Projections of human kinship for all countries.
Demographers have long attempted to project future changes in the size and composition of populations, but have ignored what these processes will mean for the size, composition, and age distribution of family networks. Kinship structures matter because family solidarity-a crucial source of informal care for millions of people around the world-is conditional on kin being alive. Here, we present innovative projections of biological kin for the 1950 to 2100 period and discuss what they imply for the availability of informal care. Overall, we project that the number of living kin for individuals will decline dramatically worldwide. While a 65-yo woman in 1950 could expect to have 41 living kin, a 65-yo woman in 2095 is projected to have just 25 [18.8 to 34.7] relatives (lower and upper 80% projection intervals). This represents a 38% [15 to 54] global decline. The composition of family networks is also expected to change, with the numbers of living grandparents and great-grandparents markedly increasing, and the numbers of cousins, nieces and nephews, and grandchildren declining. Family networks will age considerably, as we project a widening age gap between individuals and their kin due to lower and later fertility and longer lifespans. In Italy, for example, the average age of a grandmother of a 35-yo woman is expected to increase from 77.9 y in 1950 to 87.7 y [87.1 to 88.5] in 2095. The projected changes in kin supply will put pressure on the already stretched institutional systems of social support, as more individuals age with smaller and older family networks.


Preliminary investigation on presence of peste des petits ruminants in Dakawa, Mvomero district, Morogoro region, Tanzania.
Peste des petits ruminants (PPR) is an acute viral disease of small ruminants characterised by the sudden onset of depression, fever, oculonasal discharges, sores in the mouth, foul-smelling diarrhoea and death. For many years, in Africa, the disease was mainly confined to West and Central Africa but it has now spread southwards to previously PPR-free countries including Tanzania, Democratic Republic of Congo and Angola. The disease was first reported in Tanzania in 2008 when it was confined to the Northern Zone districts bordering Kenya. Presence of the disease has also been confirmed in southern Tanzania especially Mtwara region. Recently, a suspected outbreak of PPR in Dakawa area, Mvomero district, Morogoro region was reported. Clinical samples (lungs, intestines, lymph nodes, whole blood and sera) from suspected goats (n = 8) and sheep (n = 1) were submitted to Sokoine University of Agriculture for analysis. Molecular diagnosis by amplification of the nucleoprotein gene and the fusion gene of PPR virus (PPRV) using PPRV specific primers was done. Five goats and the sheep were positive for PPRV after performing RT-PCR. To our knowledge, this is the first report confirming the presence of PPR in the Mvomero district of the Morogoro region, Tanzania. Hence, more efforts should be put in place to prevent the spread of PPR in Tanzania.


beta-lipotrophin and beta-endorphin plasma levels during pregnancy.
beta-lipotrophin (beta-LPH) and beta-endorphin (beta-EP) plasma levels were measured by radioimmunoassay after glass powder extraction and Sephadex G-75 column chromatography in plasma samples from controls (ten healthy males and twenty-six young women in early follicular phase), from eighty-two pregnant women in weeks 9-40 after their last menstrual period, from nine women just after delivery and the cord blood of their neonates, in fifteen mixed cord blood samples and in seven amniotic fluid samples obtained by amniocentesis. No sex differences were found in beta-LPH (120.6 +/- 8.5 pg/ml) or beta-EP (31.1 +/- 2.4 pg/ml) plasma levels or in their molar ratio (1.34 +/- 0.09) (MR). beta-LPH plasma levels increased in early pregnancy (13-16 weeks) (185.0 +/- 27.1 pg/ml) and remained high until weeks 21-24, then declining to levels similar to those of controls. beta-EP plasma levels were significantly depressed in weeks 9-12 (20.7 +/- 5.3 pg/ml), subsequently increasing to a maximum at weeks 36-37 (42.7 +/- 6.8 pg/ml). beta-LPH/beta-EP molar ratio was about double normal in early pregnancy and decreased to normal in the second half. The present data indicate that beta-LPH and beta-EP present different patterns throughout pregnancy and that beta-EP levels increase progressively, reaching the highest concentrations at term. At delivery, both beta-LPH and beta-EP showed maximum values (beta-LPH: 230.2 +/- 20.4 pg/ml; beta-EP: 78.0 +/- 7.4 pg/ml) and a MR of 1.02 +/- 0.10 indicating that stressful situations, such as labour, stimulate a simultaneous rise in beta-LPH and beta-EP plasma levels. Cord blood specimens showed a wide range of values (beta-LPH:75-347 pg/ml; beta-EP: 16-287 pg/ml) with a MR of 1.21 +/- 0.14. Amniotic fluid samples obtained late in the third trimester of pregnancy were characterized by beta-LPH levels of 119.4 +/- 26.4 pg/ml and beta-EP levels of 29.6 +/- 7.5 pg/ml.


Allocating under the influence: Effects of alcohol intoxication and social identification on in-group favoritism.
The "social lubrication" function of alcohol during interpersonal interactions is well documented. However, less is known about the effects of alcohol consumption on group-level behavior. Empirical findings from social psychological literature suggest that individuals tend to favor those who are considered as members of their own social group. Not yet evaluated is how alcohol intoxication interacts with this group-level bias. Therefore, the current study examined experimentally the effects of intoxication on group bias. Ninety-four individuals (Mage = 20.18, SD = 2.36, 55 women, 39 men) were randomly assigned to consume an alcoholic (n = 48) or a placebo (n = 46) drink before completing manipulated allocation matrices, a task which measured the distribution of hypothetical monetary awards based on social groups. Results point to an interaction between drink condition and social group identification, whereby identification was significantly associated with in-group favoritism among intoxicated individuals only. Following alcohol consumption, participants with higher identification with their social group were more likely to demonstrate allocation strategies that favored their own group members. However, nonsignificant effects were observed for those in the placebo condition. The findings highlight how alcohol intoxication may facilitate group bias that results from social group identification. (PsycINFO Database Record


Variations in internet-related problems and psychosocial functioning in online sexual activities: implications for social and sexual development of young adults.
This survey of 760 university students examined differences in Internet-related problems and psychosocial functioning between four patterns of participation in online sexual information and entertainment activities. Students who did not participate in either online sexual activity were more satisfied with their offline life and more connected to friends and family. Those who engaged in both online sexual activities were more dependent on the Internet and reported lower offline functioning. Students who only sought sexual information maintained strong offline affiliations. Those who only sought entertainment did not report lower offline functioning. Respondents most deficient in offline social support did not report compensatory online support. Despite students' common participation in online sexual activities (OSA) as a venue for social and sexual development, those relying on the Internet and the affiliations it provides appear at risk of decreased social integration. The authors discussed the finding's implications for social and sexual development.


Theta activity in the waking EEG is a marker of sleep propensity in the rat.
In humans, EEG power in the theta frequency band (5-8 Hz) during quiet waking increases during sleep deprivation (SD), and predicts the subsequent homeostatic increase of sleep slow-wave activity (SWA; EEG power between 0.5 and 4.0 Hz). These findings indicate that theta power in waking is an EEG variable, which reflects the rise in sleep propensity. In rodents, a number of short sleep attempts, as well as SWA in the waking EEG increase in the course of SD, but neither variable predicts the subsequent homeostatic increase of EEG SWA during recovery sleep. To investigate whether there is an EEG marker for sleep propensity also in rodents, the EEG of the rat was recorded during 6 h SD in the first half of the light period (SDL, n = 7). During SDL, power of the waking EEG showed an increase in the delta (1.5-4 Hz) and low theta (5-6.5 Hz) band. Based on the neck muscle EMG, wakefulness was subdivided into active (high EMG activity) and quiet (low EMG activity) waking. During quiet waking, the theta peak occurred at 5.5 Hz, the frequency at which the increase of EEG power during SD was most pronounced. This increase was due to higher amplitude of theta waves, while wave incidence (frequency) was unchanged. Correlation analysis showed that the rise in EEG power in the 5-7 Hz band during SD predicted the subsequent enhancement of SWA in non-rapid eye movement sleep. The analysis of data of a further batch of rats which were sleep deprived for 6 h after dark onset (SDD, n = 7) revealed a significant increase in theta-wave amplitude during the SD and a tendency for a similar, positive correlation between the increase of theta power (5-7 Hz) and subsequent SWA. The results indicate that in rats, as in humans, a specific waking EEG frequency, i.e., theta power in quiet waking is a marker of sleep propensity.


Binding and Inhibition of Spermidine Synthase from Plasmodium falciparum and Implications for In Vitro Inhibitor Testing.
The aminopropyltransferase spermidine synthase (SpdS) is a promising drug target in cancer and in protozoan diseases including malaria. Plasmodium falciparum SpdS (PfSpdS) transfers the aminopropyl group of decarboxylated S-adenosylmethionine (dcAdoMet) to putrescine or to spermidine to form spermidine or spermine, respectively. In an effort to understand why efficient inhibitors of PfSpdS have been elusive, the present study uses enzyme activity assays and isothermal titration calorimetry with verified or predicted inhibitors of PfSpdS to analyze the relationship between binding affinity as assessed by KD and inhibitory activity as assessed by IC50. The results show that some predicted inhibitors bind to the enzyme with high affinity but are poor inhibitors. Binding studies with PfSpdS substrates and products strongly support an ordered sequential mechanism in which the aminopropyl donor (dcAdoMet) site must be occupied before the aminopropyl acceptor (putrescine) site can be occupied. Analysis of the results also shows that the ordered sequential mechanism adequately accounts for the complex relationship between IC50 and KD and may explain the limited success of previous efforts at structure-based inhibitor design for PfSpdS. Based on PfSpdS active-site occupancy, we suggest a classification of ligands that can help to predict the KD-IC50 relations in future design of new inhibitors. The present findings may be relevant for other drug targets that follow an ordered sequential mechanism.


Why do cyclists infringe at red lights? An investigation of Australian cyclists' reasons for red light infringement.
This study investigated the behavioural, attitudinal and traffic factors contributing to red light infringement by Australian cyclists using a national online survey. The survey was conducted from February to May 2010. In total, 2061 cyclists completed the survey and 37.3% reported that they had ridden through a signalised intersection during the red light phase. The main predictive characteristics for infringement were: gender with males more likely to offend than females (OR: 1.54, CI: 1.22-1.94); age with older cyclists less likely to infringe compared to younger cyclists 18-29 years (30-49 yrs: OR: 0.71, CI: 0.52-0.96; 50+ yrs: OR: 0.51, CI: 0.35-0.74), and; crash involvement with cyclists more likely to infringe at red lights if they had not previously been involved in a bicycle-vehicle crash while riding (OR: 1.35; CI: 1.10-1.65). The main reasons given for red light infringement were: to turn left (32.0%); because the inductive loop detector did not detect their bike (24.2%); when there was no other road users present (16.6%); at a pedestrian crossing (10.7%); and 'Other' (16.5%). A multinomial logistic regression model was constructed to examine the associations between cyclist characteristics and reasons for infringement. Findings suggest that some cyclists are motivated to infringe by their perception that their behaviour is safe and that infrastructure factors were associated with infringement. Ways to manage this, potentially risky, behaviour including behaviour programmes, more cyclist-inclusive infrastructure and enforcement are discussed.


Detection of Mycobacterium tuberculosis in clinical specimens by polymerase chain reaction method.
An insertion sequence repeated multiple times in the chromosome of Mycobacterium tuberculosis was used as a target for amplification using the polymerase chain reaction (PCR) assay for detecting Mycobacterium tuberculosis in clinical specimens. The sequences of primers were 5'-CCTGCGAGCGTAGGCGTCGG-3' (primer 1) and 5'-CTCGTCCAGCGCCGCTTCGG-3' (primer 2). One cycle of amplification consisted of denaturing at 94 degrees C for 2 min, primer annealing at 68 degrees C for 2 min, and extension at 72 degrees C for 2 min. DNA (5 fg) extracted from M. tuberculosis was detected by gel electrophoresis and Southern blot hybridization after 40 cycles of amplification. The amplification products were not obtained by DNA extracted from M. kansasii, M. intracellulare, M. avium, M. fortuitum, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Legionella pneumophila and Staphylococcus aureus; only from the M. tuberculosis complex. PCR results were compared with conventional cultural, pathological and microscopic findings in the detection of M. tuberculosis in 112 clinical specimens. There were 25 specimens that were positive for M. tuberculosis by cultural or pathological examination, of which 20 (80%) were positive by PCR. PCR detected the organism in 5 (83%) of 6 smear-positive specimens and 15 (79%) of 19 smear-negative specimens in which culture or pathology revealed M. tuberculosis. In addition, 2 smear-negative specimens and 8 smear-negative and culture-negative specimens were positive by PCR. These 10 samples were collected from the patients suspected as having tuberculosis by the clinical diagnosis based on the clinical history, characteristic radiographs, a positive PPD skin test and the effectiveness of anti-tuberculous drugs.(ABSTRACT TRUNCATED AT 250 WORDS)


ICTV Virus Taxonomy Profile: Picornaviridae.
The family Picornaviridae comprises small non-enveloped viruses with RNA genomes of 6.7 to 10.1 kb, and contains >30 genera and >75 species. Most of the known picornaviruses infect mammals and birds, but some have also been detected in reptiles, amphibians and fish. Many picornaviruses are important human and veterinary pathogens and may cause diseases of the central nervous system, heart, liver, skin, gastrointestinal tract or upper respiratory tract. Most picornaviruses are transmitted by the faecal-oral or respiratory routes. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Picornaviridae, which is available at www.ictv.global/report/picornaviridae.


The Genitourinary Pathology Society Update on Classification and Grading of Flat and Papillary Urothelial Neoplasia With New Reporting Recommendations and Approach to Lesions With Mixed and Early Patterns of Neoplasia.
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.


Glutathione-associated enzymes in anticancer drug resistance.
The importance of thiol-mediated detoxification of anticancer drugs that produce toxic electrophiles has been of considerable interest to many investigators. Glutathione and glutathione S-transferases (GST) are the focus of much attention in characterizing drug resistant cells. However, ambiguous and sometimes conflicting data have complicated the field. This article attempts to clarify some of the confusion. The following observations are well established: (a) tumors express high levels of GST, especially GST psi, although the isozyme components vary quite markedly between tissues and the isozymes are inducible; (b) nitrogen mustards are good substrates for the GST alpha family of isozymes which are frequently overexpressed in cells with acquired resistance to these drugs; (c) most drugs of the multidrug-resistant phenotype have not been shown to be GST substrates and although GST psi is frequently overexpressed in multidrug-resistant cells, most indications are that this is an accompaniment to, rather than a cause of, the resistant phenotype; (d) transfection of GST complementary DNAs has produced some lines with increased resistance to alkylating agents. Most studies of the relationships between GST and resistance have overlooked the potential importance of other enzymes involved in the maintenance of cellular glutathione homeostasis, and this has complicated data interpretation. Translational research aimed at applying our knowledge of glutathione pathways has produced preclinical and clinical testing of some glutathione and GST inhibitors, with some encouraging preliminary results. In brief, GSTs are important determinants of drug response for some, not all, anticancer drugs. Caution should be encouraged in assessing cause/effect relationships between GST overexpression and resistance mechanisms.


Cost of counselling women who undergo mastectomy.
The psychiatric morbidity associated with mastectomy and brest cancer was substantially reduced by a specialist nurse who counselled women before and after surgery and monitored their progress. A controlled study was, therefore, carried out to determine what this cost. National Health Service costs were almost wholly covered by savings made because counselled subjects who developed psychiatric problems were recognised and treated much earlier than control patients. Counselled and control subjects suffered considerable financial losses, but these were offset in the counselled group by their relatives' earlier return to work. Such counselling schemes are necessary and effective and may be implemented at little extra cost.


Monitored anesthesia care with a combination of ketamine and dexmedetomidine during cardiac catheterization.
No specific regimen has been universally accepted as ideal for sedation during cardiac catheterization in infants and children. We evaluated a combination of ketamine and dexmedetomidine for sedation during cardiac catheterization in children with congenital heart disease. The study design included a retrospective analysis of data sheets and hospital records. The protocol for sedation was standardized and data collected prospectively for an ongoing quality assurance project. Heart rate, blood pressure, and oxygen saturation were recorded every 1 minute for the first 5 minutes and then at 5-minute intervals. The efficacy of sedation was judged by the need for supplemental ketamine doses. The study cohort included 16 infants and children undergoing either diagnostic or therapeutic cardiac catheterization. Sedation was initiated with a bolus dose of ketamine (2 mg/kg) and dexmedetomidine (1 microg/kg) administered over 3 minutes followed by a continuous infusion of dexmedetomidine (2 microg/kg per hour for the initial 30 minutes followed by 1 microg/kg per hour for the duration of the case). Supplemental analgesia/sedation was provided by ketamine (1 mg/kg) as needed. The baseline heart rate was 103 +/- 21 beats/minute. After the bolus dose of ketamine and dexmedetomidine, the heart rate increased by 7 +/- 5 beats/minute. The greatest increase was 15 beats/minute. The low heart rate after the bolus dose of ketamine/dexmedetomidine or during the subsequent dexmedetomidine infusion was 91 +/- 20 beats/minute (P < 0.001 compared with baseline) and the high heart rate was 110 +/- 25 beats/minute (P < 0.01 compared with baseline). In two patients, the dexmedetomidine infusion was decreased from 2 to 1 microg/kg per hour at 12 to 15 minutes instead of 30 minutes as a result of a decreased heart rate. No clinically significant changes in blood pressure or respiratory rate were noted. Two patients developed upper airway obstruction, which responded to repositioning of the airway. No apnea was noted. During the procedure, the PaCO2 varied from 37.5 to 48 mm Hg and was > or =45 mm Hg in seven patients. No patient responded to local infiltration of the groin and placement of the arterial and venous cannulae. Three patients required a supplemental dose of ketamine (1 mg/kg) during the procedure. In two of these patients, this was required before changing the cannulae. Our preliminary data suggest that a combination of ketamine and dexmedetomidine provides effective sedation for cardiac catheterization in infants and children without significant effects on cardiovascular or ventilatory function.


Qualitative analysis and identification of pattern of errors in Clock Drawing Tests of community-dwelling older adults.
The Clock Drawing Test (CDT) is a frequently employed screening tool with different scoring systems. Quantitative and semi-quantitative scoring systems, such as Sunderland's et al. (1989), do not discriminate different error patterns. Thus, the same score can represent a number of different neuropsychological profiles. Therefore, the use of a scoring method that emphasizes qualitative aspects to determine specific error patterns is fundamental. To use a qualitative scale to analyze error patterns in the CDTs of older adults who scored 5 in a previous study. 49 CDTs with score of 5 were analyzed using the qualitative scale. Linear regression and hierarchical and non-hierarchical cluster analyses were performed. The linear regression showed a significant association between the total score and all the error patterns of the qualitative scale. The hierarchical cluster yielded three groups. However, due to the heterogeneity observed among the groups, a non-hierarchical cluster analysis was performed to better understand the results. Three groups were determined with different neuropsychological profiles and patterns of errors. The qualitative scoring of the CDT is important when examining and analyzing specific neuropsychological domains in older adults, especially executive functions.


Facilitation and interference of seedling establishment by a native legume before and after wildfire.
In semi-arid ecosystems, heterogeneous resources can lead to variable seedling recruitment. Existing vegetation can influence seedling establishment by modifying the resource and physical environment. We asked how a native legume, Lupinus argenteus, modifies microenvironments in unburned and burned sagebrush steppe, and if L. argenteus presence facilitates seedling establishment of native species and the non-native annual grass, Bromus tectorum. Field treatments examined mechanisms by which L. argenteus likely influences establishment: (1) live L. argenteus; (2) dead L. argenteus; (3) no L. argenteus; (4) no L. argenteus with L. argenteus litter; (5) no L. argenteus with inert litter; and (6) mock L. argenteus. Response variables included soil nitrogen, moisture, temperature, solar radiation, and seedling establishment of the natives Elymus multisetus and Eriogonum umbellatum, and non-native B. tectorum. In both unburned and burned communities, there was higher spring soil moisture, increased shade and reduced maximum temperatures under L. argenteus canopies. Adult L. argenteus resulted in greater amounts of soil nitrogen (N) only in burned sagebrush steppe, but L. argenteus litter increased soil N under both unburned and burned conditions. Although L. argenteus negatively affected emergence and survival of B. tectorum overall, its presence increased B. tectorum biomass and reproduction in unburned plots. However, L. argenteus had positive facilitative effects on size and survival of E. multisetus in both unburned and burned plots. Our study indicates that L. argenteus can facilitate seedling establishment in semi-arid systems, but net effects depend on the species examined, traits measured, and level of abiotic stress.


Multilayer reflectors in animals using green and gold beetles as contrasting examples
The light reflectors in the beetles Calloodes grayanus and Anoplognathus parvulus are examined. Contrasting multilayer reflectors are revealed. Calloodes grayanus appears a weak green colour, matching its background leaves, while A. parvulus is strongly metallic-gold coloured. The former reflection is diffuse, as the result of a structure causing scattering that overlies the multilayer reflector, whereas the latter reflection is strongly directional. The green colour of C. grayanus is achieved by a multilayer reflector with a fixed spatial periodicity, here termed 'regular', which is far removed from the quarterwave, or physically 'ideal', condition. The gold colour of A. parvulus is achieved by a type of reflector which involves systematically changing optical thicknesses of the component layers with depth in the structure. A layer of melanin underlies the reflector of C. grayanus to absorb the transmitted portion of light and prevent its back-reflectance, which would otherwise alter the green colour. The resultant structural reflectance from C. grayanus effectively matches green pigments, which are rare in beetles.


A Method to Assess the Relevance of Nanomaterial Dissolution During Reactivity Testing.
The reactivity of particle surfaces can be used as a criterion to group nanoforms (NFs) based on similar potential hazard. Since NFs may partially or completely dissolve over the duration of the assays, with the ions themselves inducing a response, reactivity assays commonly measure the additive reactivity of the particles and ions combined. Here, we determine the concentration of ions released over the course of particle testing, and determine the relative contributions of the released ions to the total reactivity measured. We differentiate three classes of reactivity, defined as being A) dominated by particles, B) additive of particles and ions, or C) dominated by ions. We provide examples for each class by analyzing the NF reactivity of Fe2O3, ZnO, CuO, Ag using the ferric reduction ability of serum (FRAS) assay. Furthermore, another two reactivity tests were performed: Dichlorodihydrofluorescin diacetate (DCFH2‑DA) assay and electron paramagnetic resonance (EPR) spectroscopy. We compare assays and demonstrate that the dose‑response may be almost entirely assigned to ions in one assay (CuO in DCFH2‑DA), but to particles in others (CuO in EPR and FRAS). When considering this data, we conclude that one cannot specify the contribution of ions to NF toxicity for a certain NF, but only for a certain NF in a specific assay, medium and dose. The extent of dissolution depends on the buffer used, particle concentration applied, and duration of exposure. This culminates in the DCFH2‑DA, EPR, FRAS assays being performed under different ion‑to‑particle ratios, and differing in their sensitivity towards reactions induced by either ions or particles. If applied for grouping, read‑across, or other concepts based on the similarity of partially soluble NFs, results on reactivity should only be compared if measured by the same assay, incubation time, and dose range.


Severe COVID-19 among patients with asthma and COPD: a report from the Swedish National Airway Register.
Patients with obstructive lung diseases may be at risk of hospitalization and/or death due to COVID-19. To estimate the frequency of severe COVID-19, and COVID-19-related mortality in a well-defined large population of patients with asthma and chronic inflammatory lung disease (COPD). Further to assess the frequency of asthma and COPD as registered comorbidities at discharge from hospital, and in death certificates. At the start of the pandemic, the Swedish National Airway Register (SNAR) included 271,404 patients with a physician diagnosis of asthma and/or COPD. In September 2020, after the first COVID-19 wave in Sweden, the database was linked with the National Patient Register (NPR), the Swedish Intensive Care Register and the Swedish Cause of Death Register, which all provide data about COVID-19 based on International Classification of Diseases (ICD-10) codes. Severe COVID-19 was defined as hospitalization and/or intensive care or death due to COVID-19. Among patients in SNAR, 0.5% with asthma, and 1.2% with COPD were identified with severe COVID-19. Among patients < 18 years with asthma, only 0.02% were severely infected. Of hospitalized adults, 14% with asthma and 29% with COPD died. Further, of patients in SNAR, 56% with asthma and 81% with COPD were also registered in the NPR, while on death certificates the agreement was lower (asthma 24% and COPD 71%). The frequency of severe COVID-19 in asthma and COPD was relative low. Mortality for those hospitalized was double as high in COPD compared to asthma. Comorbid asthma and COPD were not always identified among patients with severe COVID-19.


The chiropractic profession in Norway 2011.
The chiropractic profession in Norway has increased five-fold in the last two decades. As there is no academic graduate program in Norway, all chiropractors have been trained outside of Norway, in either Europe, America or Australia. This might have given Norwegian chiropractors heterogenic characteristics concerning practice routines and clinical settings. However, little is known about what characterizes this profession and how it compares to other chiropractic professions in Europe. The aim of this survey was to describe major characteristics of the chiropractic profession in Norway. Two surveys were distributed to all 530 registered chiropractors in Norway in 2011. One survey was for all chiropractors (Survey 1) and the other for clinic owners (Survey 2). Results have been reported as tables and as approximate percentages in the text for ease of reading. Response rates were 61% (Survey 1, N = 320) and 71% (Survey 2, N = 217). More than two-thirds of the chiropractors in Norway had been in practice for under a decade. Only one in four chiropractors worked in solo practice and the majority shared premises with at least one colleague, typically at least one physiotherapist and one additional health practitioner. Today, only one in five clinics possessed radiologic equipment and one in ten had access to diagnostic ultrasound equipment. The majority of the chiropractors reported to apply mainly similar treatment modalities. More than 90% reported to use manipulation techniques on most patients, with soft tissue techniques and exercise modalities being almost as common. More than 3/4 of the profession reported that their clinical practice was in accordance with available clinical guidelines and about one third were positive about participating in future clinical research. The Norwegian chiropractic profession is relatively young and members report being satisfied with their work conditions. There is a clear difference from the earlier practice pattern in that intra- and inter-professional collaboration is more common and it is considered desirable. The profession seems to follow the modern trends in evidence-based practice by using X-rays more sparingly than previously, adhering to guidelines and being positive about research.


The 'antisocial' person: an insight in to biology, classification and current evidence on treatment.
This review analyses and summarises the recent advances in understanding the neurobiology of violence and empathy, taxonomical issues on defining personality disorders characterised by disregard for social norms, evidence for efficacy of different treatment modalities and ethical implications in defining 'at-risk' individuals for preventive interventions. PubMed was searched with the keywords 'antisocial personality disorder', 'dissocial personality disorder' and 'psychopathy'. The search was limited to articles published in English over the last 10 years (1999 to 2009) Both diagnostic manuals used in modern psychiatry, the Diagnostic and Statistical Manual published by the American Psychiatric Association and the International Classification of Diseases published by the World Health Organization, identify a personality disorder sharing similar traits. It is termed antisocial personality disorder in the diagnostic and statistical manual and dissocial personality disorder in the International Classification of Diseases. However, some authors query the ability of the existing manuals to identify a special category termed 'psychopathy', which in their opinion deserves special attention. On treatment-related issues, many psychological and behavioural therapies have shown success rates ranging from 25% to 62% in different cohorts. Multisystemic therapy and cognitive behaviour therapy have been proven efficacious in many trials. There is no substantial evidence for the efficacy of pharmacological therapy. Currently, the emphasis is on early identification and prevention of antisocial behaviour despite the ethical implications of defining at-risk children. Further research is needed in the areas of neuroendocrinological associations of violent behaviour, taxonomic existence of psychopathy and efficacy of treatment modalities.


Realtime phase-amplitude coupling analysis of micro electrode recorded brain signals.
To demonstrate a method to calculate phase amplitude coupling (PAC) quickly and robustly for realtime applications. We designed and implemented a multirate PAC algorithm with efficient filter bank processing and efficient computation of PAC for many frequency-pair combinations. We tested the developed algorithm for computing PAC on simulated data and on intraoperative neural recording data obtained during deep brain stimulation (DBS) electrode implantation surgery. A combination of parallelized frequency-domain filtering and modulation index for PAC estimation provided robust results that could be calculated in real time on modest computing hardware. The standard methods for calculating PAC can be optimized for quick and robust performance. These results demonstrated that PAC can be extracted in real time and is suitable for neurofeedback applications.


The Manhattan effect: when relationship commitment fails to promote support for partners' interests.
Research on close relationships has frequently contrasted one's own interests with the interests of the partner or the relationship and has tended to view the partner's and the relationship's interests as inherently aligned. The present article demonstrated that relationship commitment typically causes people to support their partner's personal interests but that this effect gets weaker to the extent that those interests misalign or even threaten the relationship. Studies 1a and 1b showed that (a) despite their strong correlation, partner-oriented and relationship-oriented concerns in goal-directed behaviors are separable and (b) relationship commitment strengthens only the link between relationship-oriented motivation and the goal pursuit (not the link between partner-oriented motivation and the goal pursuit). The remaining 7 studies zero in on circumstances in which the partner's and the relationship's interests are in conflict, demonstrating that (c) relationship commitment reliably increases the tendency to support the partner's personal interests when those interests do not pose a strong threat to the relationship but that (d) this effect becomes weaker-and even reverses direction-as the relationship threat posed by the partner's interests becomes stronger. The reduction or reversal of the positive link between relationship commitment and propartner behaviors in such situations is termed the Manhattan effect. These findings suggest that the partner-versus-relationship conflicts provide fertile ground for novel theorizing and empirical investigations and that relationship commitment appears to be less of a partner-promoting construct than relationship science has suggested; instead, its role appears to be focused on promoting the interests of the relationship.


Immunologic and proteolytic analysis of HIV-1 reverse transcriptase structure.
HIV-1 virions contain two reverse transcriptase polypeptides that have apparent molecular weights of 66 and 51 kDa. The 51-kDa form lacks the carboxy-terminal sequences found in the 66-kDa form, and is believed to be a proteolytic digestion product. We have treated purified 66-kDa reverse transcriptase with viral and nonviral proteases. The digestion products were characterized by their ability to react with monoclonal antibodies known to recognize particular segments of the HIV-1 reverse transcriptase. The approximate location of the segments recognized by the monoclonal antibodies was determined by testing the ability of the antibodies to recognize a series of amino- and carboxy-terminal-deleted forms of HIV-1 reverse transcriptase. The segments recognized are not uniformly distributed along the primary amino acid sequence of HIV-1 reverse transcriptase. We suggest that these segments are probably on the surface of the properly folded form of reverse transcriptase. Of the tested proteases, only the viral protease was able to cleave the 66-kDa form to the 51-kDa form without producing additional cleavage products, suggesting that the viral protease cleaves the 66-kDa protein to the 51-kDa form in virions.


Dietary choline supplementation attenuated high-fat diet-induced inflammation through regulation of lipid metabolism and suppression of NFκB activation in juvenile black seabream (Acanthopagrus schlegelii).
The present study aimed to investigate whether dietary choline can regulate lipid metabolism and suppress NFκB activation and, consequently, attenuate inflammation induced by a high-fat diet in black sea bream (Acanthopagrus schlegelii). An 8-week feeding trial was conducted on fish with an initial weight of 8·16 ± 0·01 g. Five diets were formulated: control, low-fat diet (11 %); HFD, high-fat diet (17 %); and HFD supplemented with graded levels of choline (3, 6 or 12 g/kg) termed HFD + C1, HFD + C2 and HFD + C3, respectively. Dietary choline decreased lipid content in whole body and tissues. Highest TAG and cholesterol concentrations in serum and liver were recorded in fish fed the HFD. Similarly, compared with fish fed the HFD, dietary choline reduced vacuolar fat drops and ameliorated HFD-induced pathological changes in liver. Expression of genes of lipolysis pathways were up-regulated, and genes of lipogenesis down-regulated, by dietary choline compared with fish fed the HFD. Expression of nfκb and pro-inflammatory cytokines in liver and intestine was suppressed by choline supplementation, whereas expression of anti-inflammatory cytokines was promoted in fish fed choline-supplemented diets. In fish that received lipopolysaccharide to stimulate inflammatory responses, the expression of nfκb and pro-inflammatory cytokines in liver, intestine and kidney were all down-regulated by dietary choline compared with the HFD. Overall, the present study indicated that dietary choline had a lipid-lowering effect, which could protect the liver by regulating intrahepatic lipid metabolism, reducing lipid droplet accumulation and suppressing NFκB activation, consequently attenuating HFD-induced inflammation in A. schlegelii.


Influence of midgut microbiota in Anopheles stephensi on Plasmodium berghei infections.
The native gut microbiota of Anopheles mosquitoes is known to play a key role in the physiological function of its host. Interestingly, this microbiota can also influence the development of Plasmodium in its host mosquitoes. In recent years, much interest has been shown in the employment of gut symbionts derived from vectors in the control of vector-borne disease transmission. In this study, the midgut microbial diversity has been characterized among laboratory-reared adult Anopheles stephensi mosquitoes, from the colony created by rearing progeny of wild-caught mosquitoes (obtained from three different locations in southern India) for multiple generations, using 16S ribosomal RNA (rRNA) gene sequencing approach. Further, the influence of native midgut microbiota of mosquitoes on the development of rodent malaria parasite Plasmodium berghei in its host has been studied. The microbial diversity associated with the midgut of An. stephensi mosquitoes was studied by sequencing V3 region of 16S ribosomal RNA (rRNA) gene. The influence of native midgut microbiota of An. stephensi mosquitoes on the susceptibility of the mosquitoes to rodent malaria parasite P. berghei was studied by comparing the intensity and prevalence of P. berghei infection among the antibiotic treated and untreated cohorts of mosquitoes. The analysis of bacterial diversity from the midguts of An. stephensi showed Proteobacteria as the most dominant population among the three laboratory-reared strains of An. stephensi studied. Major genera identified among these mosquito strains were Acinetobacter, Pseudomonas, Prevotella, Corynebacterium, Veillonella, and Bacillus. The mosquito infectivity studies carried out to determine the implication of total midgut microbiota on P. berghei infection showed that mosquitoes whose native microbiota cleared with antibiotics had increased susceptibility to P. berghei infection compared to the antibiotic untreated mosquitoes with its natural native microbiota. The use of microbial symbiont to reduce the competence of vectors involved in disease transmission has gained much importance in recent years as an emerging alternative approach towards disease control. In this context, the present study was aimed to identify the midgut microbiota composition of An. stephensi, and its effect on the development of P. berghei. Interestingly, the analysis of midgut microbiota from An. stephensi revealed the presence of genus Veillonella in Anopheles species for the first time. Importantly, the study also revealed the negative influence of total midgut microbiota on the development of P. berghei in three laboratory strains of An. stephensi, emphasizing the importance of understanding the gut microbiota in malaria vectors, and its relationship with parasite development in designing strategies to control malaria transmission.


Breast Cancer after Augmentation: Oncologic and Reconstructive Considerations among Women Undergoing Mastectomy.
Breast augmentation with subglandular versus subpectoral implants may differentially impact the early detection of breast cancer and treatment recommendations. The authors assessed the impact of prior augmentation on the diagnosis and management of breast cancer in women undergoing mastectomy. Breast cancer diagnosis and management were retrospectively analyzed in all women with prior augmentation undergoing therapeutic mastectomy at the authors' institution from 1993 to 2014. Comparison was made to all women with no prior augmentation undergoing mastectomy in 2010. Subanalyses were performed according to prior implant placement. A total of 260 women with (n = 89) and without (n = 171) prior augmentation underwent mastectomy for 95 and 179 breast cancers, respectively. Prior implant placement was subglandular (n = 27) or subpectoral (n = 63) (For five breasts, the placement was unknown). Breast cancer stage at diagnosis (p = 0.19) and detection method (p = 0.48) did not differ for women with and without prior augmentation. Compared to subpectoral augmentation, subglandular augmentation was associated with the diagnosis of invasive breast cancer rather than ductal carcinoma in situ (p = 0.01) and detection by self-palpation rather than screening mammography (p = 0.03). Immediate two-stage implant reconstruction was the preferred reconstructive method in women with augmentation (p < 0.01). Breast cancer stage at diagnosis was similar for women with and without prior augmentation. Among women with augmentation, however, subglandular implants were associated with more advanced breast tumors commonly detected on palpation rather than mammography. Increased vigilance in breast cancer screening is recommended among women with subglandular augmentation. Therapeutic, III.


Theory of the origin, evolution, and nature of life.
Life is an inordinately complex unsolved puzzle. Despite significant theoretical progress, experimental anomalies, paradoxes, and enigmas have revealed paradigmatic limitations. Thus, the advancement of scientific understanding requires new models that resolve fundamental problems. Here, I present a theoretical framework that economically fits evidence accumulated from examinations of life. This theory is based upon a straightforward and non-mathematical core model and proposes unique yet empirically consistent explanations for major phenomena including, but not limited to, quantum gravity, phase transitions of water, why living systems are predominantly CHNOPS (carbon, hydrogen, nitrogen, oxygen, phosphorus, and sulfur), homochirality of sugars and amino acids, homeoviscous adaptation, triplet code, and DNA mutations. The theoretical framework unifies the macrocosmic and microcosmic realms, validates predicted laws of nature, and solves the puzzle of the origin and evolution of cellular life in the universe.


Two behavioural indicators of dependency and the Five-Factor Model of personality.
Residence with parents and unemployment during studies were chosen as the two behavioural indicators of dependency among 601 undergraduate students. Students completed a demographic questionnaire, Costa and McCrae's (1992) NEO-FFI and Beck, Davis, and Freeman's (1990) Typical Beliefs of DPD. Unemployed students, living with their parents, were found to be significantly more dependent, neurotic and agreeable and less extraverted, conscientious and open than employed students who did not reside with their parents. Residing with parents during one's studies was the strongest predictor of dependency and neuroticism, followed by unemployment. Unemployed male students, who resided with their parents, were the most dependent, neurotic and agreeable and the least open, extraverted and conscientious group. The relationship between dependency and the Big Five is also discussed.


Organizational effects of perinatal exposure to bisphenol-A and diethylstilbestrol on arcuate nucleus circuitry controlling food intake and energy expenditure in male and female CD-1 mice.
The endocrine disrupting compound bisphenol-A (BPA) has been reported to act as an obesogen in rodents exposed perinatally. In this study, we investigated the effects of early-life BPA exposure on adult metabolic phenotype and hypothalamic energy balance circuitry. Pregnant and lactating CD-1 dams were exposed, via specially prepared diets, to 2 environmentally relevant doses of BPA. Dams consumed an average of 0.19 and 3.49 μg/kg per day of BPA in the low and high BPA treatments prenatally and an average of 0.36 and 7.2 μg/kg per day of BPA postnatally. Offspring were weaned initially onto a normal (AIN93G) diet, then as adults exposed to either a normal or high-fat diet (HFD). Males exposed to the high dose of BPA showed impaired glucose tolerance on both diets. They also showed reduced proopiomelanocortin fiber innervation into the paraventricular nucleus of the hypothalamus, and when exposed to HFD, they demonstrated increased neuropeptide Y and Agouti-related peptide expression in the arcuate nucleus (ARC). Females exposed to the high BPA dose were heavier, ate more, and had increased adiposity and leptin concentrations with reduced proopiomelanocortin mRNA expression in the ARC when consuming a HFD. BPA-exposed females showed ARC estrogen receptor α expression patterns similar to those seen in males, suggesting a masculinizing effect of BPA. These results demonstrate that early-life exposure to the obesogen BPA leads to sexually dimorphic alterations in the structure of hypothalamic energy balance circuitry, leading to increased vulnerability for developing diet-induced obesity and metabolic impairments, such as glucose intolerance.


Potentially inappropriate prescribing and vulnerability and hospitalization in older community-dwelling patients.
The predictive validity of existing explicit process measures of potentially inappropriate prescribing (PIP) is not established. To determine the association between PIP, and vulnerability and hospital visits in older community-dwelling patients. This was a retrospective cohort study of 931 community-dwelling patients aged ≥70 years in 15 general practices in Ireland in 2010. PIP was defined by the Beers 2012 criteria and the Screening Tool of Older Person's Potentially Inappropriate Prescriptions (STOPP). Vulnerability was measured by the Vulnerable Elders Survey (score ≥3). The number of hospital visits was measured using patients' medical records and self-report for the previous 6 months. Multilevel logistic and Poisson regression was used to examine the association between PIP, and vulnerability and hospital visits after adjusting for patient and practice level covariates, socioeconomic status, comorbidity, number of drug classes, social support, and adherence. The prevalence of PIP determined by the Beers 2012 and STOPP criteria was 28% (n = 246) and 42% (n = 377), respectively. Patients with ≥2 PIP indicators were almost twice as likely to be classified as vulnerable (Beers adjusted odds ratio [OR] = 1.80; 95% CI = 1.08, 3.01; P < 0.05; STOPP adjusted OR = 1.86; 95% CI = 1.13, 3.04; P < 0.05). Patients with ≥2 STOPP indicators had an increased risk in the expected rate of hospital visits (adjusted incidence rate ratio = 1.32; 95% CI = 1.14, 1.54; P < 0.01). The Beers 2012 criteria were not associated with increased hospital visits. STOPP is a more sensitive measure of PIP than the Beers 2012 criteria and of clinical benefit in primary care settings.


Reversal of proteinuric renal disease and the emerging role of endothelin.
Proteinuria is a major long-term clinical consequence of diabetes and hypertension, conditions that lead to progressive loss of functional renal tissue and, ultimately, end-stage renal disease. Proteinuria is also a strong predictor of cardiovascular events. Convincing preclinical and clinical evidence exists that proteinuria and the underlying glomerulosclerosis are reversible processes. This Review outlines the mechanisms involved in the development of glomerulosclerosis--particularly those responsible for podocyte injury--with an emphasis on the potential capacity of endothelin receptor blockade to reverse this process. There is strong evidence that endothelin-1, a peptide with growth-promoting and vasoconstricting properties, has a central role in the pathogenesis of proteinuria and glomerulosclerosis, which is mediated via activation of the ET(A) receptor. Several antiproteinuric drugs, including angiotensin-converting-enzyme inhibitors, angiotensin receptor antagonists, statins and certain calcium channel blockers, inhibit the formation of endothelin-1. Preclinical studies have demonstrated that endothelin receptor antagonists can reverse proteinuric renal disease and glomerulosclerosis, and preliminary studies in humans with renal disease have shown that these drugs have remarkable antiproteinuric effects that are additive to those of standard antiproteinuric therapy. Additional clinical studies are needed.


Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in Tsc1/Tsc2-dependent inhibition of TORC1.
Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors are implicated in development and tumorigenesis and dual inhibitors like sunitinib are prescribed for cancer treatment. While mammalian VEGF and PDGF receptors are present in multiple isoforms and heterodimers, Drosophila encodes one ancestral PDGF/VEGF receptor, PVR. We identified PVR in an unbiased cell-based RNA interference (RNAi) screen of all Drosophila kinases and phosphatases for novel regulators of TORC1. PVR is essential to sustain target of rapamycin complex 1 (TORC1) and extracellular signal-regulated kinase (ERK) activity in cultured insect cells and for maximal stimulation by insulin. CG32406 (henceforth, PVRAP, for PVR adaptor protein), an Src homology 2 (SH2) domain-containing protein, binds PVR and is required for TORC1 activation. TORC1 activation by PVR involves Tsc1/Tsc2 and, in a cell-type-dependent manner, Lobe (ortholog of PRAS40). PVR is required for cell survival in vitro, and both PVR and TORC1 are necessary for hemocyte expansion in vivo. Constitutive PVR activation induces tumor-like structures that exhibit high TORC1 activity. Like its mammalian orthologs, PVR is inhibited by sunitinib, and sunitinib treatment phenocopies PVR loss in hemocytes. Sunitinib inhibits TORC1 in insect cells, and sunitinib-mediated TORC1 inhibition requires an intact Tsc1/Tsc2 complex. Sunitinib similarly inhibited TORC1 in human endothelial cells in a Tsc1/Tsc2-dependent manner. Our findings provide insight into the mechanism of action of PVR and may have implications for understanding sunitinib sensitivity and resistance in tumors.


Prevalence of sensitization to food allergens, reported adverse reaction to foods, food avoidance, and food hypersensitivity among teenagers.
There is a paucity of information on food hypersensitivity (FHS) among teenagers. We sought to investigate the sensitization rates, perception of FHS, food avoidance, and FHS assessed by means of food challenges among teenagers. This cohort study recruited 757 eleven-year-olds and 775 fifteen-year-olds in the United Kingdom. Sensitization rates, reported rates of FHS, and rates of food avoidance were measured. The prevalence of FHS was established by using food challenges. The prevalence of reported FHS among the 11- and 15-year-old cohorts was 11.6% (90/775) and 12.4% (94/757), respectively. One hundred twenty-two (15.7%) and 142 (18.7%) of the 11- and 15-year-olds reported they were avoiding some food. The rates of sensitization to the food allergens were 5.1% (36/699) and 4.9% (32/649) for the 11- and 15-year-olds, respectively. FHS was confirmed in 8 (1.0%) 11-year-old children and 8 (1.0%) 15-year-old children by means of open food challenge and in 1 (0.1%) 11-year-old and 4 (0.5%) 15-year-olds by means of double-blind, placebo-controlled food challenge. The prevalence of FHS, as confirmed by using open food challenges and positive skin prick test responses plus a history of adverse reactions, was 18 (2.3%) of 775 in the 11-year-old cohort and 17 (2.3%) of 757 in the 15-year-old cohort. The rate of reported FHS was significantly more than sensitization to the predetermined allergens (odds ratio, 2.17; 95% CI, 1.47-3.18; P < .001 in the 11-year-olds; odds ratio, 2.73; 95% CI, 1.81-4.13; P < .001 in the 15-year-olds). By means of objective assessment, 2.3% of both 11- and 15-year-old children had FHS, with the majority showing immediate reactions.


Quantitative MRI for analysis of peritumoral edema in malignant gliomas.
Damage to the blood-brain barrier with subsequent contrast enhancement is a hallmark of glioblastoma. Non-enhancing tumor invasion into the peritumoral edema is, however, not usually visible on conventional magnetic resonance imaging. New quantitative techniques using relaxometry offer additional information about tissue properties. The aim of this study was to evaluate longitudinal relaxation R1, transverse relaxation R2, and proton density in the peritumoral edema in a group of patients with malignant glioma before surgery to assess whether relaxometry can detect changes not visible on conventional images. In a prospective study, 24 patients with suspected malignant glioma were examined before surgery. A standard MRI protocol was used with the addition of a quantitative MR method (MAGIC), which measured R1, R2, and proton density. The diagnosis of malignant glioma was confirmed after biopsy/surgery. In 19 patients synthetic MR images were then created from the MAGIC scan, and ROIs were placed in the peritumoral edema to obtain the quantitative values. Dynamic susceptibility contrast perfusion was used to obtain cerebral blood volume (rCBV) data of the peritumoral edema. Voxel-based statistical analysis was performed using a mixed linear model. R1, R2, and rCBV decrease with increasing distance from the contrast-enhancing part of the tumor. There is a significant increase in R1 gradient after contrast agent injection (P < .0001). There is a heterogeneous pattern of relaxation values in the peritumoral edema adjacent to the contrast-enhancing part of the tumor. Quantitative analysis with relaxometry of peritumoral edema in malignant gliomas detects tissue changes not visualized on conventional MR images. The finding of decreasing R1 and R2 means shorter relaxation times closer to the tumor, which could reflect tumor invasion into the peritumoral edema. However, these findings need to be validated in the future.


Molecular interpretation of kinetic-ionic strength effects.
A recent and important approach to investigating electron transfer mechanisms of redox proteins has been through kinetic-ionic strength studies. There is, however, significant controversy as to whether such studies (1) yield information regarding the charge (or location) of the electron transfer site or (2) more simply reflect the influence of net or overall protein charge on the electrostatic interactions. A critical analysis using different theoretical approaches is made of our recent work and of the bulk of the published non-physiological small molecule-protein and protein-protein kinetic ionic strength studies; it is concluded that (1) the approximated Bronsted-Debye-Huckel equation can not be used at all for protein redox reactions, (2) irrespective of the theoretical approaches discussed, such studies do not provide information regarding the charge of the electron transfer site, (3) it is the net charge of the reactants that control the electrostatic interactions, (4) both the equation derived by Wherland and Gray and the full Bronsted-Debye-Huckel equation provide reasonably good approximations of net protein charge, (5) pH changes quantitatively modulate net protein charge, and (6) thus, protein redox rates need to be electrostatically corrected if relevant interpretations of kinetic-ionic strength experiments are to be made.


Programmable dynamic steady states in ATP-driven nonequilibrium DNA systems.
Inspired by the dynamics of the dissipative self-assembly of microtubules, chemically fueled synthetic systems with transient lifetimes are emerging for nonequilibrium materials design. However, realizing programmable or even adaptive structural dynamics has proven challenging because it requires synchronization of energy uptake and dissipation events within true steady states, which remains difficult to orthogonally control in supramolecular systems. Here, we demonstrate full synchronization of both events by ATP-fueled activation and dynamization of covalent DNA bonds via an enzymatic reaction network of concurrent ligation and cleavage. Critically, the average bond ratio and the frequency of bond exchange are imprinted into the energy dissipation kinetics of the network and tunable through its constituents. We introduce temporally and structurally programmable dynamics by polymerization of transient, dynamic covalent DNA polymers with adaptive steady-state properties in dependence of ATP fuel and enzyme concentrations. This approach enables generic access to nonequilibrium soft matter systems with adaptive and programmable dynamics.


HIV vaccines: current status worldwide and in Africa.
Since HIV-1 was identified, development of a preventive vaccine has been a major goal. Significant progress toward that goal has been made by 2010. In macaques, a vigorous T effector cell response has protected some animals from disease caused by simian immunodeficiency virus (SIV). Broadly, neutralizing human anti-HIV antibodies have been isolated and their structures, and targets are rapidly being elucidated. For the first time an AIDS vaccine has shown modest protective efficacy in a human clinical trial. To reach the final goal, there is a need for a coordinated global effort, including a range of approaches including novel high-throughput screening techniques, X-ray crystallography, and monoclonal antibody isolation, analysis of T cell responses and their impact on disease progression, human epidemiology, as well as targeted studies in nonhuman primates. African research teams as well as cohorts of healthy volunteers and HIV-infected individuals have contributed to HIV vaccine research and development in many important ways. It is essential that this work continue to speed the development and deployment of a vaccine suitable for African populations.


A systematic review of educational interventions to change behaviour of prescribers in hospital settings, with a particular emphasis on new prescribers.
Prescribing is a complex task and a high risk area of clinical practice. Poor prescribing occurs across staff grades and settings but new prescribers are attributed much of the blame. New prescribers may not be confident or even competent to prescribe and probably have different support and development needs than their more experienced colleagues. Unfortunately, little is known about what interventions are effective in this group. Previous systematic reviews have not distinguished between different grades of staff, have been narrow in scope and are now out of date. Therefore, to inform the design of educational interventions to change prescribing behaviour, particularly that of new prescibers, we conducted a systematic review of existing hospital-based interventions. Embase, Medline, SIGLE, Cinahl and PsychINFO were searched for relevant studies published 1994-2010. Studies describing interventions to change the behaviour of prescribers in hospital settings were included, with an emphasis on new prescibers. The bibliographies of included papers were also searched for relevant studies. Interventions and effectiveness were classified using existing frameworks and the quality of studies was assessed using a validated instrument. Sixty-four studies were included in the review. Only 13% of interventions specifically targeted new prescribers. Most interventions (72%) were deemed effective in changing behaviour but no particular type stood out as most effective. Very few studies have tailored educational interventions to meet needs of new prescribers, or distinguished between new and experienced prescribers. Educational development and research will be required to improve this important aspect of early clinical practice.


Lack of correlation of symptoms with specialist-assessed long-term asthma severity.
To validate three indicators of asthma severity as defined in the National Asthma Education Program (NAEP) guidelines (ie, frequency of symptoms, degree of airflow obstruction, and frequency of use of oral glucocorticoids), alone and in combination, against severity as assessed by pulmonary specialists provided with 24-month medical chart data. Cross-sectional comparison of questionnaire and clinical-based markers of asthma severity with physician-assessed severity based on chart review. The pulmonologists did not have access to the results of the baseline evaluations when making their severity assessments. Study participants were 193 asthmatic members (age range, 6 to 55 years) of a large health maintenance organization who underwent a baseline evaluation as part of a separate longitudinal study. This evaluation consisted of spirometry, skin prick testing, and a survey that included questions on symptoms and medication use. The participants in the ancillary study were selected, based on their baseline evaluation, to reflect a broad range of asthma severity. Based on the chart review, 86 of the study subjects (45%) had mild disease, 90 (45%) had moderate disease, and 17 (9%) had severe disease. This physician-assessed severity correlated highly (p < or = 0.013) with NAEP-based indices of severity based on oral glucocorticoid use (never, infrequently for attacks, frequently for attacks, and daily use) and on spirometry (FEV1 > 80% predicted, 60 to 80% predicted, and <60% predicted). It did not, however, correlate with current asthma symptoms (< or = once/week, 2 to 6 times/week, daily) (p=0.87). A composite severity score based on spirometry and the glucocorticoid use data still provided an overall agreement of 63%, with a weighted kappa of 0.40. While current symptoms are the most important concern of patients with asthma, they reflect the current level of asthma control more than underlying disease severity. Investigators must therefore use caution when comparing groups of patients for whom severity categorization is based largely on symptomatology. This observation, that symptoms alone do not reflect disease severity, becomes even more important as health-care delivery moves closer to protocols/practice guidelines and "best treatment" programs that rely heavily on symptoms to guide subsequent treatment decisions.


Dynamic coupling of photoacclimation and photoinhibition in a model of microalgae growth.
The development of mathematical models that can predict photosynthetic productivity of microalgae under transient conditions is crucial for enhancing large-scale industrial culturing systems. Particularly important in outdoor culture systems, where the light irradiance varies greatly, are the processes of photoinhibition and photoacclimation, which can affect photoproduction significantly. The former is caused by an excess of light and occurs on a fast time scale of minutes, whereas the latter results from the adjustment of the light harvesting capacity to the incoming irradiance and takes place on a slow time scale of days. In this paper, we develop a dynamic model of microalgae growth that simultaneously accounts for the processes of photoinhibition and photoacclimation, thereby spanning multiple time scales. The properties of the model are analyzed in connection to PI-response curves, under a quasi steady-state assumption for the slow processes and by neglecting the fast dynamics. For validation purposes, the model is calibrated and compared against multiple experimental data sets from the literature for several species. The results show that the model can describe the difference in photosynthetic unit acclimation strategies between Dunaliella tertiolecta (n-strategy) and Skeletonema costatum (s-strategy).


High-resolution and large dynamic range nanomechanical mapping in tapping-mode atomic force microscopy.
High spatial resolution imaging of material properties is an important task for the continued development of nanomaterials and studies of biological systems. Time-varying interaction forces between the vibrating tip and the sample in a tapping-mode atomic force microscope contain detailed information about the elastic, adhesive, and dissipative response of the sample. We report real-time measurement and analysis of the time-varying tip-sample interaction forces with recently introduced torsional harmonic cantilevers. With these measurements, high-resolution maps of elastic modulus, adhesion force, energy dissipation, and topography are generated simultaneously in a single scan. With peak tapping forces as low as 0.6 nN, we demonstrate measurements on blended polymers and self-assembled molecular architectures with feature sizes at 1, 10, and 500 nm. We also observed an elastic modulus measurement range of four orders of magnitude (1 MPa to 10 GPa) for a single cantilever under identical feedback conditions, which can be particularly useful for analyzing heterogeneous samples with largely different material components.


Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. Evidence for an autoregulatory oxygen-sensing system.
Prolyl 4-hydroxylase domain (PHD) proteins are oxygen-dependent enzymes that hydroxylate hypoxia-inducible transcription factor (HIF) alpha-subunits, leading to their subsequent ubiquitination and degradation. Paradoxically, the expression of two family members (PHD2 and PHD3) is induced in hypoxic cell culture despite the reduced availability of the oxygen co-substrate, and it has been suggested that they become functionally relevant following re-oxygenation to rapidly terminate the HIF response. Here we show that PHDs are also induced in hypoxic mice in vivo, albeit in a tissue-specific manner. As demonstrated under chronically hypoxic conditions in vitro, PHD2 and PHD3 show a transient maximum but remain up-regulated over more than 10 days, suggesting a feedback down-regulation of HIF-1alpha which then levels off at a novel set point. Indeed, hypoxic induction of PHD2 and PHD3 is paralleled by the attenuation of endogenous HIF-1alpha. Using an engineered oxygen-sensitive reporter gene in a cellular background lacking endogenous HIF-1alpha and hence inducible PHD expression, we could show that increased exogenous PHD levels can compensate for a wide range of hypoxic conditions. Similar data were obtained in a reconstituted cell-free system in vitro. In summary, these results suggest that due to their high O2 Km values, PHDs have optimal oxygen-sensing properties under all physiologically relevant oxygen concentrations; increased PHDs play a functional role even under oxygen-deprived conditions, allowing the HIF system to adapt to a novel oxygen threshold and to respond to another hypoxic insult. Furthermore, such an autoregulatory oxygen-sensing system would explain how a single mechanism works in a wide variety of differently oxygenated tissues.


A comparison of physician pre-adoption and adoption views on electronic health records in Canadian medical practices.
There is a major campaign involving large expenditures of public money to increase the adoption rate of electronic health record (EHR) systems in Canada. To maximize the chances of success in this effort, physician views on EHRs must be addressed, since user perceptions are key to successful implementation of technology innovations. We propose a theoretical model comprising behavioral factors either favoring or against EHR adoption and use in Canadian medical practices, from the physicians' point of view. EHR perceptions of physicians already using EHR systems are compared with those not using one, through the lens of this model. We conducted an online cross-sectional survey in both English and French among medical practitioners across Canada. Data were collected both from physicians using EHRs and those not using EHRs, and analyzed with structural equation modeling (SEM) techniques. We collected 119 responses from EHR users and 100 from nonusers, resulting in 2 valid samples of 102 and 83 participants, respectively. The theoretical adoption model explained 55.8% of the variance in behavioral intention to continue using EHRs for physicians already using them, and 66.8% of the variance in nonuser intention to adopt such systems. Perception of ease of use was found to be the strongest motivator for EHR users (total effect .525), while perceptions of usefulness and of ease of use were the key determinants for nonusers (total effect .538 and .519, respectively) to adopt the system. Users see perceived overall risk associated with EHR adoption as a major obstacle (total effect -.371), while nonusers perceive risk only as a weak indirect demotivator. Of the 13 paths of the SEM model, 5 showed significant differences between the 2 samples (at the .05 level): general doubts about using the system (P = .02), the necessity for the system to be relevant for their job (P < .001), and the necessity for the system to be useful (P = .049) are more important for EHR nonusers than for users, while perceptions of overall obstacles to adoption (P = .03) and system ease of use (P = .042) count more for EHR users than for nonusers. Relatively few differences in perceptions about EHR system adoption and use exist between physicians already using such systems and those not yet using the systems. To maximize the chances of success for new EHR implementations from a behavioral point of view, general doubts about the rationale for such systems must be mitigated through improving design, stressing how EHRs are relevant to physician jobs, and providing substantiating evidence that EHRs are easier to use and more effective than nonusers might expect.


Parathyroid Hormone-Induced Bone Marrow Mesenchymal Stem Cell Chondrogenic Differentiation and its Repair of Articular Cartilage Injury in Rabbits.
BACKGROUND We explored the effect of parathyroid hormone (PTH)-induced bone marrow stem cells (BMSCs) complexed with fibrin glue (FG) in the repair of articular cartilage injury in rabbits. MATERIAL AND METHODS Forty-eight rabbits randomized into four groups were subjected to articular surgery (cartilage loss). The PTH and non-PTH intervention groups included transplantation with PTH/BMSC/FG xenogeneic and BMSC/FG xenogeneic complexes, respectively, into the injured area. The injured group contained no transplant while the control group comprised rabbits without any articular injury. Samples were monitored for cartilage repair up to three months post-surgery. Immunohistochemistry as well as real-time fluorescent quantitative PCR and Western blot were used to analyze the expression of type II collagen and aggrecan in the repaired tissue. RESULTS At 12 weeks post-surgery, the loss of articular cartilage in the PTH group was fully repaired by hyaline tissue. Typical cartilage lacunae and intact subchondral bone were found. The boundary separating the surrounding normal cartilage tissue disappeared. The gross and International Cartilage Repair Society (ICRS) histological ranking of the repaired tissue was significantly higher in the PTH intervention group than in the non-PTH intervention and injury groups (p<0.05) without any significant difference compared to the control group (p>0.05). Type II collagen and aggrecan stained positive and the average optical density, relative mRNA expression and protein-integrated optical density in the PTH group were higher than in non-PTH and injured groups (p<0.05) but not significantly different from the control group (p>0.05). CONCLUSIONS PTH/BMSC/FG xenogeneic complexes effectively repaired the loss of cartilage in rabbit knee injury.


Comparison of two methods of irrigant agitation in the removal of residual filling material in retreatment.
The aim of this study was to compare the efficacy of passive ultrasonic irrigation and EasyClean for removing residual filling material in retreatment. Twenty-two maxillary lateral incisors with apical curvature were instrumented with ProTaper files and filled with Endofill using the lateral compactation technique. Removal of filling material was performed with Reciproc, Mtwo and ProDesign Logic 50/.01 files. The teeth were inserted in a silicone mould, which was placed in a metal muffle, and split to visualize the residual filling material. The samples were divided into two groups (n = 11) according to the irrigation protocol: Passive ultrasonic irrigation (PUI group) with 3 activations of 20 seconds and EasyClean (Easy Equipamentos Odontológicos, Belo Horizonte, Brazil) (EC group) used in continuous rotation with 3 activations of 20 seconds, both using NaOCl and EDTA. Environmental scanning electron microscopic images of the apical, middle, and cervical thirds were taken before and after the irrigant activation. The Kappa test was used to determine interexaminer agreement. Statistical analysis was performed using Kruskal-Wallis, Mann-Whitney, and Wilcoxon tests (p < 0.05). PUI and EC improved the removal of remnant filling material in all root canal thirds (p < 0.05). PUI and EC presented similar performance in the final step of retreatment (p > 0.05). No significant difference was observed in the removal of filling material in the apical, middle, and cervical thirds in both groups (p > 0.05). EasyClean in continuous rotary motion is useful in retreatment and was shown to be as effective as ultrasonic activation in the removal of remnant filling material.


Intramuscular delivery of a naked DNA plasmid encoding proinsulin and pancreatic regenerating III protein ameliorates type 1 diabetes mellitus.
Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of β cells. Up to now, there is still no cure for this devastating disease and alternative approach should be developed. To explore a novel gene therapy strategy combining immunotherapy and β cell regeneration, we constructed a non-viral plasmid encoding proinsulin (PI) and pancreatic regenerating (Reg) III protein (pReg/PI). Therapeutic potentials of this plasmid for T1DM were investigated. Intramuscular delivery of pReg/PI resulted in a significant reduction in hyperglycemia and diabetes incidence, with an increased insulin contents in the serum of T1DM mice model induced by STZ. Treatment with pReg/PI also restored the balance of Th1/Th2 cytokines and expanded CD4(+)CD25(+)Foxp3(+) T regulatory cells, which may attribute to the establishment of self-immune tolerance. Additionally, in comparison to the mice treated with empty vector pBudCE4.1 (pBud), attenuated insulitis and apoptosis achieved by inhibiting activation of NF-κB in the pancreas of pReg/PI treated mice were observed. In summary, these results indicate that intramuscular delivery of pReg/PI distinctly ameliorated STZ-induced T1DM by reconstructing the immunological self-tolerance and promoting the regeneration of β cells, which might be served as a promising candidate for the gene therapy of T1DM.


Repertoire and evolution of miRNA genes in four divergent nematode species.
miRNAs are approximately 22-nt RNA molecules that play important roles in post-transcriptional regulation. We have performed small RNA sequencing in the nematodes Caenorhabditis elegans, C. briggsae, C. remanei, and Pristionchus pacificus, which have diverged up to 400 million years ago, to establish the repertoire and evolutionary dynamics of miRNAs in these species. In addition to previously known miRNA genes from C. elegans and C. briggsae we demonstrate expression of many of their homologs in C. remanei and P. pacificus, and identified in total more than 100 novel expressed miRNA genes, the majority of which belong to P. pacificus. Interestingly, more than half of all identified miRNA genes are conserved at the seed level in all four nematode species, whereas only a few miRNAs appear to be species specific. In our compendium of miRNAs we observed evidence for known mechanisms of miRNA evolution including antisense transcription and arm switching, as well as miRNA family expansion through gene duplication. In addition, we identified a novel mode of miRNA evolution, termed "hairpin shifting," in which an alternative hairpin is formed with up- or downstream sequences, leading to shifting of the hairpin and creation of novel miRNA* species. Finally, we identified 21U-RNAs in all four nematodes, including P. pacificus, where the upstream 21U-RNA motif is more diverged. The identification and systematic analysis of small RNA repertoire in four nematode species described here provides a valuable resource for understanding the evolutionary dynamics of miRNA-mediated gene regulation.


"Macromolecular crowding": thermodynamic consequences for protein-protein interactions within the T4 DNA replication complex.
In vitro biochemical assays are typically performed using very dilute solutions of macromolecular components. On the other hand, total intracellular concentrations of macromolecular solutes are very high, resulting in an in vivo environment that is significantly "volume-occupied." In vitro studies with the DNA replication proteins of bacteriophage T4 have revealed anomalously weak binding of T4 gene 45 protein to the rest of the replication complex. We have used inert macromolecular solutes to mimic typical intracellular solution conditions of high volume occupancy to investigate the effects of "macromolecular crowding" on the binding equilibria involved in the assembly of the T4 polymerase accessory proteins complex. The same approach was also used to study the assembly of this complex with T4 DNA polymerase (gene 43 protein) and T4 single-stranded DNA binding protein (gene 32 protein) to form the five protein "holoenzyme". We find that the apparent association constant (Ka) of gene 45 for gene 44/62 proteins in forming both the accessory protein complex and the holoenzyme increases markedly (from approximately 7 x 10(6) to approximately 3.5 x 10(8) M-1) as a consequence of adding polymers such as polyethylene glycol and dextran. Although the processivity of the polymerase alone is not directly effected by the addition of such polymers to the solution, macromolecular crowding does significantly stabilize the holoenzyme and thus indirectly increases the observed processivity of the holoenzyme complex. The use of macromolecular crowding to increase the stability of multienzyme complexes in general is discussed, as is the relevance of these results to DNA replication in vivo.


Physiological effects of Shinrin-yoku (taking in the atmosphere of the forest) in an old-growth broadleaf forest in Yamagata Prefecture, Japan.
The physiological effects of "Shinrin-yoku" (taking in the atmosphere of the forest) were examined by investigating blood pressure, pulse rate, heart rate variability (HRV), salivary cortisol concentration, and immunoglobulin A concentration in saliva. Subjective feelings of being "comfortable", "calm", and "refreshed" were also assessed by questionnaire. The subjects were 12 male university students aged from 21 to 23 (mean+/-SD: 22.0+/-1.0). The physiological measurements were conducted six times, i.e., in the morning and evening before meals at the place of accommodation, before and after the subjects walked a predetermined course in the forest and city areas for 15 minutes, and before and after they sat still on a chair watching the scenery in the respective areas for 15 minutes. The findings were as follows. In the forest area compared to the city area, 1) blood pressure and pulse rate were significantly lower, and 2) the power of the HF component of the HRV tended to be higher and LF/(LF+HF) tended to be lower. Also, 3) salivary cortisol concentration was significantly lower in the forest area. These physiological responses suggest that sympathetic nervous activity was suppressed and parasympathetic nervous activity was enhanced in the forest area, and that "Shinrin-yoku" reduced stress levels. In the subjective evaluation, 4) "comfortable", "calm", and "refreshed" feelings were significantly higher in the forest area. The present study has, by conducting physiological investigations with subjective evaluations as supporting evidence, demonstrated the relaxing and stress-relieving effects of "Shinrin-yoku".


The effect of MTAD, an endodontic irrigant, on fibroblast attachment to periodontally affected root surfaces: A SEM analysis.
Root surface debridement (RSD) is necessary to create an environment suitable for reattachment of the periodontium. Root surface conditioning may aid the formation of a biocompatible surface suitable for cell reattachment. BioPure™ MTAD (mixture of Doxycycline, citric acid and a detergent) is an endodontic irrigant with antibacterial properties and the ability to remove smear layer. It was hypothesized that MTAD may be useful for root surface conditioning. The efficacy of MTAD as a conditioner was measured by examining fibroblast attachment to root surfaces. Thirty-two specimens of human teeth with advanced periodontal disease were used. The surfaces were root planed until smooth. Half of the specimens were treated with 0.9% saline and the other samples with Biopure MTAD. As a negative control group, five further samples were left unscaled with surface calculus. Human gingival fibroblast cells HGF1-PI1 were cultured and poured over the tooth specimens and incubated. After fixation, the samples were sputter-coated with gold and examined with a SEM. The morphology and number of attached, fixed viable cells were examined. The data was analysed using the Mann-Whitney-U statistical test. There was no significant difference between the numbers of attached cells in the experimental group treated with MTAD and the control group treated with saline. Little or no attached cells were seen in the negative control group. RSD created an environment suitable for cell growth and attachment in a laboratory setting. The use of MTAD did not promote the attachment and growth of cells on the surface of human roots following RSD.


Spliceosome-mediated decay (SMD) regulates expression of nonintronic genes in budding yeast.
We uncovered a novel role for the spliceosome in regulating mRNA expression levels that involves splicing coupled to RNA decay, which we refer to as spliceosome-mediated decay (SMD). Our transcriptome-wide studies identified numerous transcripts that are not known to have introns but are spliced by the spliceosome at canonical splice sites in Saccharomyces cerevisiae. Products of SMD are primarily degraded by the nuclear RNA surveillance machinery. We demonstrate that SMD can significantly down-regulate mRNA levels; splicing at canonical splice sites in the bromodomain factor 2 (BDF2) transcript reduced transcript levels roughly threefold by generating unstable products that are rapidly degraded by the nuclear surveillance machinery. Regulation of BDF2 mRNA levels by SMD requires Bdf1, a functionally redundant Bdf2 paralog that plays a role in recruiting the spliceosome to the BDF2 mRNA. Interestingly, mutating BDF2 5' splice site and branch point consensus sequences partially suppresses the bdf1Δ temperature-sensitive phenotype, suggesting that maintaining proper levels of Bdf2 via SMD is biologically important. We propose that the spliceosome can also repress protein-coding gene expression by promoting nuclear turnover of spliced RNA products and provide an insight for coordinated regulation of Bdf1 and Bdf2 levels in the cell.


A naturally occurring bone marrow-chimeric primate. II. Environment dictates restriction on cytolytic T lymphocyte-target cell interactions.
Restriction on cytolytic T lymphocyte (CTL)-target cell-interactions are studied in the primate S. oedipus, a naturally occurring A + B----A bone marrow-chimeric species. We show that the T cell, B cell, and myelomonocytic progenitor cell populations are chimeric in this species. We selected animals for study that are populated by fully major histocompatibility complex (MHC)-disparate hematopoietic cell populations, using a functional assay system. We then developed an in vitro system for analyzing at the clonal level the genetic restrictions on the trinitrophenyl-specific CTL-target cell interactions of this species. In this system, we have shown that tolerance to foreign MHC determinants was not, of itself, sufficient to facilitate the generation of CTL specific for target cells expressing those foreign MHC determinants. Rather, a marked preference for the expansion of CTL clones with a restriction for target cells bearing the host animals' MHC determinants was seen. Hematopoietically derived cells did not affect the repertoire of these T lymphocytes. These studies represent the first demonstration of the phenomenon of an environment dictating interactional restrictions on CTL in a naturally occurring bone marrow-chimeric animal. This is also the first demonstration of the profound influence of the environment on the repertoire of the T lymphocyte in a primate species.


Computational estimation and experimental verification of off-target silencing during posttranscriptional gene silencing in plants.
Successful application of posttranscriptional gene silencing (PTGS) for gene function study in both plants and animals depends on high target specificity and silencing efficiency. By computational analysis with genome and/or transcriptome sequences of 25 plant species, we predicted that about 50% to 70% of gene transcripts in plants have potential off-targets when used for PTGS that could obscure experimental results. We have developed a publicly available Web-based computational tool called siRNA Scan to identify potential off-targets during PTGS. Some of the potential off-targets obtained from this tool were tested by measuring the amount of off-target transcripts using quantitative reverse transcription-PCR. Up to 50% of the predicted off-target genes tested in plants were actually silenced when tested experimentally. Our results suggest that a high risk of off-target gene silencing exists during PTGS in plants. Our siRNA Scan tool is useful to design better constructs for PTGS by minimizing off-target gene silencing in both plants and animals.


Current and Future Status of Diversity in Ophthalmologist Workforce.
Increasing the level of diversity among ophthalmologists may help reduce disparities in eye care. To assess the current and future status of diversity among ophthalmologists in the workforce by sex, race, and ethnicity in the context of the available number of medical students in the United States. Data from the Association of American Medical Colleges, the American Medical Association, and US Census were used to evaluate the differences and trends in diversity among ophthalmologists, all full-time faculty except ophthalmology, ophthalmology faculty, ophthalmology residents, medical school students, and the US population between 2005 and 2015. For 2014, associations of sex, race, and ethnicity with physician practice locations were assessed. Proportions of ophthalmologists stratified by sex, race, and ethnicity between 2005 and 2015. Women and minority groups traditionally underrepresented in medicine (URM)-black, Hispanic, American Indian, Alaskan Native, Native Hawaiian, and Pacific Islander-were underrepresented as practicing ophthalmologists (22.7% and 6%, respectively), ophthalmology faculty (35.1% and 5.7%, respectively), and ophthalmology residents (44.3% and 7.7%, respectively), compared with the US population (50.8% and 30.7%, respectively). During the past decade, there had been a modest increase in the proportion of female practicing ophthalmologists who graduated from US medical schools in 1980 or later (from 23.8% to 27.1%; P < .001); however, no increase in URM ophthalmologists was identified (from 7.2% to 7.2%; P = .90). Residents showed a similar pattern, with an increase in the proportion of female residents (from 35.6% to 44.3%; P = .001) and a slight decrease in the proportion of URM residents (from 8.7% to 7.7%; P = .04). The proportion of URM groups among ophthalmology faculty also slightly decreased during the study period (from 6.2% to 5.7%; P = .01). However, a higher proportion of URM ophthalmologists practiced in medically underserved areas (P < .001). Women and URM groups remain underrepresented in the ophthalmologist workforce despite an available pool of medical students. Given the prevalent racial and ethnic disparities in eye care and an increasingly diverse society, future research and training efforts that increase the level of diversity among medical students and residents seems warranted.


Pharmacokinetics of rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data.
In clinical trials of two rifamycin antibiotics (rifampin and rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB. After single or multiple doses of rifampin or rifapentine that produced human-equivalent plasma exposures, rabbits were sacrificed at different time points after dosing. We measured site-of-disease drug pharmacokinetics and tissue drug distribution. We used pharmacokinetic-pharmacodynamic (PK/PD) modeling to estimate drug penetration into different types of tubercular lesions. Both drugs penetrated rabbit lung cellular lesions, as well as the fibrotic cavity wall of cavitary lesions (penetration coefficients ≥1 compared to plasma). For the necrotic liquefied material inside cavitary lesions known as caseum (which contains high numbers of bacteria), the penetration coefficient was 1.0 for rifampin but only 0.25 for rifapentine. When estimates of site-of-disease drug PK were substituted into clinical PK/PD models, the relationship between site-of-action exposure and sputum culture conversion was significant (P < 10-7). We propose that poor penetration of rifapentine into lung cavitary lesions explains, in part, why rifapentine doses required to improve treatment outcomes in two phase 2 clinical trials were four times higher in TB patients with large cavities compared to TB patients without cavitary lung disease.


International Olympic Committee consensus statement: harassment and abuse (non-accidental violence) in sport.
Despite the well-recognised benefits of sport, there are also negative influences on athlete health, well-being and integrity caused by non-accidental violence through harassment and abuse. All athletes have a right to engage in 'safe sport', defined as an athletic environment that is respectful, equitable and free from all forms of non-accidental violence to athletes. Yet, these issues represent a blind spot for many sport organisations through fear of reputational damage, ignorance, silence or collusion. This consensus statement extends the 2007 IOC Consensus Statement on Sexual Harassment and Abuse in Sport, presenting additional evidence of several other types of harassment and abuse-psychological, physical and neglect. All ages and types of athletes are susceptible to these problems but science confirms that elite, disabled, child and lesbian/gay/bisexual/trans-sexual (LGBT) athletes are at highest risk, that psychological abuse is at the core of all other forms and that athletes can also be perpetrators. Harassment and abuse arise from prejudices expressed through power differences. Perpetrators use a range of interpersonal mechanisms including contact, non-contact/verbal, cyber-based, negligence, bullying and hazing. Attention is paid to the particular risks facing child athletes, athletes with a disability and LGBT athletes. Impacts on the individual athlete and the organisation are discussed. Sport stakeholders are encouraged to consider the wider social parameters of these issues, including cultures of secrecy and deference that too often facilitate abuse, rather than focusing simply on psychopathological causes. The promotion of safe sport is an urgent task and part of the broader international imperative for good governance in sport. A systematic multiagency approach to prevention is most effective, involving athletes, entourage members, sport managers, medical and therapeutic practitioners, educators and criminal justice agencies. Structural and cultural remedies, as well as practical recommendations, are suggested for sport organisations, athletes, sports medicine and allied disciplines, sport scientists and researchers. The successful prevention and eradication of abuse and harassment against athletes rests on the effectiveness of leadership by the major international and national sport organisations.