Four artemisinin-based treatments in African pregnant women with malaria.
Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).


Pulmonary function in children with systemic lupus erythematosus.
Abnormalities of pulmonary function have been found in children with systemic lupus erythematosus (SLE) even in the absence of clinical or radiographic evidence of pulmonary involvement. It is unknown whether these abnormalities represent an early sign of progressive lung disease or whether they are associated with disease activity. After a mean of 4.5 years, respiratory function (forced vital capacity (FVC) and single breath gas transfer factor (TLCO)) and disease activity were reexamined in 13 of 15 previously studied children with SLE. Disease activity was assessed by a validated index of SLE activity (SLE activity measure (SLAM)). In spite of the high prevalence of abnormalities of respiratory function at the baseline investigation, no chest radiographic abnormalities or overt clinical signs of lung disease were found at baseline, in the interval between the two investigations, or at the re-evaluation in any patient. From baseline to the second investigation the mean value of SLAM decreased and there was a trend toward an improvement in FVC and TLCO. TLCO was more severely impaired than FVC, being found as an isolated abnormality in a high percentage of patients (45% at baseline and 35% at follow up). There was a relationship between baseline TLCO and disease activity, expressed as a SLAM score. Moreover, there was a correlation between the changes in the SLAM score from baseline to the second investigation and the corresponding changes in the TLCO value, but not with the corresponding changes in the FVC value. In this series of patients the decrease in SLE activity from the first to the second investigation was associated with an improvement in pulmonary function. The presence of early isolated functional abnormalities was not associated with subsequent development of lung disease.


The effect of acetazolamide on hypercapnic and eucapnic/poikilocapnic hypoxic ventilatory responses in normal subjects.
We have studied the effect of acetazolamide 500 mg bd for three days on ventilatory response to CO2 (HCVR) and hypoxia under both isocapnic and poikilocapnic conditions (isocapnic and poikilocapnic HVR) in five normal subjects. Although acetazolamide reduced calculated arterial pH (7.41 [SEM] 0.01 to 7.37 [SEM] 0.01: p less than 0.01) there was no significant change in either isocapnic HVR (with PetCO2 held at the post-drug resting level) or poikilocapnic HVR in terms of slope and ventilation at SaO2 = 80%. HCVR slope rose slightly (+1.82 [SEM] 0.43 to +2.2 [SEM] 0.29 l/min/mmHg: NS) and there was a significant increase in ventilation at Pet-CO2 = 50 mmHg (9.42 [SEM] 3.3 to 31.4 [SEM] 6.31/min: p less than 0.01). These findings are consistent with the claim that acetazolamide stimulates central chemoreceptors and inhibits peripheral chemoreceptors. Increased sensitivity to CO2 would reverse the suppressive effect of respiratory alkalosis on hypoxic ventilatory drive following rapid ascent to high altitude, and this probably accounts for the efficacy of acetazolamide in the prophylaxis of acute mountain sickness. However, inhibition of peripheral chemoreceptors may also result in symptomatic benefit by reducing sleep disturbance due to periodic breathing.


Enhancement of the folate content in Egyptian pita bread.
Egypt has a high incidence of neural tube defects related to folate deficiency. One major food source for folate is pita (baladi) bread, which is consumed daily. Bioprocessing (e.g. germination) has been reported to increase the folate content in cereals. The aim was to produce pita bread with increased folate content using germinated wheat flour (GWF). Prior to milling the effects of germination and drying conditions on folate content in wheat grains were studied. Pita bread was baked from wheat flour substituted with different levels of GWF. The folate content in dough and bread and rheological properties of dough were determined. Germination of wheat grains resulted in, depending on temperature, 3- to 4-fold higher folate content with a maximum of 61 µg/100 g DM (dry matter). The folate content in both flour and bread increased 1.5 to 4-fold depending on the level of flour replacement with GWF. Pita bread baked with 50% sieved GWF was acceptable with respect to colour and layer separation, and had a folate content of 50 µg/100 g DM compared with 30 µg/100 g DM in conventional pita bread (0% GWF). Using 50% GWF, pita bread with increased folate content, acceptable for the Egyptian consumer, was produced. Consumption of this bread would increase the average daily folate intake by 75 µg.


Academic stress and personality interact to increase the neural response to high-calorie food cues.
Psychosocial stress is associated with an increased intake of palatable foods and weight gain in stress-reactive individuals. Personality traits have been shown to predict stress-reactivity. However, it is not known if personality traits influence brain activity in regions implicated in appetite control during psychosocial stress. The current study assessed whether Gray's Behavioural Inhibition System (BIS) scale, a measure of stress-reactivity, was related to the activity of brain regions implicated in appetite control during a stressful period. Twenty-two undergraduate students participated in a functional magnetic resonance imaging (fMRI) experiment once during a non-exam period and once during final exams in a counter-balanced order. In the scanner, they viewed food and scenery pictures. In the exam compared with the non-exam condition, BIS scores related to increased perceived stress and correlated with increased blood-oxygen-level dependent (BOLD) response to high-calorie food images in regions implicated in food reward and subjective value, such as the ventromedial prefrontal cortex, (vmPFC) and the amygdala. BIS scores negatively related to the functional connectivity between the vmPFC and the dorsolateral prefrontal cortex. The results demonstrate that the BIS trait influences stress reactivity. This is observed both as an increased activity in brain regions implicated in computing the value of food cues and decreased connectivity of these regions to prefrontal regions implicated in self-control. This suggests that the effects of real life stress on appetitive brain function and self-control is modulated by a personality trait. This may help to explain why stressful periods can lead to overeating in vulnerable individuals.


The Association Between Social Media Use and Hazardous Alcohol Use Among Youths: A Four-Country Study.
To examine the continuing role of daily popular social media use in youth hazardous alcohol consumption in four countries across continents. A web-based survey was given to youths aged 15-25 in the USA (n = 1212), South Korea (n = 1192), Finland (n = 1200) and Spain (n = 1212). Hazardous alcohol use (alcohol use disorders identification test-C) was the dependent variable. Main independent variables measured daily use of different social media services. Controls included compulsive Internet use, offline belonging, psychological distress, impulsivity, risk-taking, age and gender. Linear regression models and mediation analyses with bootstrapping were done for each country. Daily use of Facebook and Instagram was associated with higher hazardous alcohol use among youths in Finland, South Korea and Spain. Daily instant messaging was related to higher hazardous alcohol use among South Korean and Finnish youths. Daily YouTube use was associated with higher hazardous alcohol use among youths in South Korea, but lower hazardous alcohol use among youths in the USA and Finland. Daily Twitter use was related to lower hazardous drinking among youths in Finland but higher hazardous drinking among youths in Spain. The mediation analyses revealed that uploading pictures to social media is a possible facilitator of social media-related hazardous alcohol use among youths in the USA and Spain. Certain social media platforms might inspire and/or attract hazardously drinking youths, contributing to the growing opportunities for social media interventions.


Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation.
Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations.


The effect of conditioning period on loin muscle tenderness in crossbred lambs with or without the Texel muscling QTL (TM-QTL).
A Texel muscling quantitative trait locus (TM-QTL) has been identified on chromosome 18, which increases loin muscling, but may also have a negative impact on mechanically-measured loin tenderness in crossbred lambs, depending on conditioning time. This study investigated the influence of a range of conditioning times (3, 5, 7 or 9 days) on the effect of TM-QTL on loin muscle tenderness. Using Texel rams heterozygous for TM-QTL, mated to non-carrier Mule ewes, heterozygous (n=45) and wild-type (n=50) crossbred lambs were produced. Weight of the valuable Longissimus lumborum muscle was higher in TM-QTL carriers than non-carriers, when compared at a fixed age (+11.5%; P=0.038), with the same trend at a fixed carcass weight (+10.2%; P=0.064). Toughness, measured by shear force, was significantly higher in samples from TM-QTL carriers than non-carriers, after conditioning for 3 days (P=0.002), 5 days (P=0.003) or 7 days (P=0.03), but was not significantly different after 9 days of conditioning (P=0.32). Compared to non-carrier lambs, the proportion of samples above consumer acceptability thresholds for toughness was greater in the TM-QTL carrier lambs after 3 and 5 days of conditioning, similar at 7 days, but lower at 9 days. The results suggest that the negative effect of TM-QTL on loin tenderness in crossbred lambs can be overcome by conditioning for more than 7 days. Marketing of TM-QTL carrier lambs through companies that use enhanced processing protocols could be beneficial, due to higher loin muscle weights, without negative effects on meat quality.


Characteristic immunostimulation by angelan isolated from Angelica gigas Nakai.
The immunopharmacological characteristics of angelan, a polysaccharide purified from Angelica gigas Nakai, were investigated in relation to the specificity to immune cells. The treatment of angelan increased the expression of IL-2, IL-4, IL-6, and IFN-gamma. The expression of IL-6 and IFN-gamma was rapidly augmented but that of IL-2 responded later. In the case of IL-4, angelan stimulated at early time after exposure but down-regulated thereafter. These results suggested that macrophages and natural killer cells involved in nonspecific immunity were primarily activated and helper T cells were secondarily affected by angelan. Angelan also had lympho-proliferative potential to B cells, specifically. The specificity of angelan was also elucidated in a cell fractionation experiment. The activated B cells by angelan also increased antibody production. The direct activation of B cells, macrophages, and accessory cells and the indirect activation of helper T cells coordinately increased immune functions such as in vitro and in vivo T-dependent immunization and antibody production. The experiment of host resistance to syngeneic tumors also showed that angelan potentiated the immune functions. In conclusion, angelan, a purified polysaccharide from an oriental herbal drug, showed characteristic immunostimulation, which was different from clinically used polysaccharides such as lentinan and PSK.


Regulation of Bacterial Gene Expression by Transcription Attenuation.
A wide variety of mechanisms that control gene expression in bacteria are based on conditional transcription termination. Generally, in these mechanisms, a transcription terminator is located between a promoter and a downstream gene(s), and the efficiency of the terminator is controlled by a regulatory effector that can be a metabolite, protein, or RNA. The most common type of regulation involving conditional termination is transcription attenuation, in which the primary regulatory target is an essential element of a single terminator. The terminator can be either intrinsic or Rho dependent, with each presenting unique regulatory targets. Transcription attenuation mechanisms can be divided into five classes based primarily on the manner in which transcription termination is rendered conditional. This review summarizes each class of control mechanisms from a historical perspective, describes important examples in a physiological context and the current state of knowledge, highlights major advances, and discusses expectations of future discoveries.


Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I.
We analyzed the mechanism of axonal transport of the amyloid precursor protein (APP), which plays a major role in the development of Alzheimer's disease. Coimmunoprecipitation, sucrose gradient, and direct in vitro binding demonstrated that APP forms a complex with the microtubule motor, conventional kinesin (kinesin-I), by binding directly to the TPR domain of the kinesin light chain (KLC) subunit. The estimated apparent Kd for binding is 15-20 nM, with a binding stoichiometry of two APP per KLC. In addition, association of APP with microtubules and axonal transport of APP is greatly decreased in a gene-targeted mouse mutant of the neuronally enriched KLC1 gene. We propose that one of the normal functions of APP may be as a membrane cargo receptor for kinesin-I and that KLC is important for kinesin-I-driven transport of APP into axons.


Reassessing bioavailability of silymarin.
Silymarin, a flavonolignan derived from Silybum marianum, possesses diverse pharmacological activities, including hepatoprotective, antioxidant, anti-inflammatory, anticancer, and cardioprotective. Although clinical trials have shown silymarin is safe at high doses (>1500 mg/day) in humans, the pharmacokinetic studies over the past three decades related to absorption, distribution, metabolism, and excretion of silymarin have revealed poor absorption, rapid metabolism, and ultimately poor oral bioavailability. For optimum silymarin bioavailability, issues of solubility, permeability, metabolism, and excretion must be addressed. An array of methods have been described in recent years that can improve its bioavailability, including complexation with β-cyclodextrins, solid dispersion method, formation of microparticles and nanoparticles, self-microemulsifying drug delivery systems, micelles, liposomes, and phytosomes. This article critically reviews the recent published literature on various techniques for increasing the bioavailability of silymarin.


Lord Mountbatten's The Last Supper: How the British empire botched up the future of India, Pakistan and Bangladesh.
The Lancet, a leading health science journal, has published a political editorial, raising interest in the impact of British colonization on the current status of healthcare, economy and development of the Indian subcontinent. Over two centuries, the East India Company and the British empire siphoned out at least £ 9.2 trillion; or $44.6 trillion; since the exchange rate was $4.8 per pound sterling during much of the colonial period. It is to be noted that the life expectancy of Indians at birth was just 22 years in 1911. Food grain was available, however the purchasing power of ordinary Indians was being squeezed. The per capita annual consumption of food grains went down from 200kg in 1900 to 157kg on the eve of World War II, and further down to 37kg by 1946 (Prof Utsa Patnaik). The Indian sub-continent has still not recovered from the systemic malnutrition inflicted upon the population. Today, just under two billion people, or a quarter of the earth's population, live in India, Pakistan and Bangladesh. The landlocked populations of these countries are known as the black hole of humanity, waiting for ultimate catastrophe- either natural or man-made humanitarian crisis. What happens to these countries now was determined long before and planned by the British empire when their representatives packed bags and transferred power to the local natives. The partition of India was the most tragic ever human genocide artificially perpetrated in the human history. More than 14 million people were displaced and close to two million people died or went missing. It was the parting gift by the British empire to the people of the Indian sub-continent. This was more tragic than the holocaust. A permanent scar and hatred that would not heal even after a century was created by the British empire. The 200 years of anti-incumbency and hatred against the British was forgotten and used to build a civil war. Enough hatred was fumed between the native population of India and Pakistan. This hatred was further institutionalized between the two countries by having them develop separate militaries. It was a grand exit plan for the empire, leaving behind no traces of the crime, while keeping their aura of pride and benevolence intact. After seventy years, it is important to revisit the political circumstances prevailing during the colonial period. It is important for the people India, Pakistan and Bangladesh to think about the future and not be victims of the political game rolled out as an exit plan by the empire.


Hippocampal plasticity underpins long-term cognitive gains from resistance exercise in MCI.
Dementia affects 47 million individuals worldwide, and assuming the status quo is projected to rise to 150 million by 2050. Prevention of age-related cognitive impairment in older persons with lifestyle interventions continues to garner evidence but whether this can combat underlying neurodegeneration is unknown. The Study of Mental Activity and Resistance Training (SMART) trial has previously reported within-training findings; the aim of this study was to investigate the long-term neurostructural and cognitive impact of resistance exercise in Mild Cognitive Impairment (MCI). For the first time we show that hippocampal subareas particularly susceptible to volume loss in Alzheimer's disease (AD) are protected by resistance exercise for up to one year after training. One hundred MCI participants were randomised to one of four training groups: (1) Combined high intensity progressive resistance and computerised cognitive training (PRT+CCT), (2) PRT+Sham CCT, (3) CCT+Sham PRT, (4) Sham physical+sham cognitive training (SHAM+SHAM). Physical, neuropsychological and MRI assessments were carried out at baseline, 6 months (directly after training) and 18 months from baseline (12 months after intervention cessation). Here we report neuro-structural and functional changes over the 18-month trial period and the association with global cognitive and executive function measures. PRT but not CCT or PRT+CCT led to global long-term cognitive improvements above SHAM intervention at 18-month follow-up. Furthermore, hippocampal subfields susceptible to atrophy in AD were protected by PRT revealing an elimination of long-term atrophy in the left subiculum, and attenuation of atrophy in left CA1 and dentate gyrus when compared to SHAM+SHAM (p = 0.023, p = 0.020 and p = 0.027). These neuroprotective effects mediated a significant portion of long-term cognitive benefits. By contrast, within-training posterior cingulate plasticity decayed after training cessation and was unrelated to long term cognitive benefits. Neither general physical activity levels nor fitness change over the 18-month period mediated hippocampal trajectory, demonstrating that enduring hippocampal subfield plasticity is not a simple reflection of post-training changes in fitness or physical activity participation. Notably, resting-state fMRI analysis revealed that both the hippocampus and posterior cingulate participate in a functional network that continued to be upregulated following intervention cessation. Multiple structural mechanisms may contribute to the long-term global cognitive benefit of resistance exercise, developing along different time courses but functionally linked. For the first time we show that 6 months of high intensity resistance exercise is capable of not only promoting better cognition in those with MCI, but also protecting AD-vulnerable hippocampal subfields from degeneration for at least 12 months post-intervention. These findings emphasise the therapeutic potential of resistance exercise; however, future work will need to establish just how long-lived these outcomes are and whether they are sufficient to delay dementia.


Nurse-physician relations and quality of nursing care: findings from a national survey of nurses.
This article investigates the association between nurse-physician working relations and nurse-rated quality of nursing team care.The analysis is based on a nationally representative sample of registered nurses working in Canadian hospitals. Multiple logistic regression was used to examine the association between the quality of nurse-physician working relations and nurses' reports of fair or poor nursing team care on the last shift worked. Unfavourable quality of nurse-physician working relations was significantly related to lower quality of nursing team care, controlling for other potential influences. These influences included low nurse co-worker support, job dissatisfaction, and self-rated poor general health, each of which was also related to lower care quality.The analysis highlights the importance of interprofessional working relations to nurse-perceived quality of patient care in Canadian hospitals.


The suppressive field of neurons in lateral geniculate nucleus.
The responses of neurons in lateral geniculate nucleus (LGN) exhibit powerful suppressive phenomena such as contrast saturation, size tuning, and masking. These phenomena cannot be explained by the classical center-surround receptive field and have been ascribed to a variety of mechanisms, including feedback from cortex. We asked whether these phenomena might all be explained by a single mechanism, contrast gain control, which is inherited from retina and possibly strengthened in thalamus. We formalized an intuitive model of retinal contrast gain control that explicitly predicts gain as a function of local contrast. In the model, the output of the receptive field is divided by the output of a suppressive field, which computes the local root-mean-square contrast. The model provides good fits to LGN responses to a variety of stimuli; with a single set of parameters, it captures saturation, size tuning, and masking. It also correctly predicts that responses to small stimuli grow proportionally with contrast: were it not for the suppressive field, LGN responses would be linear. We characterized the suppressive field and found that it is similar in size to the surround of the classical receptive field (which is eight times larger than commonly estimated), it is not selective for stimulus orientation, and it responds to a wide range of frequencies, including very low spatial frequencies and high temporal frequencies. The latter property is hardly consistent with feedback from cortex. These measurements thoroughly describe the visual properties of contrast gain control in LGN and provide a parsimonious explanation for disparate suppressive phenomena.


Prevalence and impact of cardiovascular risk factors among patients presenting with acute coronary syndrome in the middle East.
The authors explored the prevalence and impact of the cardiovascular risk factors (CVRFs) in patients presenting with acute coronary syndrome (ACS). During a five-month period in 2007, six adjacent Middle Eastern countries participated in the Gulf Registry of acute coronary events. CVRFs were identified on admission. Patients' characteristics and in-hospital outcomes were analyzed across the types of ACS. Among 6704 consecutive patients with ACS, 61% had non-ST elevation ACS (NSTEACS) and 39% had ST-elevation myocardial infarction (STEMI). Female sex, old age, diabetes mellitus, hypertension, dyslipidemia, and obesity were more prevalent in NSTEACS patients. STEMI patients were more likely to be smokers and less likely to be taking aspirin prior to the index admission. Chronic renal failure (CRF) and diabetes mellitus were independent predictors of in-hospital heart failure in NSTEACS, while CRF and hypertension were predictors of STEMI. Female sex and CRF were independent predictors of mortality in STEMI (odds ratio, 2.0; 95% confidence interval, 1.19-3.13 and odds ratio, 5.0; 95% confidence interval, 3.47-7.73, respectively). Assessment of the prevalence of CVRF in the acute coronary presentation is of important prognostic value for in-hospital morbidity and mortality. CVRF and its impact may differ according to ACS type, age, and sex. Coronary heart disease (CHD) is the leading cause of mortality and morbidity worldwide. To achieve a significant reduction in the prevalence of CHD, it is essential to adopt effective preventive strategies with adequate awareness of the epidemiology of cardiovascular risk factors (CVRFs).1 CVRFs include traditional and nontraditional factors. However, the US Preventive Services Task Force concluded that the evidence is insufficient to assess the balance of benefits and harms of using nontraditional risk factors.2,3 The World Health Organization has recognized obesity, hypertension, hypercholesterolemia, and smoking among the top10 traditional risk factors for premature death and morbidity.4 Since these risk factors are usually evident before developing CHD, knowledge of their prevalence in a given population allows the prediction of the likely burden of CHD.3 The American Heart Association has recognized many risk factors; some can be modified, treated, or controlled and some can not.5 The more risk factors present, the greater the likelihood of developing CHD. Currently, most reports for prevention of CHD are mainly derived from European centers and suggest that risk factors for CHD are varying from country to country.6 However, data from the Arab Middle East that evaluate the prevalence and impact of these risk factors in acute coronary events are scarce.4,7,8 We explore the prevalence of CVRFs in patients with acute coronary syndrome (ACS) who are living in the Arab Middle East and the impact of these factors on in-hospital heart failure (HF) and mortality. Copyright © 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose.


Surveillance Systems to Track Progress Toward Polio Eradication - Worldwide, 2015-2016.
Global measures to eradicate polio began in 1988; as of 2014, four of six World Health Organization (WHO) regions have been certified polio-free. Within the two endemic regions (African and Eastern Mediterranean), Nigeria, Afghanistan, and Pakistan have never interrupted transmission of wild poliovirus (WPV) (1). The primary means of detecting poliovirus transmission is surveillance for acute flaccid paralysis (AFP) among children aged <15 years, combined with collection and testing of stool specimens from persons with AFP for detection of WPV and vaccine-derived polioviruses (VDPVs) (viruses that differ genetically from vaccine viruses and can emerge in areas with low vaccination coverage and cause paralysis) in WHO-accredited laboratories within the Global Polio Laboratory Network (2,3). AFP surveillance is supplemented by environmental surveillance for polioviruses in sewage from selected locations (4). Genomic sequencing of the VP1-coding region of isolated polioviruses enables mapping transmission by time and place, assessment of potential gaps in surveillance, and identification of the emergence of VDPVs. This report presents poliovirus surveillance data from 2015 and 2016, with particular focus on 20 countries in the African Region and six in the Eastern Mediterranean Region that reported WPV or circulating VDPVs (cVDPVs) during 2011-2016, as well as the three countries most affected by the 2014-2015 Ebola virus disease (Ebola) outbreak (Guinea, Liberia, and Sierra Leone). During 2016, 12 (60%) of the 20 African Region countries and all six of the Eastern Mediterranean Region countries met both surveillance quality indicators (nonpolio AFP rates of ≥2 per 100,000 persons aged <15 years per year and ≥80% of AFP cases with adequate stool specimens [stool adequacy]) at the national level; however, provincial-level variation was seen. To complete and certify polio eradication, surveillance gaps must be identified and surveillance activities, including supervision, monitoring, and specimen collection and handling, further strengthened.


Training inpatient mental health staff how to enhance patient engagement with medications: Medication Alliance training and dissemination outcomes in a large US mental health hospital.
The Medication Alliance training programme has previously been shown to be effective in enhancing clinician knowledge, attitudes and skills in regard to non-adherent individuals in a community-based psychiatric setting. The current study attempts to replicate these findings in an inpatient setting and assess the feasibility of dissemination using a train-the-trainer model. One hundred and thirteen staff from four wards at an inpatient psychiatric facility attended Medication Alliance training workshops over 3 days. Two wards comprised an expert trained group (n = 67); and the remaining two wards made up a novice trained group (n = 46). The novice trained group attended training 6 months after the expert group, and were trained by selected trainees from the expert group. Participants completed a package of questionnaires both before and after their training to determine if Medication Alliance resulted in any changes in knowledge, attitudes and skills. Paired t-tests showed significant improvements across both groups for knowledge, attitudes and one skill domain following training in Medication Alliance. There were no differences at baseline between groups and analysis of post-test scores yielded no significant difference between the groups in terms of training effect for knowledge, attitudes or skills. Medication Alliance can be successfully implemented in an inpatient setting, enhancing knowledge, attitudes and at least some skill domains of staff in dealing with non-adherent patients. The equivalence of results between the expert and novice trained training groups suggests that Medication Alliance may be more broadly disseminated using a cost-effective train-the-trainer model.


GPI-anchored protein organization and dynamics at the cell surface.
The surface of eukaryotic cells is a multi-component fluid bilayer in which glycosylphosphatidylinositol (GPI)-anchored proteins are an abundant constituent. In this review, we discuss the complex nature of the organization and dynamics of GPI-anchored proteins at multiple spatial and temporal scales. Different biophysical techniques have been utilized for understanding this organization, including fluorescence correlation spectroscopy, fluorescence recovery after photobleaching, single particle tracking, and a number of super resolution methods. Major insights into the organization and dynamics have also come from exploring the short-range interactions of GPI-anchored proteins by fluorescence (or Förster) resonance energy transfer microscopy. Based on the nanometer to micron scale organization, at the microsecond to the second time scale dynamics, a picture of the membrane bilayer emerges where the lipid bilayer appears inextricably intertwined with the underlying dynamic cytoskeleton. These observations have prompted a revision of the current models of plasma membrane organization, and suggest an active actin-membrane composite.


Effectiveness of Proactive Tobacco Cessation Treatment Outreach Among Smokers With Serious Mental Illness.
People with serious mental illness (SMI) have a high smoking prevalence and low quit rates. Few cessation treatments are tested in smokers with SMI. Mental health (MH) providers are reluctant to address smoking. Proactive tobacco cessation treatment strategies reach out directly to smokers to offer counseling and medication and improve treatment utilization and quit rates. The current study is a secondary analysis of a randomized controlled trial of proactive outreach for tobacco cessation treatment in VA MH patients. Participants (N = 1938, 83% male, mean age 55.7) across four recruitment sites, who were current smokers and had a MH visit in the past 12 months, were identified using the electronic medical record. Participants were randomized to Intervention (telephone outreach call plus invitation to engage in MH tailored telephone counseling and assistance obtaining nicotine replacement therapy) or Control (usual care). The current study assessed outcomes in participants with SMI (N = 982). Compared to the Control group, participants assigned to the Intervention group were more likely to engage in telephone counseling (22% vs. 3%) and use nicotine replacement therapy (51% vs. 41%). Participants in the Intervention group were more likely to be abstinent (7-day point prevalence; 18%) at 12 months than participants in the Control group (11%) but equally likely to make quit attempts. Proactive tobacco cessation treatment is an effective strategy for tobacco users with SMI. Proactive outreach had a particularly strong effect on counseling utilization. Future randomized clinical trials examining proactive tobacco treatment approaches in SMI treatment settings are needed. Few effective treatment models exist for smokers with SMI. Proactive tobacco cessation outreach with connections to MH tailored telephone counseling and medication promotes tobacco abstinence among smokers with SMI and is an effective treatment strategy for this underserved population.


Commitment to relationships and preferences for femininity and apparent health in faces are strongest on days of the menstrual cycle when progesterone level is high.
Previous studies of changes in women's behavior during the menstrual cycle have offered insight into the motivations underpinning women's preferences for social cues associated with possible direct benefits (e.g., investment, low risk of infection) and indirect benefits (e.g., offspring viability). Here we sought to extend this work by testing for systematic variation in women's preferences for male and female faces and in their attitudes to their romantic relationship during the menstrual cycle. In Study 1, we found partnered women's reported commitment to their romantic relationship and preferences for femininity in male and female faces were strongest on days of the menstrual cycle when progesterone levels are increased (and fertility is low). Happiness in relationships did not change across the cycle. In Study 2, we found that the effect of cycle phase on women's preference for feminine faces was independent of increased attraction to apparent health in faces during the luteal phase. Collectively, these findings are further evidence that women's preferences for social cues associated with possible direct benefits and commitment to relationships are strongest during conditions characterized by raised progesterone level, while attraction to men displaying cues associated with possible indirect benefits is strongest when women are most fertile.


Collagen-based structures containing the peptoid residue N-isobutylglycine (Nleu): synthesis and biophysical studies of Gly-Nleu-Pro sequences by circular dichroism and optical rotation.
Single-chain peptide-peptoid structures, Ac-(Gly-Nleu-Pro)n-NH2 (n = 3, 6, and 10) and (Gly-Nleu-Pro)n-NH2 (n = 1 and 9), and template-assembled collagen analogs, KTA-[Gly-(Gly-Nleu-Pro)n-NH2]3 (n = 3 and 6; KTA represents cis,cis-1,3,5-trimethylcyclohexane-1,3, 5-tricarboxylic acid, also known as the Kemp triacid; Nleu denotes N-isobutylglycine), were prepared by solid-phase peptide synthesis methods. Biophysical studies using circular dichroism (CD) and optical rotation measurements show that these collagen analogs form triple-helical conformations when the chain is longer than a critical length. Unlike collagen-based structures composed of Gly-Pro-Hyp and Gly-Pro-Nleu sequences, results reveal that the presence of a positive CD peak between 220 and 225 nm is indicative of triple-helical conformations for these collagen-based structures composed of Gly-Nleu-Pro sequences. Results also indicate that the Gly-Nleu-Pro sequence possesses a higher triple-helical propensity than the Gly-Pro-Nleu sequence as demonstrated by the higher melting temperatures, the faster triple-helix folding, and the lower minimum concentration necessary to detect triple-helicity for the single-chain structures. Therefore, we conclude that the Nleu residue in the second position of the trimeric repeat is more effective in inducing triple-helix formation than Pro in the same position.


Adaptive neuro-fuzzy inference system for real-time monitoring of integrated-constructed wetlands.
Monitoring large-scale treatment wetlands is costly and time-consuming, but required by regulators. Some analytical results are available only after 5 days or even longer. Thus, adaptive neuro-fuzzy inference system (ANFIS) models were developed to predict the effluent concentrations of 5-day biochemical oxygen demand (BOD5) and NH4-N from a full-scale integrated constructed wetland (ICW) treating domestic wastewater. The ANFIS models were developed and validated with a 4-year data set from the ICW system. Cost-effective, quicker and easier to measure variables were selected as the possible predictors based on their goodness of correlation with the outputs. A self-organizing neural network was applied to extract the most relevant input variables from all the possible input variables. Fuzzy subtractive clustering was used to identify the architecture of the ANFIS models and to optimize fuzzy rules, overall, improving the network performance. According to the findings, ANFIS could predict the effluent quality variation quite strongly. Effluent BOD5 and NH4-N concentrations were predicted relatively accurately by other effluent water quality parameters, which can be measured within a few hours. The simulated effluent BOD5 and NH4-N concentrations well fitted the measured concentrations, which was also supported by relatively low mean squared error. Thus, ANFIS can be useful for real-time monitoring and control of ICW systems.


Charge-transport model for conducting polymers.
The growing technological importance of conducting polymers makes the fundamental understanding of their charge transport extremely important for materials and process design. Various hopping and mobility edge transport mechanisms have been proposed, but their experimental verification is limited to poor conductors. Now that advanced organic and polymer semiconductors have shown high conductivity approaching that of metals, the transport mechanism should be discernible by modelling the transport like a semiconductor with a transport edge and a transport parameter s. Here we analyse the electrical conductivity and Seebeck coefficient together and determine that most polymers (except possibly PEDOT:tosylate) have s = 3 and thermally activated conductivity, whereas s = 1 and itinerant conductivity is typically found in crystalline semiconductors and metals. The different transport in polymers may result from the percolation of charge carriers from conducting ordered regions through poorly conducting disordered regions, consistent with what has been expected from structural studies.


Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli.
Chaperone-usher pathway pili are extracellular proteinaceous fibres ubiquitously found on Gram-negative bacteria, and mediate host-pathogen interactions and biofilm formation critical in pathogenesis in numerous human diseases1. During pilus assembly, an outer membrane macromolecular machine called the usher catalyses pilus biogenesis from the individual subunits that are delivered as chaperone-subunit complexes in the periplasm. The usher orchestrates pilus assembly using all five functional domains: a 24-stranded transmembrane β-barrel translocation domain, a β-sandwich plug domain, an amino-terminal periplasmic domain and two carboxy-terminal periplasmic domains (CTD1 and CTD2)2-6. Despite extensive structural and functional characterization, the mechanism by which the usher is activated to initiate pilus biogenesis is unknown. Here, we present the crystal structure of the full-length PapC usher from Escherichia coli in complex with its cognate PapDG chaperone-subunit complex in a pre-activation state, elucidating molecular details of how the usher is specifically engaged by allosteric interactions with its substrate preceding activation and how the usher facilitates the transfer of subunits from the amino-terminal periplasmic domain to the CTDs during pilus assembly. This work elucidates the intricate workings of a molecular machine that catalyses chaperone-usher pathway pilus assembly and opens the door for the development of potent inhibitors to block pilus biogenesis.


Upregulation of transmembrane endothelial junction proteins in human cerebral cavernous malformations.
Cerebral cavernous malformations (CCMs) are among the most prevalent cerebrovascular malformations, and endothelial cells seem to play a major role in the disease. However, the underlying mechanisms, including endothelial intercellular communication, have not yet been fully elucidated. In this article, the authors focus on the endothelial junction proteins CD31, VE-cadherin, and occludin as important factors for functional cell-cell contacts known as vascular adhesion molecules and adherence and tight junctions. Thirteen human CCM specimens and 6 control tissue specimens were cryopreserved and examined for the presence of VE-cadherin, occludin, and CD31 by immunofluorescence staining. Protein quantification was performed by triplicate measurements using western blot analysis. Immunofluorescent analyses of the CCM sections revealed a discontinuous pattern of dilated microvessels and capillaries as well as increased expression of occludin, VE-cadherin, and CD31 in the intima and in the enclosed parenchymal tissue compared with controls. Protein quantification confirmed these findings by showing upregulation of the levels of these proteins up to 2-6 times. A protocol enabling the molecular and morphological examination of the intercellular contact proteins in human CCM was validated. The abnormal and discontinuous pattern in these endothelial cell-contact proteins compared with control tissue explains the loose intercellular junctions that are considered to be one of the causes of CCM-associated bleeding or transendothelial oozing of erythrocytes. Despite the small number of specimens, this study demonstrates for the first time a quantitative analysis of endothelial junction proteins in human CCM.


Aluminum bases for the highly chemoselective preparation of aryl and heteroaryl aluminum compounds.
Selective C-H activation with a series of neutral aluminum trisamide bases led to a wide range of polyfunctional aryl and heteroaryl aluminum reagents. Ester and cyano groups are stable under the reaction conditions for this direct alumination, and donor oxygen substituents are efficient directing groups. High metalation regioselectivities were observed with O,S and N,S heterocycles (see example).


Liposomal pemetrexed: formulation, characterization and in vitro cytotoxicity studies for effective management of malignant pleural mesothelioma.
Pemetrexed (PMX) is a newly developed multi-targeted anti-folate with promising clinical activity in many solid tumors including malignant pleural mesothelioma (MPM). However, PMX does not show sufficient anti-tumor activity in vivo when used alone either due to inefficient delivery of adequate concentrations to tumor tissue or dose-limiting side effects. In order to overcome these problems and to achieve potent anti-tumor activity, PMX was encapsulated into a liposomal delivery system. In the present study, various formulations of liposomal PMX were prepared. The effect of formulation parameters on the encapsulation efficiency of PMX within liposomes was evaluated. In addition, the influence of drug release rate on the in vitro cytotoxicity was investigated. Encapsulation of PMX within liposomes was remarkably increased by the incorporation of cholesterol within liposomal membranes and by increasing the total lipid concentration. Encapsulation efficiency was found to be unaffected by the type of phospholipid used or the inclusion of a cation lipid, DC-6-14. Interestingly, encapsulation of PMX within "fluid" liposomes was found to allow efficient release of PMX from liposomes resulting in a potent in vitro cytotoxicity against MPM MSTO-211H cell line. On the other hand, entrapment of PMX within "solid" liposomes substantially hindered PMX release from liposomes, and thus PMX failed to exert any in vitro cytotoxicity. These results suggest that encapsulation of PMX within "fluid" liposomes might represent a novel strategy to enhance the therapeutic efficacy of PMX while minimizing the side effect encountered by the non selective delivery of free PMX to various body tissues.


Instruments for measuring meaningful learning in healthcare students: a systematic psychometric review.
To identify, evaluate and describe the psychometric properties of instruments that measure learning outcomes in healthcare students. Meaningful learning is an active process that enables a wider and deeper understanding of concepts. It is the result of an interaction between new and prior knowledge and produces a long-standing change in knowledge and skills. In the field of education, validated and reliable instruments for assessing meaningful learning are needed. A psychometric systematic review. MEDLINE CINAHL, SCOPUS, ERIC, Cochrane Library, Psychology & Behavioural Sciences Collection Database from 1990-December 2013. Using pre-determined inclusion criteria, three reviewers independently identified studies for full-text review. Then they extracted data for quality appraisal and graded instrument validity using the Consensus-based Standards for the selection of the health status Measurement INstruments checklist and the Psychometric Grading Framework. Of the 57 studies identified for full-text review, 16 met the inclusion criteria and 13 different instruments were assessed. Following quality assessment, only one instrument was considered of good quality but it measured meaningful learning only in part; the others were either fair or poor. The Psychometric Grading Framework indicated that one instrument was weak, while the others were very weak. No instrument displayed adequate validity. The systematic review produced a synthesis of the psychometric properties of tools that measure learning outcomes in students of healthcare disciplines. Measuring learning outcomes is very important when educating health professionals. The identified tools may constitute a starting point for the development of other assessment tools.


Amantadine and rimantadine for preventing and treating influenza A in adults.
Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but these drugs are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. The objective of this review was to assess the effectiveness and safety ("effects") of amantadine and rimantadine in healthy adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2003), MEDLINE (January 1966 to November week 2, 2003), EMBASE (January 1990 to September 2003) and the reference lists of articles. We also contacted manufacturers, researchers and authors. Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control antivirals or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. For prevention trials the numbers of participants with clinical influenza (influenza-like-illness or ILI), i.e. confirmed influenza A, and adverse effects were analysed. Analysis for treatment trials included the mean duration of fever and length of hospital stay, and the number of adverse effects. Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.3). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prevention were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. Amantadine and rimantadine have comparable effectiveness in the prevention and treatment of influenza A in healthy adults, although rimantadine causes fewer adverse effects than amantadine.


Comparative study of fixation density maps.
Fixation density maps (FDM) created from eye tracking experiments are widely used in image processing applications. The FDM are assumed to be reliable ground truths of human visual attention and as such, one expects a high similarity between FDM created in different laboratories. So far, no studies have analyzed the degree of similarity between FDM from independent laboratories and the related impact on the applications. In this paper, we perform a thorough comparison of FDM from three independently conducted eye tracking experiments. We focus on the effect of presentation time and image content and evaluate the impact of the FDM differences on three applications: visual saliency modeling, image quality assessment, and image retargeting. It is shown that the FDM are very similar and that their impact on the applications is low. The individual experiment comparisons, however, are found to be significantly different, showing that inter-laboratory differences strongly depend on the experimental conditions of the laboratories. The FDM are publicly available to the research community.


Interplay of Dirac fermions and heavy quasiparticles in solids.
Many-body interactions in crystalline solids can be conveniently described in terms of quasiparticles with strongly renormalized masses as compared with those of non-interacting particles. Examples of extreme mass renormalization are on the one hand graphene, where the charge carriers obey the linear dispersion relation of massless Dirac fermions, and on the other hand heavy-fermion materials where the effective electron mass approaches the mass of a proton. Here we show that both extremes, Dirac fermions, like they are found in graphene and extremely heavy quasiparticles characteristic for Kondo materials, may not only coexist in a solid but can also undergo strong mutual interactions. Using the example of EuRh₂Si₂, we explicitly demonstrate that these interactions can take place at the surface and in the bulk. The presence of the linear dispersion is imposed solely by the crystal symmetry, whereas the existence of heavy quasiparticles is caused by the localized nature of the 4f states.


Sex, ecology and the brain: evolutionary correlates of brain structure volumes in Tanganyikan cichlids.
Analyses of the macroevolutionary correlates of brain structure volumes allow pinpointing of selective pressures influencing specific structures. Here we use a multiple regression framework, including phylogenetic information, to analyze brain structure evolution in 43 Tanganyikan cichlid species. We analyzed the effect of ecological and sexually selected traits for species averages, the effect of ecological traits for each sex separately and the influence of sexual selection on structure dimorphism. Our results indicate that both ecological and sexually selected traits have influenced brain structure evolution. The patterns observed in males and females generally followed those observed at the species level. Interestingly, our results suggest that strong sexual selection is associated with reduced structure volumes, since all correlations between sexually selected traits and structure volumes were negative and the only statistically significant association between sexual selection and structure dimorphism was also negative. Finally, we previously found that monoparental female care was associated with increased brain size. However, here cerebellum and hypothalamus volumes, after controlling for brain size, associated negatively with female-only care. Thus, in accord with the mosaic model of brain evolution, brain structure volumes may not respond proportionately to changes in brain size. Indeed selection favoring larger brains can simultaneously lead to a reduction in relative structure volumes.


A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack.
Effective early management of patients with transient ischaemic attacks (TIA) is undermined by an inability to predict who is at highest early risk of stroke. We derived a score for 7-day risk of stroke in a population-based cohort of patients (n=209) with a probable or definite TIA (Oxfordshire Community Stroke Project; OCSP), and validated the score in a similar population-based cohort (Oxford Vascular Study; OXVASC, n=190). We assessed likely clinical usefulness to front-line health services by using the score to stratify all patients with suspected TIA referred to OXVASC (n=378, outcome: 7-day risk of stroke) and to a hospital-based weekly TIA clinic (n=210; outcome: risk of stroke before appointment). A six-point score derived in the OCSP (age [> or =60 years=1], blood pressure [systolic >140 mm Hg and/or diastolic > or =90 mm Hg=1], clinical features [unilateral weakness=2, speech disturbance without weakness=1, other=0], and duration of symptoms in min [> or =60=2, 10-59=1, <10=0]; ABCD) was highly predictive of 7-day risk of stroke in OXVASC patients with probable or definite TIA (p<0.0001), in the OXVASC population-based cohort of all referrals with suspected TIA (p<0.0001), and in the hospital-based weekly TIA clinic-referred cohort (p=0.006). In the OXVASC suspected TIA cohort, 19 of 20 (95%) strokes occurred in 101 (27%) patients with a score of 5 or greater: 7-day risk was 0.4% (95% CI 0-1.1) in 274 (73%) patients with a score less than 5, 12.1% (4.2-20.0) in 66 (18%) with a score of 5, and 31.4% (16.0-46.8) in 35 (9%) with a score of 6. In the hospital-referred clinic cohort, 14 (7.5%) patients had a stroke before their scheduled appointment, all with a score of 4 or greater. Risk of stroke during the 7 days after TIA seems to be highly predictable. Although further validations and refinements are needed, the ABCD score can be used in routine clinical practice to identify high-risk individuals who need emergency investigation and treatment.


Beyond narratives: German critical psychology revisited.
In 2 articles, this journal has presented critical psychology (CP), which emerged in Germany during the 1980s, as an exemplary paradigm that committed itself to both scientific and political objectives and became a victim of Cold-War confrontations. The presentation was mainly based on narratives and writings circulating within CP itself. I have reexamined the case using archival materials and supplementary literary sources. This allows for a more complete and balanced account of postwar psychology and the contemporary political situation in general. In particular, I argue against Teo's hypothesis that CP was an indigenous paradigm that had to assert itself against American psychology. Marxism, constructivism, and subject orientation are analyzed as principal components of CP, and a claim for sole representation is identified as a predominant reason for the isolation of CP within German psychology. Finally, I briefly report on CP following the collapse of Soviet communism and comment on the present historicization of CP. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for 2004-2009.
The results of a surveillance study conducted by the International Nosocomial Infection Control Consortium (INICC) from January 2004 through December 2009 in 422 intensive care units (ICUs) of 36 countries in Latin America, Asia, Africa, and Europe are reported. During the 6-year study period, using Centers for Disease Control and Prevention (CDC) National Healthcare Safety Network (NHSN; formerly the National Nosocomial Infection Surveillance system [NNIS]) definitions for device-associated health care-associated infections, we gathered prospective data from 313,008 patients hospitalized in the consortium's ICUs for an aggregate of 2,194,897 ICU bed-days. Despite the fact that the use of devices in the developing countries' ICUs was remarkably similar to that reported in US ICUs in the CDC's NHSN, rates of device-associated nosocomial infection were significantly higher in the ICUs of the INICC hospitals; the pooled rate of central line-associated bloodstream infection in the INICC ICUs of 6.8 per 1,000 central line-days was more than 3-fold higher than the 2.0 per 1,000 central line-days reported in comparable US ICUs. The overall rate of ventilator-associated pneumonia also was far higher (15.8 vs 3.3 per 1,000 ventilator-days), as was the rate of catheter-associated urinary tract infection (6.3 vs. 3.3 per 1,000 catheter-days). Notably, the frequencies of resistance of Pseudomonas aeruginosa isolates to imipenem (47.2% vs 23.0%), Klebsiella pneumoniae isolates to ceftazidime (76.3% vs 27.1%), Escherichia coli isolates to ceftazidime (66.7% vs 8.1%), Staphylococcus aureus isolates to methicillin (84.4% vs 56.8%), were also higher in the consortium's ICUs, and the crude unadjusted excess mortalities of device-related infections ranged from 7.3% (for catheter-associated urinary tract infection) to 15.2% (for ventilator-associated pneumonia).


Learning the Lie groups of visual invariance.
A fundamental problem in biological and machine vision is visual invariance: How are objects perceived to be the same despite transformations such as translations, rotations, and scaling? In this letter, we describe a new, unsupervised approach to learning invariances based on Lie group theory. Unlike traditional approaches that sacrifice information about transformations to achieve invariance, the Lie group approach explicitly models the effects of transformations in images. As a result, estimates of transformations are available for other purposes, such as pose estimation and visuomotor control. Previous approaches based on first-order Taylor series expansions of images can be regarded as special cases of the Lie group approach, which utilizes a matrix-exponential-based generative model of images and can handle arbitrarily large transformations. We present an unsupervised expectation-maximization algorithm for learning Lie transformation operators directly from image data containing examples of transformations. Our experimental results show that the Lie operators learned by the algorithm from an artificial data set containing six types of affine transformations closely match the analytically predicted affine operators. We then demonstrate that the algorithm can also recover novel transformation operators from natural image sequences. We conclude by showing that the learned operators can be used to both generate and estimate transformations in images, thereby providing a basis for achieving visual invariance.


Repeatability of circadian behavioural variation revealed in free-ranging marine fish.
Repeatable between-individual differences in the behavioural manifestation of underlying circadian rhythms determine chronotypes in humans and terrestrial animals. Here, we have repeatedly measured three circadian behaviours, awakening time, rest onset and rest duration, in the free-ranging pearly razorfish, Xyrithchys novacula, facilitated by acoustic tracking technology and hidden Markov models. In addition, daily travelled distance, a standard measure of daily activity as fish personality trait, was repeatedly assessed using a State-Space Model. We have decomposed the variance of these four behavioural traits using linear mixed models and estimated repeatability scores (R) while controlling for environmental co-variates: year of experimentation, spatial location of the activity, fish size and gender and their interactions. Between- and within-individual variance decomposition revealed significant Rs in all traits suggesting high predictability of individual circadian behavioural variation and the existence of chronotypes. The decomposition of the correlations among chronotypes and the personality trait studied here into between- and within-individual correlations did not reveal any significant correlation at between-individual level. We therefore propose circadian behavioural variation as an independent axis of the fish personality, and the study of chronotypes and their consequences as a novel dimension in understanding within-species fish behavioural diversity.


Non-laboratory-based self-assessment screening score for non-alcoholic fatty liver disease: development, validation and comparison with other scores.
Non-alcoholic fatty liver disease (NAFLD) is a prevalent and rapidly increasing disease worldwide; however, no widely accepted screening models to assess the risk of NAFLD are available. Therefore, we aimed to develop and validate a self-assessment score for NAFLD in the general population using two independent cohorts. The development cohort comprised 15676 subjects (8313 males and 7363 females) who visited the National Health Insurance Service Ilsan Hospital in Korea in 2008-2010. Anthropometric, clinical, and laboratory data were examined during regular health check-ups and fatty liver diagnosed by abdominal ultrasound. Logistic regression analysis was conducted to determine predictors of prevalent NAFLD and to derive risk scores/models. We validated our models and compared them with other existing methods using an external cohort (N = 66868). The simple self-assessment score consists of age, sex, waist circumference, body mass index, history of diabetes and dyslipidemia, alcohol intake, physical activity and menopause status, which are independently associated with NAFLD, and has a value of 0-15. A cut-off point of ≥ 8 defined 58% of males and 36% of females as being at high-risk of NAFLD, and yielded a sensitivity of 80% in men (77% in women), a specificity of 67% (81%), a positive predictive value of 72% (63%), a negative predictive value of 76% (89%) and an AUC of 0.82 (0.88). Comparable results were obtained using the validation dataset. The comprehensive NAFLD score, which includes additional laboratory parameters, has enhanced discrimination ability, with an AUC of 0.86 for males and 0.91 for females. Both simple and comprehensive NAFLD scores were significantly increased in subjects with higher fatty liver grades or severity of liver conditions (e.g., simple steatosis, steatohepatitis). The new non-laboratory-based self-assessment score may be useful for identifying individuals at high-risk of NAFLD. Further studies are warranted to evaluate the utility and feasibility of the scores in various settings.


The costs and benefits of self-monitoring for higher functioning children and adolescents with autism.
The ability to regulate behaviors and emotions depends in part on the ability to flexibly monitor one's own progress toward a goal. Atypical patterns of response monitoring have been reported in individuals with autism spectrum disorders (ASD). In the current study we examined the error related negativity (ERN), an electrophysiological index of response monitoring, in relation to behavioral, social cognitive, and emotional presentation in higher functioning children (8-16 years) diagnosed with autism (HFA: N = 38) and an age- and IQ-matched sample of children without autism (COM: N = 36). Both HFA and COM participants displayed larger amplitude responses to error compared to correct response trials and these amplitudes did not differ by diagnostic group. For participants with HFA, larger ERN amplitudes were associated with more parent-reported autistic symptoms and more self-reported internalizing problems. However, across the full sample, larger ERN amplitudes were associated with better performance on theory of mind tasks. The results are discussed in terms of the utility of electrophysiological measures for understanding essential moderating processes that contribute to the spectrum of behavioral expression in the development of ASD.


Repeated premature hemofilter clotting during regional citrate anticoagulation as indicator of heparin induced thrombocytopenia.
Early clinical signs of heparin induced thrombocytopenia (HIT) are nonspecific and include a sudden drop in the number of platelets as well as formation of arterial and venous thromboses. Regional citrate anticoagulation (RCA) is increasingly used as a very effective modality to prevent filter clotting during renal replacement therapy (RRT). We report the first case where repeated premature filter clotting despite RCA indicated a manifestation of HIT. A 71-year old woman admitted to the ICU for a compartment syndrome of the leg developed septic shock with acute kidney injury requiring continuous veno-venous hemodialysis (CVVHD). Because of unexpected and repeated premature filter clotting during CVVHD using RCA, HIT was suspected. The diagnosis of HIT was confirmed by the presence of IgG antibodies against heparin and platelet factor (PF) 4 complexes and six points in the 4T score. Discontinuation of heparin administration and initiation of systemic anticoagulation with danaparoid sodium resulted in the normalization of platelet count and hemofilter lifetime. RCA does not seem to be sufficient to prevent hemofilter clotting during HIT. Thus, in case of repeated premature filter clotting despite RCA, one should suspect HIT and prompt diagnostic workup as well as a switch to alternative anticoagulation.


Health services appraisal and the transition to Medicaid Managed Care from fee for service.
Many states are transitioning fee-for-service (FFS) Medicaid into Medicaid Managed Care (MMC) for people with disabilities. This study examined managed care's impact on health services appraisal (HSA) and unmet medical needs of individuals with disabilities receiving Medicaid. Key questions included 1) Do participant demographics and enrollment in MMC impact unmet medical needs and HSA? 2) Within MMC, do demographics and continuity of care relate to unmet medical needs? 3) Within MMC, do demographics, unmet medical needs and continuity of care relate to HSA? We collected cross-sectional survey data (n = 1615) from people with disabilities in MMC operated by for-profit insurance companies (n = 849) and a similar group remaining in FFS (n = 766) in one state. Regression analyses were conducted across these groups and within MMC only. Across Medicaid groups, MMC enrollment was not related to either HSA or unmet needs; health status, having a mental health disability and unmet transportation needs related to HSA and health status, unmet transportation needs and having a mental health or physical disability related to higher unmet medical needs. Within MMC, in addition to better health and fewer unmet medical needs, less continuity of care significantly decreased HSA. Higher unmet transportation needs, poorer health status, having a physical or mental health disability, and less continuity of care significantly decreased unmet medical needs. This research points to the importance of meeting unmet needs of individuals in MMC and the need for increased continuity of care as people transition from FFS.


Variations in critical morphine biosynthesis genes and their potential to influence human health.
Endogenous morphine has been detected in human tissues from the vascular, immune and nervous systems. The genes/enzymes (CYP2D6, COMT and PNMT) that are involved in the biosynthesis of morphine have variations that affect their functionality. Some of these variations are the result of single nucleotide polymorphisms of DNA sequences. This review highlights some of the functional differences in the critical enzymes required for the biosynthesis of morphine that may affect human health. These variations have been shown to change the way animals react to stressors, perceive pain and behave. The presence of morphine signaling in almost all organ systems suggests that it is most likely playing a role in maintaining the health and promoting the normal functioning of these physiological systems.


Highly favorable antiviral activity and resistance profile of the novel thiocarboxanilide pentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 replication.
The novel human immunodeficiency virus type 1-specific thiocarboxanilide derivatives that contain either a substituted furanyl (UC-781) or thienyl (UC-82) ring linked to the thiocarboxy group and a pentenyloxyether chain linked to the 4-chlorophenyl ring in meta position show highly favorable antiviral properties. Compounds UC-781 and UC-82 discovered by scientists at Uniroyal Chemical Ltd. proved to be > or = 5-10-fold more inhibitory to wild-type human immunodeficiency virus type 1 strains (EC50 approximately 0.002 microgram/ml) than the thiocarboxanilide oxime ether UC-10 and other non-nucleoside reverse transcriptase inhibitors such as nevirapine, bis(heteroaryl)piperazine, and tetrahydroimidazo[4,5,l-jk][1,4]-benzodiazepin-2(1H)-one. In addition, the compounds were able to knock out virus replication in cell culture at concentrations that were 20-50-fold lower than those of nevirapine or bis(heteroaryl)piperazine. They were also highly efficient (EC50 < or = 0.02 microgram/ml) in suppressing the replication of mutant virus strains that contained mutations in their reverse transcriptase that conferred resistance to other non-nucleoside reverse transcriptase inhibitors (i.e., Tyr181 to Cys, Lys103 to Asn, Val106 to Ala, and Leu100 to Ile). The compounds selected for virus mutants that were only marginally resistant to the thiocarboxanilides ( < 10-20-fold). The antiviral activity of the compounds was only slightly affected by the presence of high concentrations of human serum, and the compounds were shown to be highly stable in the presence of human serum for at least 24 hr at room temperature.


Microalgae as biological treatment for municipal wastewater - effects on the sludge handling in a treatment plant.
A mix of microalgae and bacteria was cultivated on pre-sedimented municipal wastewater in a continuous operated microalgae-activated sludge process. The excess material from the process was co-digested with primary sludge in mesophilic and thermophilic conditions in semi-continuous mode (5 L digesters). Two reference digesters (5 L digesters) fed with waste-activated sludge (WAS) and primary sludge were operated in parallel. The methane yield was slightly reduced (≈10%) when the microalgal-bacterial substrate was used in place of the WAS in thermophilic conditions, but remained approximately similar in mesophilic conditions. The uptake of heavy metals was higher with the microalgal-bacterial substrate in comparison to the WAS, which resulted in higher levels of heavy metals in the digestates. The addition of microalgal-bacterial substrate enhanced the dewaterability in thermophilic conditions. Finally, excess heat can be recovered in both mesophilic and thermophilic conditions.


Effects of a behavioral intervention on treatment adherence and stress management in adolescents with IDDM.
To evaluate the effects of a behavioral program to increase treatment adherence and to improve stress management in adolescents with IDDM. A quasi-experimental pretest-posttest design with a nonequivalent control group was used. Eighteen subjects were assigned to the experimental group, which received the program, while nineteen subjects made up the control group, which received routine medical care. During the 12 intervention sessions with diabetic adolescents, different procedures were applied: instruction, blood glucose discrimination training, role-playing, relaxation exercises, self-instructions, problem-solving strategies, and homework, among others. The results show significant changes in the experimental group in variables related to diabetes information (patients and their parents), adherence, daily hassles, uneasiness and likelihood of response in social interactions, skills and frequency of glycemic analyses, blood glucose estimate errors, and negative family support (parents). The program had no effect on either dietary and physical exercise or glycemic control. The improvements, which were maintained at a follow-up carried out 13 months after finishing the program, were: patients' information about physiopathology (P = 0.000), diet (P = 0.000), physical exercise (P = 0.048), glucose testing (P = 0.030), and insulin (P = 0.000), barriers to adherence frequency (P = 0.000), severity of daily hassles (P = 0.006), and degree of uneasiness in social interaction (P = 0.000). This research introduces the novelty of integrating several behavioral procedures within a wide-ranging package that affects aspects implied in diabetes control such as treatment adherence and stress management. The testing of similar programs on samples of subjects with glycemic control difficulties would be useful.


Effectiveness of Extracorporeal Shock Wave Therapy Without Local Anesthesia in Patients With Recalcitrant Plantar Fasciitis: A Meta-Analysis of Randomized Controlled Trials.
The objective of this meta-analysis was to investigate the efficacy of extracorporeal shock wave therapy in the treatment of recalcitrant plantar fasciitis without local anesthesia. The Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched from inception to September 2015 for randomized controlled trials comparing ESWT without local anesthesia versus placebo for treatment of plantar fasciitis in adults. The primary outcome was the 12-week post-intervention success rate of reducing the visual analog scale score by 60% from baseline at the first step in the morning, reducing the VAS score by 60% from baseline during daily activities, reducing the Roles and Maudsley score, reducing overall heel pain, and reducing pain after applying a force meter. Nine studies were included in the meta-analysis. Compared with placebo, ESWT significantly improved the success rate of reducing overall heel pain, reducing the VAS score by 60% at the first step in the morning and during daily activities, improving the Roles and Maudsley score to excellent or good, and reducing heel pain after application of a pressure meter. ESWT seems to be particularly effective in relieving pain associated with RPF. ESWT should be considered when traditional treatments have failed. Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to (1) understand the recovery rates for nonsurgical treatment of plantar fasciitis, (2) understand the role of extracorporeal shockwave therapy (ESWT) in the treatment of recalcitrant plantar fasciitis, and (3) understand the indications to incorporate ESWT in the treatment plan of recalcitrant plantar fasciitis. Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Summary health statistics for the U.S. population: National Health Interview Survey, 2004.
This report presents both age-adjusted and unadjusted health statistics from the 2004 National Health Interview Survey (NHIS) for the civilian noninstitutionalized population of the United States, classified by sex, age, race, Hispanic or Latino origin and race, education, family income, poverty status, health insurance coverage (where appropriate), place of residence, and region of residence. The topics covered are respondent-assessed health status, limitations in activities, special education or early intervention services, injuries and poisonings, health care access and utilization, and health insurance coverage. NHIS is a household, multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention's National Center for Health Statistics. In 2004, household interviews were completed for 94,460 persons living in 36,579 households, reflecting a household response rate of 86.9%. Nearly 7 in 10 persons were in excellent or very good health in 2004. About 34 million persons (12%) were limited in their usual activities due to one or more chronic health conditions, and about 4 million persons (2%) required the help of another person with activities of daily living. About 6% of children received special education or early intervention services. Among persons under age 65 years, about 41 million (17%) did not have any health insurance coverage. The most common reason for lacking health insurance was cost, followed by a change in employment.


Depression trajectories, inflammation, and lifestyle factors in adolescence: The TRacking Adolescents' Individual Lives Survey.
In adults, depression and inflammation are bidirectionally related. This association is less clear in adolescents. Moreover, somatic and cognitive depressive symptoms might be differentially related to inflammation. Lifestyle factors, as in adults, may play an important mediating role in adolescents. For the current study we evaluated trajectories of depressive symptoms in adolescence over a 5-year course and their relation with subsequent high-sensitivity C-reactive protein (hsCRP) levels, and examined lifestyle factors as mediators. Participants of the TRacking Adolescents' Individual Lives' Survey (TRAILS; N = 1166) were followed from 2001 until 2008. Three biennial youth self-report (YSR) assessments of depressive symptoms were taken. Demographics, health, and lifestyle factors and levels of hsCRP were assessed at Wave 3. Latent-class analysis was used to determine trajectories of depression and general linear models to determine the association between depression trajectories and hsCRP. Finally, mediation analysis was performed to test mediation of lifestyle factors. Persistently moderate to high depressive symptoms were associated with higher hsCRP levels. Results were unaltered when we adjusted for demographics and health variables. Smoking mediated the association between depressive symptoms total score and hsCRP, in large part. Persistently higher scores on somatic and cognitive symptom subscales were associated with higher levels of hsCRP than persistently low scores. These results were rendered nonsignificant after covariate adjustment. Persistent depressive symptoms were associated with subsequent higher levels of hsCRP, with somatic and cognitive symptoms contributing equally. The association was mediated by smoking behavior. These findings suggest that reducing adolescent depression and smoking are important starting points in the prevention of inflammatory diseases.


Steady-state plasma fentanyl in the rabbit.
Linear pharmacokinetic models were obtained for fentanyl in anaesthetized rabbits. A composite model was used to predict the bolus dose and infusion rates necessary to achieve rapidly a steady-state concentration of fentanyl in plasma. When this was tested in a further six rabbits, steady-state concentrations were greater than predicted. The most likely reasons for this are imperfect mixing between plasma and the central compartment, and substantial uptake of fentanyl by the lung. These sources of error were allowed for in modifications to the model. On further testing, a 4-h infusion set to achieve a plasma fentanyl concentration of 10 ng ml-1 yielded actual concentrations ranging from a mean low of 8.7 ng ml-1 to a mean high of 18.0 ng ml-1. The second model described more precisely the disposition of fentanyl, although a tendency to overestimate dosing requirement remained. This tendency is probably a consequence of continuing lung uptake of fentanyl. The demonstrated ability to obtain rapidly and maintain for 4h "steady" blood fentanyl concentrations suggests that the methods merits further investigation with other drugs both in animals and man.


The evolving classification of dementia: placing the DSM-V in a meaningful historical and cultural context and pondering the future of "Alzheimer's".
Alzheimer's disease is a 100-year-old concept. As a diagnostic label, it has evolved over the 20th and 21st centuries from a rare diagnosis in younger patients to a worldwide epidemic common in the elderly, said to affect over 35 million people worldwide. In this opinion piece, we use a constructivist approach to review the early history of the terms "Alzheimer's disease" and related concepts such as dementia, as well as the more recent nosological changes that have occurred in the four major editions of the Diagnostic and Statistical Manual since 1952. A critical engagement of the history of Alzheimer's disease and dementia, specifically the evolution of those concepts in the DSM over the past 100 years, raises a number of questions about how those labels and emergent diagnoses, such as Neurocognitive Disorders and Mild Cognitive Impairment, might continue to evolve in the DSM-V, due for release in 2013.


Durability of mitral valve repair: A single center experience.
This study aims to present clinical outcomes of mitral valve repair in patients with different etiologies. Between June 2006 and August 2017, a total of 421 consecutive patients (266 males, 155 females; mean age 53.1±15.6 years; range, 5 to 89 years) who underwent mitral valve repair with or without concomitant cardiac procedures were retrospectively analyzed. All pre-, intra-, and postoperative data were collected. Echocardiographic examinations were performed at discharge and during follow-up. Kaplan-Meier analysis was used to estimate overall survival and from residual severe mitral regurgitation, endocarditis and reoperation-free survival rates. The mean follow-up was 58.9±35.1 months. Of the patients, 12 (2.8%) had previous cardiac operations. The most predominant pathology was degenerative disease in 265 patients (62.9%). Repair techniques included ring annuloplasty (n=366, 86.9%), artificial chordae implantation (n=185, 44%), and commissurotomy (n=38, 9%). Overall in-hospital mortality rate was 1.2% (n=5). Echocardiography before discharge showed no/trivial mitral regurgitation in 64.9% (n=270) and mild mitral regurgitation in 34.85% (n=145) of the patients. At the late postoperative period, transthoracic echocardiography revealed moderate mitral regurgitation in 23 patients (5.7%) and severe in 11 patients (2.7%). The mean late survival and freedom from endocarditis, reoperation, and recurrent severe mitral regurgitation rates were 92±0.03%, 98.5±0.07%, 98.1±0.01%, and 94.7±0.02%, respectively. Our study results suggest that mitral valve repair is a safe and effective procedure associated with favorable longterm outcomes in experienced centers.


Effect of plasmonic gold nanoparticles on benign and malignant cellular autofluorescence: a novel probe for fluorescence based detection of cancer.
Due to the strong surface fields of noble metal nanoparticles, absorption and scattering of electromagnetic radiation is greatly enhanced. Noble metallic nanoparticles represent potential novel optical probes for simultaneous molecular imaging and photothermal cancer therapy using the enhanced scattering and absorption of light. Further, gold nanoparticles can affect molecular fluorescence via chemical, electronic, or photonic interactions. Live cells generate fluorescence due to intracellular and extracellular molecules. Differences in the biochemical composition between healthy and malignant cells can be exploited in vivo to help identify cancer spectroscopically. The interaction of gold nanoparticles with cellular autofluorescence has not yet been characterized. We hypothesized that gold nanoparticles delivered to live cells in vitro would alter cellular autofluorescence and may be useful as a novel class of contrast agent for fluorescence based detection of cancer. The fluorescence of two fluorophores that are responsible for tissue autofluorescence, NADH and collagen, and of two oral squamous carcinoma cell lines and one immortalized benign epithelial cell line were measured in vitro. Gold nanoparticles of different shapes, both spheres and rods, quenched the fluorescence of the soluble NADH and collagen. Reduction of NADH fluorescence was due to oxidation of NADH to NAD+ catalyzed by gold nanoparticles (results we previously published). Reduction of collagen fluorescence appears due to photonic absorption of light. Furthermore, a mean quenching of 12/8% (p<0.00050) of the tissue autofluorescence of cell suspensions was achieved in this model when nanospheres were incubated with the live cells. Gold nanospheres significantly decrease cellular autofluorescence of live cells under physiological conditions when excited at 280nm. This is the first report to our knowledge to suggest the potential of developing targeted gold nanoparticles optical probes as contrast agents for fluorescence based diagnoses of cancer.


Association of insurance with cancer care utilization and outcomes.
Advances in the prevention, early detection, and treatment of cancer have resulted in an almost 14% decrease in the death rates from all cancers combined from 1991 to 2004 in the overall US population, with remarkable declines in mortality for the top 3 causes of cancer death in men (lung, colorectal, and prostate cancer) and 2 of the top 3 cancers in women (breast and colorectal cancer). However, not all segments of the population have benefited equally from this progress, and evidence suggests that some of these differences are related to lack of access to health care. Lack of adequate health insurance appears to be a critical barrier to receipt of appropriate health care services. This article provides an overview of systems of health insurance in the United States, demographic and socioeconomic characteristics associated with health insurance coverage, and economic burdens related to health care among individuals and families. This article also presents data on the association between health insurance status and screening, stage at diagnosis, and survival for breast and colorectal cancer based on analyses of the National Health Interview Survey and the National Cancer Data Base. Although this article focuses on associations between health insurance and cancer care utilization and outcomes, it is important to recognize that barriers to receipt of optimal cancer care are complex and involve patient-level, provider, and health system factors. Evidence presented in this paper suggests that addressing insurance and cost-related barriers to care is a critical component of efforts to ensure that all Americans are able to share in the progress that can be achieved by access to high-quality cancer prevention, early detection, and treatment services.


Inactive C-terminal telomerase reverse transcriptase insertion splicing variants are dominant-negative inhibitors of telomerase.
Maintenance of telomere length and structure is essential for cell survival. Telomere synthesis is mediated by the ribonucleoprotein telomerase in 90% of cancer cells, and is regulated mainly by transcription of the human telomerase reverse transcriptase subunit, hTERT. However, transcriptome analysis reveals complex splicing patterns and to date, twenty-two alternatively-spliced hTERT mRNAs have been reported, yet their functions have not been fully elucidated. The best characterized hTERT spliced variants encode for inactive proteins that possess specific deletions within the hTERT catalytic domains. We studied two less well characterized hTERT splice variants (termed INS3 and 4) that encode proteins with intact reverse transcriptase motifs, but alternative C-domains due to insertion of intronic sequences. We determined the prevalence of these mRNA variants in primary cells, telomerase-positive cells and in alternative lengthening of telomere (ALT) cells and found the transcripts to be expressed mainly in telomerase-positive cell lines and to be translated into proteins as illustrated by their association with polysomes. These variants were inactive when expressed in vitro or in cells, retained DNA substrate binding in vitro but were impaired in binding the telomerase RNA component when expressed in, and immunoprecipitated from either telomerase-positive or telomerase-negative ALT cells coexpressing the telomerase RNA component. Stable expression of INS3 and INS4 variants in a hepatocarcinoma cell line inhibited telomerase activity, shortened telomeres and slowed cell growth suggesting a potential dominant-negative function.


How to Test Mandatory Text Templates: The European Patient Information Leaflet.
The structure of patient information leaflets (PILs) supplied with medicines in the European Union is largely determined by a regulatory template, requiring a fixed sequence of pre-formulated headings and sub-headings. The template has been criticized on various occasions, but it has never been tested with users. This paper proposes an alternative template, informed by templates used in the USA and Australia, and by previous user testing.The main research question is whether the revision better enables users to find relevant information. Besides, the paper proposes a methodology for testing templates. Testing document templates is complex, as they are "empty". For both the current and the alternative template, we produced a document with bogus text and real headings (reflecting the empty template) and a real-life document with readable text (reflecting the "filled" template). The documents were tested both in Dutch and in English, with 64 British and 64 Dutch users. The test used a set of scenario questions that covers the full range of template (sub)topics; users needed to indicate the text locations where they expected each question to be answered. The revised template improved findability of information; this effect was strongest for the "filled" template with readable text. When participants were shown both filled templates, there was a clear preference for the revised template. A closer analysis of the findability data revealed question-specific effects of topic grouping, topic ordering, subtopic granularity and wording of headings. Most of these favoured the revised template, but our revision led to adverse effects as well, for instance in the new heading Check with your doctor. Language-specific effects showed that the wording of the headings is a delicate task. Generally, we conclude that document template designs can be analyzed in terms of the four parameters grouping, ordering, granularity and wording. Furthermore, they need to be tested on their effects on information findability, with template translations requiring separate testing. The methodology used in this study seems an appropriate one for such tests. More specifically, we find that the new patient information leaflet template proposed here provides better information findability.


Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.
Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).