk, with 160 (84.2%; 95% confidence interval [CI] 78.1% to 88.9%) appropriately given prophylaxis. In the nonoccupational exposure group, 287 patients (46.7%) had a high-risk exposure, with 208 (72.5%; 95% CI 66.8% to 77.5%) given prophylaxis, for a difference of 11.7% (95% CI 3.8% to 19.1%). For low-risk exposures, appropriate management of both occupational and nonoccupational exposure was similar (92.4% versus 93.0%). At the index ED visit, 90.5% of occupational exposure patients and 76.7% of nonoccupational exposure patients received HIV testing, for a difference of 13.8% (95% CI 10.1% to 17.7%). At 6 months, 25.4% of patients with an occupational exposure and 35.0% of patients with a nonoccupational exposure had a follow-up test, for a difference of -9.6% (95% CI -14.2% to -5.1%). Of patients who had follow-up testing within 6 months, 4 of 215 (1.9%) in the nonoccupational exposure group tested newly positive for HIV, whereas 0 of 345 (0%) in the occupational exposure group tested positive. For ED patients with blood or body fluid exposures, those with high-risk nonoccupational exposures were not given HIV prophylaxis nearly twice as often as those with high-risk occupational exposure. Although 6-month follow-up testing rates were low, 1.9% of high-risk nonoccupational exposure patients seroconverted.


Attitudes and barriers to evidence-based practice in optometry educators.
Evidence-based practice (EBP) is an essential component of good quality, patient-centered health care. This requires practitioners to acquire EBP skills and knowledge during undergraduate and continuing education. Evidence-based practice education exists in a range of health care disciplines, including optometry. Evidence-based practice education, however, depends on relevant skills and knowledge in educators. Courses and workshops exist for the development of EBP teaching skills in some areas of health care but not in optometry. Here, we describe a pilot workshop designed to enhance the teaching of EBP and to investigate the perspectives of optometric educators on EBP including their attitudes and perceived barriers to EBP and its teaching. Twenty-seven optometric educators including 8 facilitators participated. Of these, 14 were academics (including the 8 facilitators) and 13 were practitioners. Evidence-based practice attitudes were assessed using the Evidence-Based Practice Attitude Scale-50 with appropriate modifications for optometry. Workshop design incorporated strategies to trigger discussion among participants. A nominal group technique was used to identify, prioritize, and reach consensus on barriers to EBP. Although some participants expressed reservations about EBP, a common understanding of the contemporary definition of EBP emerged in educators. Thirty-five barriers to EBP were identified; "time" was selected in the top five barriers by most participants and attracted the highest total score, well above any other barrier (negative attitude to EBP, volume of evidence, integration with clinical practice, and lack of lifelong learning mind-set). Attitudes toward EBP were generally positive and negatively correlated with age and time since graduation, respectively. A group of optometrists and academics new to implementing education in EBP displayed positive attitudes to EBP but considered that its application and teaching could be significantly hindered by a lack of time to access and appraise the large volume of available research evidence in the field of eye care.


Fibromyalgia syndrome and serotonin.
Although disturbances in the musculoskeletal system, in the neuroendocrine system and in the central nervous system (CNS) have been implicated in the pathophysiology of fibromyalgia syndrome (FMS), the primary mechanisms underlying the etiopathogenesis of FMS remain elusive. It has been postulated that disturbances in serotonin metabolism and transmission, along with disturbances in several other chemical pain mediators, are present in patients with FMS. In this article we review published studies on the pathophysiological role of serotonin in FMS. Although studies that indirectly measured the function of serotonin in the CNS in FMS revealed some abnormalities in the metabolism and transmission of serotonin, the role of serotonin in the pathophysiology of syndrome remains inconclusive and warrants more studies.


[Pharmacogenetics: relevant aspects for the practicing veterinarian].
Pharmacogenetics is the study of genetic determinants of different responses to drug therapy and deals with differences in metabolic pathways and therapeutic effects as well as adverse reactions. A common genetic defect found in veterinary medicine is the MDR1 mutation occurring in Collies and related breeds that leads to an altered P-glycoprotein. Genetic mutations of enzymes (cytochrome P450, thiopurine s-methyltransferase, n-acetyltransferase, UDP-glucuronyltransferase, plasma esterase or sulfotransferase), which are responsible for the metabolism of drugs, are found as well. A decreased functional level of these enzymes can lead to an increased plasma concentration of the drug with a consequent relative overdose.


Understanding the role of iron in the magnetism of Fe doped ZnO nanoparticles.
The actual role of transition metals like iron in the room temperature ferromagnetism (RTFM) of Fe doped ZnO nanoparticles is still an unsolved problem. While some studies concluded that the Fe ions participate in the magnetic interaction, others in contrast do not believe Fe to play a direct role in the magnetic exchange interaction. To contribute to the understanding of this issue, we have carefully investigated the structural, optical, vibrational and magnetic properties of sol-gel synthesized Zn1-xFexO (0 < x < 0.10) nanoparticles. No Fe(2+) was detected in any sample. We found that high spin Fe(3+) ions are substitutionally incorporated at the Zn(2+) in the tetrahedral-core sites and in pseudo-octahedral surface sites in ZnO. Superficial OH(-) was observed in all samples. For x ≤ 0.03, an increment in Fe doping concentration decreased a and c lattice parameters, average Zn-O bond length, average crystallite size and band gap; while it increased the degree of distortion and quadrupole splitting. Undoped ZnO nanoparticles exhibited very weak RTFM with a saturation magnetization (Ms) of ∼0.47 memu g(-1) and this value increased to ∼2.1 memu g(-1) for Zn0.99Fe0.01O. Very interestingly, the Ms for Zn0.99Fe0.01O and Zn0.97Fe0.03O increased by a factor of about ∼2.3 by increasing annealing for 1 h to 3 h. For x ≥ 0.05, ferrimagnetic disordered spinel ZnFe2O4 was formed and this phase was found to become more ordered with increasing annealing time. Fe does not contribute directly to the RTFM, but its presence promoted the formation of additional single charged oxygen vacancies, zinc vacancies, and more oxygen-ended polar terminations at the nanoparticle surface. These defects, which are mainly superficial, altered the electronic structure and are considered as the main sources of the observed ferromagnetism.


The location of splenic NKT cells favours their rapid activation by blood-borne antigen.
Natural killer T (NKT) cells play an important role in mounting protective responses to blood-borne infections. However, though the spleen is the largest blood filter in the body, the distribution and dynamics of NKT cells within this organ are not well characterized. Here we show that the majority of NKT cells patrol around the marginal zone (MZ) and red pulp (RP) of the spleen. In response to lipid antigen, these NKT cells become arrested and rapidly produce cytokines, while the small proportion of NKT cells located in the white pulp (WP) exhibit limited activation. Importantly, disruption of the splenic MZ by chemical or genetic approaches results in a severe reduction in NKT cell activation indicating the need of cooperation between both MZ macrophages and dendritic cells for efficient NKT cell responses. Thus, the location of splenic NKT cells in the MZ and RP facilitates their access to blood-borne antigen and enables the rapid initiation of protective immune responses.


Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database.
To quantify the unintended effects of statins according to type, dose, and duration of use. Prospective open cohort study using routinely collected data. 368 general practices in England and Wales supplying data to the QResearch database. 2 004 692 patients aged 30-84 years of whom 225 922 (10.7%) were new users of statins: 159 790 (70.7%) were prescribed simvastatin, 50 328 (22.3%) atorvastatin, 8103 (3.6%) pravastatin, 4497 (1.9%) rosuvastatin, and 3204 (1.4%) fluvastatin. Cox proportional hazards models were used to estimate effects of statin type, dose, and duration of use. The number needed to treat (NNT) or number needed to harm (NNH) was calculated and numbers of additional or fewer cases estimated for 10 000 treated patients. First recorded occurrence of cardiovascular disease, moderate or serious myopathic events, moderate or serious liver dysfunction, acute renal failure, venous thromboembolism, Parkinson's disease, dementia, rheumatoid arthritis, cataract, osteoporotic fracture, gastric cancer, oesophageal cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer. Individual statins were not significantly associated with risk of Parkinson's disease, rheumatoid arthritis, venous thromboembolism, dementia, osteoporotic fracture, gastric cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer. Statin use was associated with decreased risks of oesophageal cancer but increased risks of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataract. Adverse effects were similar across statin types for each outcome except liver dysfunction where risks were highest for fluvastatin. A dose-response effect was apparent for acute renal failure and liver dysfunction. All increased risks persisted during treatment and were highest in the first year. After stopping treatment the risk of cataract returned to normal within a year in men and women. Risk of oesophageal cancer returned to normal within a year in women and within 1-3 years in men. Risk of acute renal failure returned to normal within 1-3 years in men and women, and liver dysfunction within 1-3 years in women and from three years in men. Based on the 20% threshold for cardiovascular risk, for women the NNT with any statin to prevent one case of cardiovascular disease over five years was 37 (95% confidence interval 27 to 64) and for oesophageal cancer was 1266 (850 to 3460) and for men the respective values were 33 (24 to 57) and 1082 (711 to 2807). In women the NNH for an additional case of acute renal failure over five years was 434 (284 to 783), of moderate or severe myopathy was 259 (186 to 375), of moderate or severe liver dysfunction was 136 (109 to 175), and of cataract was 33 (28 to 38). Overall, the NNHs and NNTs for men were similar to those for women, except for myopathy where the NNH was 91 (74 to 112). Claims of unintended benefits of statins, except for oesophageal cancer, remain unsubstantiated, although potential adverse effects at population level were confirmed and quantified. Further studies are needed to develop utilities to individualise the risks so that patients at highest risk of adverse events can be monitored closely.


Unique Effects of Acute Aripiprazole Treatment on the Dopamine D2 Receptor Downstream cAMP-PKA and Akt-GSK3β Signalling Pathways in Rats.
Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream cAMP-PKA and Akt-GSK3β signalling pathways in comparison with a D2R antagonist--haloperidol and a D2R partial agonist--bifeprunox. Rats were injected once with aripiprazole (0.75 mg/kg, i.p.), bifeprunox (0.8 mg/kg, i.p.), haloperidol (0.1 mg/kg, i.p.) or vehicle. Five brain regions--the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3β were measured by Western Blotting; the cAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3β in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R.


Engineering an endothelialized, endocrine Neo-Pancreas: Evaluation of islet functionality in an ex vivo model.
Islet-based recellularization of decellularized, repurposed rat livers may form a transplantable Neo-Pancreas. The aim of this study is the establishment of the necessary protocols, the evaluation of the organ structure and the analysis of the islet functionality ex vivo. After perfusion-based decellularization of rat livers, matrices were repopulated with endothelial cells and mesenchymal stromal cells, incubated for 8 days in a perfusion chamber, and finally repopulated on day 9 with intact rodent islets. Integrity and quality of re-endothelialization was assessed by histology and FITC-dextran perfusion assay. Functionality of the islets of Langerhans was determined on day 10 and day 12 via glucose stimulated insulin secretion. Blood gas analysis variables confirmed the stability of the perfusion cultivation. Histological staining showed that cells formed a monolayer inside the intact vascular structure. These findings were confirmed by electron microscopy. Islets infused via the bile duct could histologically be found in the parenchymal space. Adequate insulin secretion after glucose stimulation after 1-day and 3-day cultivation verified islet viability and functionality after the repopulation process. We provide the first proof-of-concept for the functionality of islets of Langerhans engrafted in a decellularized rat liver. Furthermore, a re-endothelialization step was implemented to provide implantability. This technique can serve as a bioengineered platform to generate implantable and functional endocrine Neo-Pancreases.


Modulation of Xenopus embryo mesoderm-specific gene expression and dorsoanterior patterning by receptors that activate the phosphatidylinositol cycle signal transduction pathway.
A role for the phosphatidylinositol (PI) cycle signal transduction pathway in Xenopus mesoderm induction has been revealed by observations of PI cycle activation coincident with this process, combined with the demonstration that Li+ (a PI cycle inhibitor) blocks this response and hyperdorsalizes mesoderm induction in intact embryos or augments growth factor-mediated induction in animal caps. It has been suggested that spatially restricted PI cycle activity in the marginal zone might modulate (but not, itself, activate) mesoderm induction. To better characterize the ability of PI cycle activity to modulate the pattern of mesoderm-specific gene expression elicited by mesoderm-inducing growth factors we have expressed in the embryo exogenous 5-hydroxytryptamine receptors that activate the PI cycle. In embryos, ventral expression and activation of these receptors during mesoderm induction are without obvious effect, whereas dorsal expression and activation yield dorsoanterior-deficient tadpoles. In animal caps induced with activin, simultaneous activation of exogenous 5-hydroxytryptamine receptors inhibits both convergent extension movements associated with dorsal mesoderm induction and the expression of goosecoid, a dorsal-specific gene, but is without effect on expression of a 149 generic mesodermal marker, Xbra. All of these effects of a 149 PI cycle-stimulating receptor are the opposites of those previously reported for the PI cycle inhibitor, Li+. PI cycle activity thus proves able to modulate the dorsal/ventral character of early mesodermal gene expression elicited by growth factor, suggesting a model for mesodermal patterning.


Separate intramolecular pathways for reduction and oxidation of cytochrome c in electron transport chain reactions.
The monoiodotyrosine 74, formyltryptophan 59, mononitrotyrosine 67, and carboxymethylmethionine 80 derivatives of horse cytochrome c are defective in their ability to accept electrons from the succinate-cytochrome c reductase system, while their reactions with purified cytochrome c oxidase are essentially those of the native protein. The 4-nitrobenzo-2-oxa-1,3-diazole derivative of lysine 13 of horse cytochrome c and the bis-phenylglyoxal derivative of arginine 13 of Candida krusei cytochrome c have the opposite properties, in that they are readily reduced by the succinate-cytochrome c reductase (EC 22.214.171.124) system but are defective in their capability of transferring electrons to cytochrome c oxidase (EC 188.8.131.52). We conclude that electrons from mitochondrial cytochrome c reductase are transmitted to ferricytochrome c by a different pathway than electrons from ferrocytochrome c to cytochrome c oxidase. The present results are compatible with the concept that the mechanism of reduction involves an aromatic ring channel comprising residues 74, 59, 67, and 80, leading from the "left back" part of the protein to the heme iron. On the other hand, since residue 13 is immediately above the edge of the heme that is at the "front surface" of the molecule, we suggest that the electron leaves ferrocytochrome c to cytochrome c oxidase by way of the edge of pyrrole ring II or the adjacent surface-located sulfur of cysteinyl residue 17, which is thioether bonded to the heme. On this basis, the sites of electron entry and exit in cytochrome c would appear to be some 110 degrees of arc away from each other along the surface of the protein, explaining several previously observed phenomena.


The acute effects of green tea and carbohydrate coingestion on systemic inflammation and oxidative stress during sprint cycling.
Green tea (Camellia sinensis) has anti-oxidative and anti-inflammatory effects, which may be beneficial to athletes performing high-intensity exercise. This study investigated the effects of carbohydrate and green tea coingestion on sprint cycling performance and associated oxidative stress and immunoendocrine responses to exercise. In a crossover design, 9 well-trained male cyclists completed 3 sets of 8 repetitions of 100-m uphill sprint cycling while ingesting green tea and carbohydrate (TEA) (22 mg/kg body mass catechins, 6 mg/kg body mass caffeine, 230 mg/kg glucose, and 110 mg/kg fructose) or carbohydrate only (CHO) (230 mg/kg body mass glucose and 110 mg/kg body mass fructose) during each 10-min recovery period between sets. Blood samples were collected before exercise, 10 min after exercise, and 14 h after exercise. There was no effect of acute TEA ingestion on cycling sprint performance (p = 0.29), although TEA maintained postexercise testosterone and lymphocyte concentrations, which decreased significantly in the CHO group (p < 0.001). While there was a trend for lower postexercise neutrophil count with TEA (p = 0.05), there were no significant differences between TEA and CHO for circulating cytokines (p > 0.20), markers of oxidative stress and antioxidant capacity (p > 0.17), adiponectin concentration (p = 0.60), or muscle damage markers (p > 0.64). While acute green tea ingestion prevents the postexercise decrease in testosterone and lymphocytes, it does not appear to benefit cycling sprint performance or reduce markers of oxidation and inflammation when compared with carbohydrate alone.


High-quality draft genome sequence of Gracilimonas tropica CL-CB462(T) (DSM 19535(T)), isolated from a Synechococcus culture.
Gracilimonas tropica Choi et al. 2009 is a member of order Sphingobacteriales, class Sphingobacteriia. Three species of the genus Gracilimonas have been isolated from marine seawater or a salt mine and showed extremely halotolerant and mesophilic features, although close relatives are extremely halophilic or thermophilic. The type strain of the type species of Gracilimonas, G. tropica DSM19535(T), was isolated from a Synechococcus culture which was established from the tropical sea-surface water of the Pacific Ocean. The genome of the strain DSM19535(T) was sequenced through the Genomic Encyclopedia of Type Strains, Phase I: the one thousand microbial genomes project. Here, we describe the genomic features of the strain. The 3,831,242 bp long draft genome consists of 48 contigs with 3373 protein-coding and 53 RNA genes. The strain seems to adapt to phosphate limitation and requires amino acids from external environment. In addition, genomic analyses and pasteurization experiment suggested that G. tropica DSM19535(T) did not form spore.


ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses.
Genotoxic stress triggers the activation of checkpoints that delay cell-cycle progression to allow for DNA repair. Studies in fission yeast implicate members of the Rad family of checkpoint proteins, which includes Rad17, Rad1, Rad9 and Hus1, as key early-response elements during the activation of both the DNA damage and replication checkpoints. Here we demonstrate a direct regulatory linkage between the human Rad17 homologue (hRad17) and the checkpoint kinases, ATM and ATR. Treatment of human cells with genotoxic agents induced ATM/ATR-dependent phosphorylation of hRad17 at Ser 635 and Ser 645. Overexpression of a hRad17 mutant (hRad17AA) bearing Ala substitutions at both phosphorylation sites abrogated the DNA-damage-induced G2 checkpoint, and sensitized human fibroblasts to genotoxic stress. In contrast to wild-type hRad17, the hRad17AA mutant showed no ionizing-radiation-inducible association with hRad1, a component of the hRad1-hRad9-hHus1 checkpoint complex. These findings demonstrate that ATR/ATM-dependent phosphorylation of hRad17 is a critical early event during checkpoint signalling in DNA-damaged cells.


Microglia development follows a stepwise program to regulate brain homeostasis.
Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.


Gaps in Knowledge Relevant to the "Guidelines for Limiting Exposure to Time-Varying Electric and Magnetic Fields (1 Hz-100 kHz)".
Sources of low-frequency fields are widely found in modern society. All wires or devices carrying or using electricity generate extremely low frequency (ELF) electric fields (EFs) and magnetic fields (MFs), but they decline rapidly with distance to the source. High magnetic flux densities are usually found in the vicinity of power lines and close to equipment using strong electrical currents, but can also be found in buildings with unbalanced return currents, or indoor transformer stations. For decades, epidemiological as well as experimental studies have addressed possible health effects of exposure to ELF-MFs. The main goal of ICNIRP is to protect people and the environment from detrimental exposure to all forms of non-ionizing radiation (NIR). To this end, ICNIRP provides advice and guidance by developing and disseminating exposure guidelines based on the available scientific research. Research in the low-frequency range began more than 40 years ago, and there is now a large body of literature available on which ICNIRP set its protection guidelines. A review of the literature has been carried out to identify possible relevant knowledge gaps, and the aim of this statement is to describe data gaps in research that would, if addressed, assist ICNIRP in further developing guidelines and setting revised recommendations on limiting exposure to electric and magnetic fields. It is articulated in two parts: the main document, which reviews the science related to LF data gaps, and the annex, which explains the methodology used to identify the data gaps.


Stiff substrates enhance monocytic cell capture through E-selectin but not P-selectin.
The stiffening of blood vessel walls is associated with inflammatory diseases, including atherosclerosis, diabetes, and obesity. These diseases are driven by the excessive recruitment of inflammatory leukocytes out of the bloodstream and into tissues, but whether vascular stiffening plays a direct role in this process is not clear. In this study, we investigated the possibility that leukocyte capture from blood flow is enhanced on stiffer substrates. We modeled blood flow in vitro by perfusing monocytic cells over hydrogels that matched the stiffness of healthy and diseased arteries. The hydrogels were coated with either E-selectin or P-selectin, which are the endothelial adhesion proteins known to mediate immune cell capture from flow. Interestingly, we discovered that cell attachment to P-selectin coated gels was not dependent on substrate stiffness, while attachment through E-selectin was enhanced on stiffer gels. Specifically we found that on E-selectin coated gels, cells attached in greater numbers, remained attached for longer time periods, and rolled more slowly on stiff gels than soft gels. These results suggest that vascular stiffening could promote leukocyte adhesion to vessel walls where E-selectin is expressed, but may have less of an effect when P-selectin is also present.


Identification of cell surface targets through meta-analysis of microarray data.
High-resolution image guidance for resection of residual tumor cells would enable more precise and complete excision for more effective treatment of cancers, such as medulloblastoma, the most common pediatric brain cancer. Numerous studies have shown that brain tumor patient outcomes correlate with the precision of resection. To enable guided resection with molecular specificity and cellular resolution, molecular probes that effectively delineate brain tumor boundaries are essential. Therefore, we developed a bioinformatics approach to analyze micro-array datasets for the identification of transcripts that encode candidate cell surface biomarkers that are highly enriched in medulloblastoma. The results identified 380 genes with greater than a two-fold increase in the expression in the medulloblastoma compared with that in the normal cerebellum. To enrich for targets with accessibility for extracellular molecular probes, we further refined this list by filtering it with gene ontology to identify genes with protein localization on, or within, the plasma membrane. To validate this meta-analysis, the top 10 candidates were evaluated with immunohistochemistry. We identified two targets, fibrillin 2 and EphA3, which specifically stain medulloblastoma. These results demonstrate a novel bioinformatics approach that successfully identified cell surface and extracellular candidate markers enriched in medulloblastoma versus adjacent cerebellum. These two proteins are high-value targets for the development of tumor-specific probes in medulloblastoma. This bioinformatics method has broad utility for the identification of accessible molecular targets in a variety of cancers and will enable probe development for guided resection.


Our Italian experience using lung ultrasound for identification, grading and serial follow-up of severity of lung involvement for management of patients with COVID-19.
Lung ultrasound (LU) has rapidly become a tool for assessment of patients stricken by the novel coronavirus 2019 (COVID-19). Over the past two and a half months (January, February, and first half of March 2020) we have used this modality for identification of lung involvement along with pulmonary severity in patients with suspected or documented COVID-19 infection. Use of LU has helped us in clinical decision making and reduced the use of both chest x-rays and computed tomography (CT).


Validating a decision tree for serious infection: diagnostic accuracy in acutely ill children in ambulatory care.
Acute infection is the most common presentation of children in primary care with only few having a serious infection (eg, sepsis, meningitis, pneumonia). To avoid complications or death, early recognition and adequate referral are essential. Clinical prediction rules have the potential to improve diagnostic decision-making for rare but serious conditions. In this study, we aimed to validate a recently developed decision tree in a new but similar population. Diagnostic accuracy study validating a clinical prediction rule. Acutely ill children presenting to ambulatory care in Flanders, Belgium, consisting of general practice and paediatric assessment in outpatient clinics or the emergency department. Physicians were asked to score the decision tree in every child. The outcome of interest was hospital admission for at least 24 h with a serious infection within 5 days after initial presentation. We report the diagnostic accuracy of the decision tree in sensitivity, specificity, likelihood ratios and predictive values. In total, 8962 acute illness episodes were included, of which 283 lead to admission to hospital with a serious infection. Sensitivity of the decision tree was 100% (95% CI 71.5% to 100%) at a specificity of 83.6% (95% CI 82.3% to 84.9%) in the general practitioner setting with 17% of children testing positive. In the paediatric outpatient and emergency department setting, sensitivities were below 92%, with specificities below 44.8%. In an independent validation cohort, this clinical prediction rule has shown to be extremely sensitive to identify children at risk of hospital admission for a serious infection in general practice, making it suitable for ruling out. NCT02024282.


Gender differences in the treatment of patients with acute myocardial infarction. A multihospital, community-based perspective.
As part of a community-wide study examining temporal trends in the incidence and survival rates of acute myocardial infarction, we examined differences between the sexes in overall utilization rates and changes over time, therein, of various therapies used in the management of acute myocardial infarction. Nonconcurrent prospective study. Three thousand three hundred sixty-one men and 2119 women hospitalized with validated acute myocardial infarction in 16 hospitals in the Worcester, Mass, metropolitan area during 1975, 1978, 1981, 1984, 1986, 1988, and 1990. After controlling, by means of a logistic regression analysis, for a variety of patient-related factors that could affect physician prescribing patterns, women were significantly more likely to receive diuretics during hospitalization for acute myocardial infarction, whereas men were significantly more likely to receive antiplatelet agents, lidocaine, and other antiarrhythmic agents. No statistically significant differences were seen between men and women with regard to the use of anticoagulants, beta-blockers, calcium channel blockers, digoxin, nitrates, and thrombolytic agents. Marked increases over time (1975 through 1990) were seen in the use of anticoagulants, antiplatelet agents, beta-blockers, lidocaine, and nitrates in each of the sexes, while declines were seen in the use of digoxin and diuretics. Use of thrombolytic therapy increased between 1986 and 1990, whereas use of calcium channel blockers decreased over this period for both men and women. The results of this multihospital, population-based, observational study suggest that physician practice patterns in the pharmacologic treatment of men and women hospitalized with acute myocardial infarction are very similar.