Association of Use of an Intravascular Microaxial Left Ventricular Assist Device vs Intra-aortic Balloon Pump With In-Hospital Mortality and Major Bleeding Among Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock.
Acute myocardial infarction (AMI) complicated by cardiogenic shock is associated with substantial morbidity and mortality. Although intravascular microaxial left ventricular assist devices (LVADs) provide greater hemodynamic support as compared with intra-aortic balloon pumps (IABPs), little is known about clinical outcomes associated with intravascular microaxial LVAD use in clinical practice. To examine outcomes among patients undergoing percutaneous coronary intervention (PCI) for AMI complicated by cardiogenic shock treated with mechanical circulatory support (MCS) devices. A propensity-matched registry-based retrospective cohort study of patients with AMI complicated by cardiogenic shock undergoing PCI between October 1, 2015, and December 31, 2017, who were included in data from hospitals participating in the CathPCI and the Chest Pain-MI registries, both part of the American College of Cardiology's National Cardiovascular Data Registry. Patients receiving an intravascular microaxial LVAD were matched with those receiving IABP on demographics, clinical history, presentation, infarct location, coronary anatomy, and clinical laboratory data, with final follow-up through December 31, 2017. Hemodynamic support, categorized as intravascular microaxial LVAD use only, IABP only, other (such as use of a percutaneous extracorporeal ventricular assist system, extracorporeal membrane oxygenation, or a combination of MCS device use), or medical therapy only. The primary outcomes were in-hospital mortality and in-hospital major bleeding. Among 28 304 patients undergoing PCI for AMI complicated by cardiogenic shock, the mean (SD) age was 65.0 (12.6) years, 67.0% were men, 81.3% had an ST-elevation myocardial infarction, and 43.3% had cardiac arrest. Over the study period among patients with AMI, an intravascular microaxial LVAD was used in 6.2% of patients, and IABP was used in 29.9%. Among 1680 propensity-matched pairs, there was a significantly higher risk of in-hospital death associated with use of an intravascular microaxial LVAD (45.0%) vs with an IABP (34.1% [absolute risk difference, 10.9 percentage points {95% CI, 7.6-14.2}; P < .001) and also higher risk of in-hospital major bleeding (intravascular microaxial LVAD [31.3%] vs IABP [16.0%]; absolute risk difference, 15.4 percentage points [95% CI, 12.5-18.2]; P < .001). These associations were consistent regardless of whether patients received a device before or after initiation of PCI. Among patients undergoing PCI for AMI complicated by cardiogenic shock from 2015 to 2017, use of an intravascular microaxial LVAD compared with IABP was associated with higher adjusted risk of in-hospital death and major bleeding complications, although study interpretation is limited by the observational design. Further research may be needed to understand optimal device choice for these patients.


Proprioceptive Interaction between the Two Arms in a Single-Arm Pointing Task.
Proprioceptive signals coming from both arms are used to determine the perceived position of one arm in a two-arm matching task. Here, we examined whether the perceived position of one arm is affected by proprioceptive signals from the other arm in a one-arm pointing task in which participants specified the perceived position of an unseen reference arm with an indicator paddle. Both arms were hidden from the participant's view throughout the study. In Experiment 1, with both arms placed in front of the body, the participants received 70-80 Hz vibration to the elbow flexors of the reference arm (= right arm) to induce the illusion of elbow extension. This extension illusion was compared with that when the left arm elbow flexors were vibrated or not. The degree of the vibration-induced extension illusion of the right arm was reduced in the presence of left arm vibration. In Experiment 2, we found that this kinesthetic interaction between the two arms did not occur when the left arm was vibrated in an abducted position. In Experiment 3, the vibration-induced extension illusion of one arm was fully developed when this arm was placed at an abducted position, indicating that the brain receives increased proprioceptive input from a vibrated arm even if the arm was abducted. Our results suggest that proprioceptive interaction between the two arms occurs in a one-arm pointing task when the two arms are aligned with one another. The position sense of one arm measured using a pointer appears to include the influences of incoming information from the other arm when both arms were placed in front of the body and parallel to one another.


Modeling the consequences of thermal trait variation for the cane toad invasion of Australia.
Mechanistic species distribution models (SDMs) are ideally suited for predicting the nonnative distributions of invasive species, but require accurate parameterization of key functional traits. Importantly, any ability of the invader to acclimate or adapt rapidly to local conditions must be incorporated. Our field and laboratory studies measured phenotypic variation and tested for plasticity in the thermal sensitivity of locomotor performance and low-temperature tolerance of adult cane toads Bufo marinus in eastern Australia. We used a biophysical model to explore the adaptive significance of this variation and how it affected distribution predictions. Laboratory trials showed that geographic differences in low-temperature tolerance (i.e., the critical thermal minimum; CTMin) of field-caught toads reflect thermal acclimation, whereas populations differed in the thermal dependence of locomotor performance even after acclimation. Incorporating low-temperature tolerance as a dimension of the fundamental niche reduced the predicted southern distribution. To test whether these factors predicted to be range limiting were consistent with reduced performance for individuals, we used the biophysical model and daily climate data to conduct "virtual transplants." These models predicted that acclimation reduced cold stress by 32-100% for toads sheltering near the ground surface; toads inside burrows could remain above their CTMin, but the required burrow depth increased with latitude. Low-temperature tolerance of the adult phase may constrain the southern range limit of the cane toad in Australia, and plasticity in this trait may have facilitated the southward range expansion.


A retrospective cohort study of PD-L1 prevalence, molecular associations and clinical outcomes in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape Project.
The PD-L1 biomarker is an important factor in selecting patients with non-small cell lung cancer for immunotherapy. While several reports suggest that PD-L1 positivity is linked to a poor prognosis, others suggest that PD-L1 positive status portends a good prognosis. PD-L1 positivity prevalence, assessed via immunohistochemistry (IHC) on tissue microarrays (TMAs), and its association with clinicopathological characteristics, molecular profiles and patient outcome- Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS)- is explored in the ETOP Lungscape cohort of stage I-III non-small cell lung cancer (NSCLC). Tumors are considered positive if they have ≥1/5/25/50% neoplastic cell membrane staining. PD-L1 expression was assessed in 2182 NSCLC cases (2008 evaluable, median follow-up 4.8 years, 54.6% still alive), from 15 ETOP centers. Adenocarcinomas represent 50.9% of the cohort (squamous cell: 42.4%). Former smokers are 53.7% (current: 31.6%, never: 10.5%). PD-L1 positivity prevalence is present in more than one third of the Lungscape cohort (1%/5% cut-offs). It doesn't differ between adenocarcinomas and squamous cell histologies, but is more frequently detected in higher stages, never smokers, larger tumors (1/5/25% cut-offs). With ≥1% cut-off it is significantly associated with IHC MET overexpression, expression of PTEN, EGFR and KRAS mutation (only for adenocarcinoma). Results for 5%, 25% and 50% cut-offs were similar, with MET being significantly associated with PD-L1 positivity both for AC (p < 0.001, 5%/25%/50% cut-offs) and SCC (p < 0.001, 5% & 50% cut-offs and p = 0.0017 for 25%). When adjusting for clinicopathological characteristics, a significant prognostic effect was identified in adenocarcinomas (adjusted p-values: 0.024/0.064/0.063 for RFS/TTR/OS 1% cut-off, analogous for 5%/25%, but not for 50%). Similar results obtained for the model including all histologies, but no effect was found for the squamous cell carcinomas. PD-L1 positivity, when adjusted for clinicopathological characteristics, is associated with a better prognosis for non-metastatic adenocarcinoma patients.


Predators reduce extinction risk in noisy metapopulations.
Spatial structure across fragmented landscapes can enhance regional population persistence by promoting local "rescue effects." In small, vulnerable populations, where chance or random events between individuals may have disproportionately large effects on species interactions, such local processes are particularly important. However, existing theory often only describes the dynamics of metapopulations at regional scales, neglecting the role of multispecies population dynamics within habitat patches. By coupling analysis across spatial scales we quantified the interaction between local scale population regulation, regional dispersal and noise processes in the dynamics of experimental host-parasitoid metapopulations. We find that increasing community complexity increases negative correlation between local population dynamics. A potential mechanism underpinning this finding was explored using a simple population dynamic model. Our results suggest a paradox: parasitism, whilst clearly damaging to hosts at the individual level, reduces extinction risk at the population level.


Oral paracetamol (acetaminophen) for cancer pain.
Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat mild to moderate cancer pain, and are recommended for this purpose in the WHO cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on NSAIDs, updates the evidence. To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries. We included randomised, double-blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single-blind and open studies were also eligible for inclusion. The minimum study size was 25 participants per treatment arm at the initial randomisation. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel-group, and two had a cross-over design. All used paracetamol as an add-on to established treatment with strong opioids (median daily morphine equivalent doses of 60 mg, 70 mg, and 225 mg, with some participants taking several hundred mg of oral morphine equivalents daily). Other non-paracetamol medication included non-steroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, or neuroleptics. All studies were at high risk of bias for incomplete outcome data and small size; none was unequivocally at low risk of bias.None of the studies reported any of our primary outcomes: participants with pain reduction of at least 50%, and at least 30%, from baseline; participants with pain no worse than mild at the end of the treatment period; participants with Patient Global Impression of Change (PGIC) of much improved or very much improved (or equivalent wording). What pain reports there were indicated no difference between paracetamol and placebo when added to another treatment. There was no convincing evidence of paracetamol being different from placebo with regards to quality of life, use of rescue medication, or participant satisfaction or preference. Measures of harm (serious adverse events, other adverse events, and withdrawal due to lack of efficacy) were inconsistently reported and provided no clear evidence of difference.Our GRADE assessment of evidence quality was very low for all outcomes, because studies were at high risk of bias from several sources. There is no high-quality evidence to support or refute the use of paracetamol alone or in combination with opioids for the first two steps of the three-step WHO cancer pain ladder. It is not clear whether any additional analgesic benefit of paracetamol could be detected in the available studies, in view of the doses of opioids used.


Childhood lead exposure and uptake in teeth in the Cleveland area during the era of leaded gasoline.
Childhood uptake of lead from exposure to atmospheric leaded gasoline in the United States has been studied using mainly blood lead levels. Since reliable blood lead techniques were used only after the peak use of leaded gasoline, the prior exposure history is unclear. The well-documented decline in blood lead levels after the mid-1970s could represent the continuation of a historic steady decline in exposure from many sources. Alternatively, the post-1970s decline might represent the declining phase of a unimodal rise and fall corresponding closely to usage of leaded gasoline. To assess these possibilities, lead concentration and 207Pb/206Pb isotope ratios were measured in the enamel of permanent molar teeth formed between 1936 and 1993 in mainly African-American donors who grew up in the Cleveland area. Tooth enamel preserves the lead concentration and isotope ratio that prevails during tooth formation. Historical trends in enamel lead concentration were significantly correlated with surrogates of atmospheric lead exposure: lead in sediments of two dated Lake Erie cores, and lead consumed in gasoline. About two-thirds of the total lead uptake into enamel in this period was attributable to leaded gasoline, and the remainder to other sources (e.g. paint). Enamel 207Pb/206Pb isotope ratios were similar to those of one lake sediment. Multivariate analysis revealed significant correlation in neighborhoods with higher levels of traffic, and including lake sediment data, accounted for 53% of the variation in enamel lead levels. Enamel lead concentration was highly correlated with reported African-American childhood blood levels. The extrapolated peak level of 48microg/dL (range 40 to 63) is associated with clinical and behavioral impairments, which may have implications for adults who were children during the peak gasoline lead exposure. In sum, leaded gasoline emission was the predominant source of lead exposure of African-American Cleveland children during the latter two-thirds of the 20th century.


New synthetic surfactants: the next generation?
Surfactant preparations have been proven to improve clinical outcome of infants at risk for or having respiratory distress syndrome (RDS). In clinical trials, ani mal-derived surfactant preparations reduce the risk of pneumothorax and mortality when compared to non-protein-containing synthetic surfactant preparations. In part, this is thought to be due to the presence of surfactant proteins in animal-derived surfactant preparations. Four native surfactant proteins have been identified. The hydrophobic surfactant proteins B (SP-B) and C (SP-C) are tightly bound to phospholipids. These proteins have important roles in maintaining the surface tension-lowering properties of pulmonary surfactant. Surfactant protein A (SP-A) and D (SP-D) are extremely hydrophilic and are not retained in the preparation of any commercial animal-derived surfactant products. These proteins are thought to have a role in recycling surfactant and improving host defense. There is concern that animal-derived products may have some batch-to-batch variation regarding the levels of native pulmonary surfactant proteins. In addition, there is concern regarding the hypothetical risk of transmission of viral or unconventional infectious agents from an animal source. New surfactant preparations, composed of synthetic phospholipids and essential hydrophobic surfactant protein analogs, have been developed. These surfactant protein analogs have been produced by peptide synthesis and recombinant technology to provide a new class of synthetic surfactants that may be a suitable alternative to animal-derived surfactants. Preliminary clinical studies have shown that treatment with these novel surfactant preparations can ameliorate RDS and improve clinical outcome. Clinicians will need to further understand any differences in clinical effects between available products.


Regulation of non-conventional therapies in Portugal: lessons learnt for strengthening human resources in health.
The integration of non-conventional therapies (NCT) into health policies and health services delivery is a worldwide trend and might have a role in achieving Universal Health Coverage. WHO has encouraged countries to integrate NCT into health service delivery and to increase the interest and utilization by consumers. Following two resolutions by the European Parliament and by the Council of Europe, in the late 1990s, recommending the recognition of NCT and calling for EU legislation on non-conventional forms of medicine, Portugal initiated, in 2003, its path towards regulation of NCT. We analyze this process and discuss its implications and impacts in terms of health policies, health services delivery and overall health workforce. The need to regulate NCT in Portugal stemmed from a growing demand for NCT (and acceptability) among lay citizens and a positive attitude among conventional health professionals which also advocated for a regulatory framework. Political efforts undertaken since 2003 allowed for important advances in the regulation of NCT, beneficiating safe professional practices, and ensuring future academic training at the highest standards, with the defining moment of the social and legal model transition occurring in 2013, when acupuncture, chiropractic, homeopathy, naturopathy, osteopathy, phytotherapy and traditional Chinese Medicine were recognized and regulated. Nevertheless, and because the process knew important time gaps, significant deficiencies arose, mainly between regulation of the training and of the professional activities and the capacity to ensure the continuous production of NCT professionals at an acceptable rate and with minimum quality standards guaranteed. The regulation of NCT in Portugal was lengthy but steady and was able to bring consumers a safer practice environment and NCT professionals a legal and deontological umbrella for their training, practice, and professional development. Nevertheless, and despite the growing acceptability and normative quality assurance of NCT and its workforce, the regulation process has highlighted some fragilities in terms of accessibility and availability that need attention and urgent action to achieve universal coverage.


Photosynthetic energy conversion efficiency: setting a baseline for gauging future improvements in important food and biofuel crops.
The conversion efficiency (ε(c)) of absorbed radiation into biomass (MJ of dry matter per MJ of absorbed photosynthetically active radiation) is a component of yield potential that has been estimated at less than half the theoretical maximum. Various strategies have been proposed to improve ε(c), but a statistical analysis to establish baseline ε(c) levels across different crop functional types is lacking. Data from 164 published ε(c) studies conducted in relatively unstressed growth conditions were used to determine the means, greatest contributors to variation, and genetic trends in ε(c )across important food and biofuel crop species. ε(c) was greatest in biofuel crops (0.049-0.066), followed by C4 food crops (0.046-0.049), C3 nonlegumes (0.036-0.041), and finally C3 legumes (0.028-0.035). Despite confining our analysis to relatively unstressed growth conditions, total incident solar radiation and average growing season temperature most often accounted for the largest portion of ε(c) variability. Genetic improvements in ε(c), when present, were less than 0.7% per year, revealing the unrealized potential of improving ε(c) as a promising contributing strategy to meet projected future agricultural demand.


Multiple PU.1 sites cooperate in the regulation of p40(phox) transcription during granulocytic differentiation of myeloid cells.
The p40(phox) protein, a regulatory component of the phagocyte NADPH oxidase, is preferentially expressed in cells of myeloid lineage. We investigated transcriptional regulation of the p40(phox) gene in HL-60 myeloid cells. Deletion analysis of approximately 6 kb of the 5'-flanking sequence of the gene demonstrated that the proximal 106 base pair of the promoter exhibited maximum reporter activity. This region contains 3 potential binding sites for PU.1, a myeloid-restricted member of the ets family of transcription factors. Mutation or deletion of each PU.1 site decreased promoter activity, and the level of activity mediated by each site correlated with its binding avidity for PU.1, as determined by gel shift competition assays. Mutation of all 3 sites abolished promoter activity in myeloid cells. PU.1-dependent expression was also observed in the Raji B-cell line, whereas the moderate level of promoter reporter activity in the nonmyeloid HeLa cell line was independent of PU.1. Chromatin immunoprecipitation assay demonstrated occupation of the PU.1 sites by PU.1 in vivo in HL-60 cells. Cotransfection of the pGL3-p40-106 reporter construct with a dominant-negative PU.1 mutant dramatically reduced promoter activity, whereas the overexpression of PU.1 increased promoter activity. Promoter activity and transcript levels of p40(phox) increased in HL-60 cells during dimethyl sulfoxide-induced differentiation toward the granulocyte phenotype, and this was associated with increased cellular levels of PU.1 protein. Our findings demonstrate that PU.1 binding at multiple sites is required for p40(phox) gene transcription in myeloid cells and that granulocytic differentiation is associated with the coordinated up-regulation of PU.1 and p40(phox) expression.


Deep brain stimulation for the treatment of addiction: basic and clinical studies and potential mechanisms of action.
Deep brain stimulation (DBS) has achieved substantial success as a treatment for movement disorders such as Parkinson's disease. The therapeutic efficacy and relative lack of serious side effects resulted in the expansion of DBS into the treatment of many other diseases, including obsessive-compulsive disorder, Tourette's, and depression, among others. More recently, a limited number of basic and clinical studies indicated that DBS may also be useful in the treatment of various addictions. Here, we briefly summarize the history of DBS and review the basic and clinical studies focused on DBS and addiction. We also examine the potential mechanisms that may underlie the effects of DBS. The available data indicate that DBS is a promising therapeutic modality for the treatment of addiction. Thus far, the nucleus accumbens and subthalamic nucleus are the most promising sites for DBS, reversing aspects of addiction. The mechanisms underlying DBS are complex and likely vary from region to region. Emerging evidence indicates that DBS of the nucleus accumbens produces its effects, at least in part, by antidromic activation of cortico-accumbal afferents that stimulate inhibitory medial prefrontal cortex interneurons via recurrent collaterals.


Lycopene ameliorates oxidative stress in the aging chicken ovary via activation of Nrf2/HO-1 pathway.
After 480 days of age, high-producing hens are likely to be subject to ovarian aging, mainly due to oxidative stress. In this study, the amelioration of ovarian aging in chickens, using a plant antioxidant, lycopene, was investigated. The activity of the Nrf2/HO-1 pathway in chicken ovaries at different ages (90, 150, 280 and 580 days old) were compared to elucidate any age-related changes. Subsequently, the putative attenuating effect of lycopene (100 ng/mL) on ovarian aging was evaluated through the establishment of a D-gal-induced aging ovarian culture model. The cultured ovarian tissues of young (280 days) and old (580 days) hens were treated with lycopene for 72 h to verify protective effects of lycopene on naturally aged ovaries. Results showed that the Nrf2/HO-1 pathway was down-regulated during the ovarian aging process. Lycopene rescued the decreased antioxidant capacity by increasing the activities of antioxidases and activating the Nrf2/HO-1 pathway in both D-gal-induced and naturally aged ovaries. Moreover, lycopene promoted cell proliferation and inhibited apoptosis in both D-gal-induced and naturally aged ovaries. Lycopene also alleviated D-gal-induced mitochondrial damage in the living granulosa cells. In conclusion, lycopene can effectively ameliorate the oxidative stress in aging hen ovaries via the activation of the Nrf2/HO-1 pathway.


Area-wide traffic calming for preventing traffic related injuries.
It is estimated that by 2020 road traffic crashes will have moved from ninth to third in the world disease burden ranking, as measured in disability adjusted life years, and second in developing countries. The identification of effective strategies for the prevention of traffic related injuries is of global health importance. Area-wide traffic calming schemes that discourage through traffic on residential roads is one such strategy. To evaluate the effectiveness of area-wide traffic calming in preventing traffic related crashes, injuries, and deaths. We searched the following electronic databases: Cochrane Injuries Group's Specialised Register, Cochrane Controlled Trials Register, MEDLINE, EMBASE and TRANSPORT (NTIS, TRIS, TRANSDOC). We searched the web sites of road safety organisations, handsearched conference proceedings, checked reference lists of relevant papers and contacted experts in the area. The search was not restricted by language or publication status. Randomised controlled trials, and controlled before-after studies of area-wide traffic calming schemes. Two reviewers independently extracted data on type of study, characteristics of intervention and control areas, and length of data collection periods. Before and after data were collected on the total number of road traffic crashes, all road user deaths and injuries, pedestrian-motor vehicle collisions and road user deaths. The statistical package STATA was used to calculate rate ratios for each study, which were then pooled to give an overall estimate using a random effects model. We found no randomised controlled trials, but 16 controlled before-after trials met our inclusion criteria. Seven studies were done in Germany, six in the UK, two in Australia and one in the Netherlands. There were no studies in low or middle income countries. Eight trials reported the number of road traffic crashes resulting in deaths. The pooled rate ratio was 0.63 (0.14, 2.59 95% CI). Sixteen studies reported the number of road traffic crashes resulting in injuries (fatal and non fatal). The pooled rate ratio was 0.89 (0.80, 1.00 95% CI). Nine studies reported the total number of road traffic crashes. The pooled rate ratio was 0.95 (0.81, 1.11 95% CI). Thirteen trials reported the number of pedestrian-motor vehicle collisions. The pooled rate ratio was 1.00 (0.84, 1.18). There was significant heterogeneity for the total number of crashes and deaths and injuries. The results from this review suggest that area-wide traffic calming in towns and cities may be a promising intervention for reducing the number of road traffic injuries, and deaths. However, further rigorous evaluations of this intervention are needed.


The HELIO-geophysical storminess health effects in the cardio-vascular system of a human in the middle and high latitudes.
cardiovascular impairment remains one of the most current problems of today's life and the definition of the connection between its development and the state of heliogeophysical storminess is currently important. The results of long-term researches of communication between cardiovascular catastrophes (myocardial infarction) and heliogeophysical storminess in the middle and high latitudes are shown in this work. to study the influence of space weather parameters on human cardio-vascular system in the high and middle latitudes. To define the particular space weather parameters and the mechanisms of their influence on human myocardial infarction progressing. for the statistical processing of medical records data we use a spectral-time analysis, a correlation method and a method of overlapping of epochs. We have studied about 145 thousand medical records of ambulance medical services for the period of 1992 -2001. In order to define the reasons influencing the development of a myocardial infarction, we have made a comparison of myocardial infarction progress cases with Kp-index characterizing the level of geomagnetic storminess. the coincidence of geomagnetic storminess maximum with the cases of myocardial infarction, as well as the number of heart attacks excess in 1.5 times per a year near the maximum heliogeophysical activity (1992) compared to the year near the minimum of activity (1998) indicate possible influence of geomagnetic storminess on the myocardial infarction development of people living in subauroral latitudes. it was concluded that the appearance of heliogeophysical storminess in the myocardial infarction development in the mid-latitudes is largely due to the presence of Pc1 geomagnetic pulsations, and in the high latitudes, especially in maximum years of heliogeophysical storminess, it is due to the geomagnetic storminess caused by the parameters of the solar wind and the interplanetary magnetic field.


The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q.
Primary nocturnal enuresis (PNE), or bedwetting at night, affects approximately 10% of 6 year old children. Genetic components contribute to the pathogenesis and recently one locus was assigned to chromosome 13q. We evaluated the genetic factors and the pattern of inheritance for PNE in 392 families. Dominant transmission was observed in 43% and an apparent recessive mode of inheritance was observed in 9% of the families. Among the 392 probands the ratio of males to females was 3:1 indicating sex linked or sex influenced factors. Linkage to candidate regions was tested in 16 larger families segregating for autosomal dominant PNE. A gene for PNE was excluded from chromosome 13q in 11 families, whereas linkage to the interval D13S263-D13S291 was suggested (Zmax = 2.1) in three families. Further linkage analyses excluded about 1/3 of the genome at a 10 cM resolution except the region around D12S80 on chromosome 12q that showed a positive two point lod score in six of the families (Zmax = 4.2). This locus remains suggestive because the material was not sufficiently large to give evidence for heterogeneity. Our pedigree analysis indicates that major genes are involved in a large proportion of PNE families and the linkage results suggest that such a gene is located on chromosome 12q.


A Biomimetic Phosphatidylcholine-Terminated Monolayer Greatly Improves the In Vivo Performance of Electrochemical Aptamer-Based Sensors.
The real-time monitoring of specific analytes in situ in the living body would greatly advance our understanding of physiology and the development of personalized medicine. Because they are continuous (wash-free and reagentless) and are able to work in complex media (e.g., undiluted serum), electrochemical aptamer-based (E-AB) sensors are promising candidates to fill this role. E-AB sensors suffer, however, from often-severe baseline drift when deployed in undiluted whole blood either in vitro or in vivo. We demonstrate that cell-membrane-mimicking phosphatidylcholine (PC)-terminated monolayers improve the performance of E-AB sensors, reducing the baseline drift from around 70 % to just a few percent after several hours in flowing whole blood in vitro. With this improvement comes the ability to deploy E-AB sensors directly in situ in the veins of live animals, achieving micromolar precision over many hours without the use of physical barriers or active drift-correction algorithms.


Using an erythrocyte fatty acid fingerprint to predict risk of all-cause mortality: the Framingham Offspring Cohort.
RBC long-chain omega-3 (n-3) fatty acid (FA) percentages (of total fatty acids) are associated with lower risk for total mortality, but it is unknown if a suite of FAs could improve risk prediction. The objective of this study was to compare a combination of RBC FA levels with standard risk factors for cardiovascular disease (CVD) in predicting risk of all-cause mortality. Framingham Offspring Cohort participants without prevalent CVD having RBC FA measurements and relevant baseline clinical covariates (n = 2240) were evaluated during 11 y of follow-up. A forward, stepwise approach was used to systematically evaluate the association of 8 standard risk factors (age, sex, total cholesterol, HDL cholesterol, hypertension treatment, systolic blood pressure, smoking status, and prevalent diabetes) and 28 FA metrics with all-cause mortality. A 10-fold cross-validation process was used to build and validate models adjusted for age and sex. Four of 28 FA metrics [14:0, 16:1n-7, 22:0, and omega-3 index (O3I; 20:5n-3 + 22:6n-3)] appeared in ≥5 of the discovery models as significant predictors of all-cause mortality. In age- and sex-adjusted models, a model with 4 FA metrics was at least as good at predicting all-cause mortality as a model including the remaining 6 standard risk factors (C-statistic: 0.778; 95% CI: 0.759, 0.797; compared with C-statistic: 0.777; 95% CI: 0.753, 0.802). A model with 4 FA metrics plus smoking and diabetes (FA + Sm + D) had a higher C-statistic (0.790; 95% CI: 0.770, 0.811) compared with the FA (P < 0.01) or Sm + D models alone (C-statistic: 0.766; 95% CI: 0.739, 0.794; P < 0.001). A variety of other highly correlated FAs could be substituted for 14:0, 16:1n-7, 22:0, or O3I with similar predicted outcomes. In this community-based population in their mid-60s, RBC FA patterns were as predictive of risk for death during the next 11 y as standard risk factors. Replication is needed in other cohorts to validate this FA fingerprint as a predictor of all-cause mortality.


Immersive technology and the elderly: a mini-review.
Technologies that provide immersive experiences continue to become more ubiquitous across all age groups. This paper presents a review of the literature to provide a snapshot of the current state of research involving the use of immersive technologies and the elderly. A narrative literature review was conducted using the ScienceDirect, EBSCOhost, Springerlink and ERIC databases to summarize primary studies from which conclusions were drawn into a holistic interpretation. The majority of the studies examined the effect of immersive technologies on elder peoples' age-related declines, including sensory and motor changes (vision, hearing, motor skills), cognitive changes and social changes. Various immersive technologies have been described and tested to address these age-related changes, and have been categorized as 'games and simulations', 'robotics' and 'social technologies'. In most cases, promising results were found for immersive technologies to challenge age-related declines, especially through the increase of morale.


An evaluation of hepatotoxicity in breast cancer patients receiving injection Doxorubicin.
Hepatic dysfunction in the cancer unit has a significant impact on patient outcomes. The therapeutic application of anthracycline antibiotics are limited by side-effects mainly myelosuppression, chronic cardiotoxicity, and hepatotoxicity. To assess the risk of Hepatotoxicity in breast cancer patients receiving Inj. Doxorubicin. The investigation was a prospective study that was conducted in cancer patients receiving Inj. Doxorubicin doses of 50 mg/m(2), and 75 mg/m(2) at a South Indian tertiary care hospital. Sample collection was carried out from pre-chemotherapy to 4(th) cycle. Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), direct bilirubin and total bilirubin were assessed to determine hepatotoxicity. Data were analyzed using unpaired t-test, Pearson correlation using Graph-Pad Prism version 5.00 for Windows, Graph-Pad Software, San Diego, California, USA, www.graphpad.com. Breast cancer patients comprised 37% (49/132) of the total female cancer patient population, of which 46 patients with a mean age of 46.6 (13.4) years were included and 30.4% (14/46) patients were developed hepatotoxicity. The mean standard deviation of SGOT, SGPT, direct bilirubin, total bilirubin in the pre-chemotherapy cycle to fourth chemotherapy cycle were found to be 21.97 (5.798) U/L and 181.3 (103.6) U/L, 23.17 (6.237) U/L and 147.6 (90.9) U/L, 0.1351 (0.1186) mg/dL and 0.5445 (0.4587) mg/dL, 0.3094 (1.346) mg/dL and 2.7163 (1.898) mg/dL simultaneously where P < 0.05 which were statistically significant. There exist a strong correlation between the use of Inj. Doxorubicin and risk for developing hepatotoxicity. The health-care professionals dealing with breast cancer patients need to have awareness for hepatotoxicity with the use of Inj. Doxorubicin therapy.


BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension.
Primary pulmonary hypertension (PPH) is a potentially lethal disorder, because the elevation of the pulmonary arterial pressure may result in right-heart failure. Histologically, the disorder is characterized by proliferation of pulmonary-artery smooth muscle and endothelial cells, by intimal hyperplasia, and by in situ thrombus formation. Heterozygous mutations within the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2), of the transforming growth factor beta (TGF-beta) cell-signaling superfamily, have been identified in familial and sporadic cases of PPH. We report the molecular spectrum of BMPR2 mutations in 47 additional families with PPH and in three patients with sporadic PPH. Among the cohort of patients, we have identified 22 novel mutations, including 4 partial deletions, distributed throughout the BMPR2 gene. The majority (58%) of mutations are predicted to lead to a premature termination codon. We have also investigated the functional impact and genotype-phenotype relationships, to elucidate the mechanisms contributing to pathogenesis of this important vascular disease. In vitro expression analysis demonstrated loss of BMPR-II function for a number of the identified mutations. These data support the suggestion that haploinsufficiency represents the common molecular mechanism in PPH. Marked variability of the age at onset of disease was observed both within and between families. Taken together, these studies illustrate the considerable heterogeneity of BMPR2 mutations that cause PPH, and they strongly suggest that additional factors, genetic and/or environmental, may be required for the development of the clinical phenotype.


A wet-chemistry-based hydrogel sensing platform for 2D imaging of pressure, chemicals and temperature.
Human skin can perceive pressure, chemical compounds and temperature with a high spatial resolution via specific receptors. Inspired by human skin, we present a wet-chemistry based hydrogel sensing platform for 2D imaging sensitive to specific external stimuli, e.g., pressure, chemicals and temperature. This platform is composed of a hydrogel pyramidal array on a single electrode. Each pyramid serves as a spatially separated reservoir for chemical reactions, enabling independent pixels for sensing without individual electrodes. Depending on the electrochemiluminescence (ECL) electrolyte for specific stimuli, our platform possesses 2D imaging capabilities with high sensitivity for pH and temperature in addition to pressure via the deformation of the viscoelastic hydrogel. This work represents an important step toward the application of sensitive chemical reactions for various external stimuli to biocompatible electronic skins based on hydrogels without addressing circuit for each pixel.


Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes.
We identify a human mutation (E1053K) in the ankyrin-binding motif of Na(v)1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Na(v)1.5. The E1053K mutation abolishes binding of Na(v)1.5 to ankyrin-G, and also prevents accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. Ankyrin-G and Na(v)1.5 are both localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na(v)1.5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates from rat heart. These data suggest that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 localization at excitable membranes in cardiomyocytes. Together with previous work in neurons, these results in cardiomyocytes suggest that ankyrin-G participates in a common pathway for localization of voltage-gated Na(v) channels at sites of function in multiple excitable cell types.


Compartmentation of metals in foliage of Populus tremula grown on soils with mixed contamination. II. Zinc binding inside leaf cell organelles.
The phytoextraction potential of plants for removing heavy metals from polluted soils is determined by their capacity to store contaminants in aboveground organs and complex them safely. In this study, the metal compartmentation, elemental composition of zinc deposits and zinc complexation within leaves from poplars grown on soil with mixed metal contamination was analysed combining several histochemical and microanalytical approaches. Zinc was the only heavy metal detected and was stored in several organelles in the form of globoid deposits showing β-metachromasy. It was associated to oxygen anions and different cations, noteworthy phosphorous. The deposit structure, elemental composition and element ratios indicated that zinc was chelated by phytic acid ligands. Maturation processes in vacuolar vs. cytoplasmic deposits were suggested by differences in size and amounts of complexed zinc. Hence, zinc complexation by phytate contributed to metal detoxification and accumulation in foliage but could not prevent toxicity reactions therein.


Prediction of the basicities of pyridines in the gas phase and in aqueous solution.
The basicities of 125 pyridine derivatives in the gas phase and in water have been correlated with the electron density properties within the framework of quantum topological molecular similarity (QTMS). We used the theory of quantum chemical topology (QCT) to provide ab initio descriptors that are able to predict pK(b) values. Partial least squares (PLS) and the machine-learning technique Kriging generated validated models. Properties were considered for systems in their neutral and protonated forms. The compounds were divided into a training set, used to develop the models, and a test set, for which the predicted values of the different models were compared with the experimental ones. The results were found to be good for those compounds with substituents in the meta and para positions, whereas the use of Kriging was required to obtain reasonable results when ortho derivatives were included. The basicity was found to be better described in the gas phase than in water. Special attention was paid to external validation.


Comparison of Variable and Single-Rate Applications of Aldicarb on Cotton Yield in Fields Infested with Meloidogyne incognita.
Variable-rate applications of the nematicide aldicarb were compared to producer standard rates in eight field tests over 3 years. Test areas (308 to 1,015 m long) were divided into eight or five blocks. Each block contained two plots with a variable-rate treatment (VRT) of aldicarb and a producer standard treatment (PST) of aldicarb. Each VRT plot was divided into three subunits and intensively sampled for Meloidogyne incognita in either the fall or spring before planting. Rates of aldicarb were assigned to each subunit for VRT based on M. incognita population density. In three of the eight tests, VRT resulted in either higher yield or similar yields, but less nematicide applied. In two tests there were no differences between PST and VRT in yields or average rates of aldicarb applied. In three tests, VRT used more aldicarb (>0.17 kg a.i./ha difference) than PST and yields were not significantly different between treatments. In two of the cases where VRT was superior to PST, the producer's rate of aldicarb was judged to be either too low or too high for the average M. incognita density present in the field. In all three cases where PST was superior to VRT, perennial weeds were an important factor also limiting yield. Variable-rate application of aldicarb did not consistently provide for higher yields or lower nematicide usage than standard application rates.


A clampless and sutureless aortic anastomosis technique using an endograft connector for aortoiliac occlusive disease in which the aorta cannot be clamped or sewn due to calcification or scarring.
Bypass surgery in aortoiliac or aortofemoral occlusive disease can be technically demanding and hazardous due to huge calcifications and/or patient co-morbidities. We report about mid-term results of a telescoping sutureless aortic anastomosis technique using endografts as connectors to address such challenging situations. This is a single-center experience (2004-2011) in seven patients (63 ± 6 years) requiring aortoiliac (three) or aortofemoral (four) bypass surgery. In six cases, an aortic stent graft was telescoped into the infrarenal aorta and partly deployed within the aorta and partly outside the aorta. In the first case, a bifurcated stent graft was deployed and the iliac legs were prolonged extra-anatomically with surgical grafts to reach the femoral bifurcation. In the following five cases, a tapered tubular stent graft was deployed through the aortic wall, landing inside a bifurcated surgical graft that was extra-anatomically connected to the iliac or femoral arteries. In the last case, which presented a hostile abdomen and high-risk for extensive surgery, a similar technique was used, but on the iliac artery level. In that case, an iliac stent graft re-loaded 'upside down' was deployed through the left common iliac wall, landing distally inside a hand-made 10 × 10 mm bifurcated surgical graft that was extra-anatomically connected to the left external iliac artery and to the right femoral artery. The distal anastomoses on the seven cases were performed either with running sutures (ten) or with VORTEC (four). Telescoping aortic and/or iliac anastomosis was successful in all patients. There was no perioperative mortality. One patient developed postoperative hyperperfusion of the left leg and necessitated fasciotomy. During a mean follow-up of 1.8 ± 2 years (minimum: 270 days, maximum: 7.1 years), all of the grafts remained patent and there was neither stent-graft migration nor stenosis on the level of the aortic or iliofemoral connection. One patient showed disease progression and required percutaneous transluminal angioplasty on the external iliac artery during follow-up. The uneventful perioperative course in these seven patients, with a follow-up of up to six years, underscores that this new technique can be considered in patients with aortoiliac or aortofemoral occlusive disease and in whom clamping and/or anastomosis is expected to be cumbersome or impossible.


Resting-State Static and Dynamic Functional Abnormalities in Active Professional Fighters With Repetitive Head Trauma and With Neuropsychological Impairments.
Previous neuroimaging studies have identified structural brain abnormalities in active professional fighters with repetitive head trauma and correlated these changes with fighters' neuropsychological impairments. However, functional brain changes in these fighters derived using neuroimaging techniques remain unclear. In this study, both static and dynamic functional connectivity alterations were investigated (1) between healthy normal control subjects (NC) and fighters and (2) between non-impaired and impaired fighters. Resting-state fMRI data were collected on 35 NC and 133 active professional fighters, including 68 impaired fighters and 65 non-impaired fighters, from the Professional Fighters Brain Health Study at our center. Impaired fighters performed worse on processing speed (PSS) tasks with visual-attention and working-memory demands. The static functional connectivity (sFC) matrix was estimated for every pair of regions of interest (ROI) using a subject-specific parcellation. The dynamic functional connectivity (dFC) was estimated using a sliding-window method, where the variability of each ROI pair across all windows represented the temporal dynamics. A linear regression model was fitted for all 168 subjects, and different t-contrast vectors were used for between-group comparisons. An association analysis was further conducted to evaluate FC changes associated with PSS task performances without creating artificial impairment group-divisions in fighters. Following corrections for multiple comparisons using network-based statistics, our study identified significantly reduced long-range frontal-temporal, frontal-occipital, temporal-occipital, and parietal-occipital sFC strengths in fighters than in NCs, corroborating with previously observed structural damages in corresponding white matter tracts in subjects experiencing repetitive head trauma. In impaired fighters, significantly decreased sFC strengths were found among key regions involved in visual-attention, executive and cognitive process, as compared to non-impaired fighters. Association analysis further reveals similar sFC deficits to worse PSS task performances in all 133 fighters. With our choice of dFC indices, we were not able to observe any significant dFC changes beyond a trend-level increased temporal variability among similar regions with weaker sFC strengths in impaired fighters. Collectively, our functional brain findings supplement previously reported structural brain abnormalities in fighters and are important to comprehensively understand brain changes in fighters with repetitive head trauma.


Forced expression of Nanog or Esrrb preserves the ESC status in the absence of nucleostemin expression.
Nucleostemin (NS) is a nucleolar GTP-binding protein that is involved in a plethora of functions including ribosomal biogenesis and maintenance of telomere integrity. In addition to its expression in cancerous cells, the NS gene is expressed in stem cells including embryonic stem cells (ESCs). Previous knockdown and knockout studies have demonstrated that NS is important to preserve the self-renewality and high expression levels of pluripotency marker genes in ESCs. Here, we found that forced expression of Nanog or Esrrb, but not other pluripotency factors, resulted in the dispensability of NS expression in ESCs. However, the detrimental phenotypes of ESCs associated with ablation of NS expression were not mitigated by forced expression of Rad51 or a nucleolar localization-defective NS mutant that counteracts the damage associated with loss of NS expression in other NS-expressing cells such as neural stem/progenitor cells. Thus, our results indicate that NS participates in preservation of the viability and integrity of ESCs, which is distinct from that in other NS-expressing cells.


Perinatal complications and aging indicators by midlife.
Perinatal complications predict increased risk for morbidity and early mortality. Evidence of perinatal programming of adult mortality raises the question of what mechanisms embed this long-term effect. We tested a hypothesis related to the theory of developmental origins of health and disease: that perinatal complications assessed at birth predict indicators of accelerated aging by midlife. Perinatal complications, including both maternal and neonatal complications, were assessed in the Dunedin Multidisciplinary Health and Development Study cohort (N = 1037), a 38-year, prospective longitudinal study of a representative birth cohort. Two aging indicators were assessed at age 38 years, objectively by leukocyte telomere length (TL) and subjectively by perceived facial age. Perinatal complications predicted both leukocyte TL (β = -0.101; 95% confidence interval, -0.169 to -0.033; P = .004) and perceived age (β = 0.097; 95% confidence interval, 0.029 to 0.165; P = .005) by midlife. We repeated analyses with controls for measures of family history and social risk that could predispose to perinatal complications and accelerated aging, and for measures of poor health taken in between birth and the age-38 follow-up. These covariates attenuated, but did not fully explain the associations observed between perinatal complications and aging indicators. Our findings provide support for early-life developmental programming by linking newborns' perinatal complications to accelerated aging at midlife. We observed indications of accelerated aging "inside," as measured by leukocyte TL, an indicator of cellular aging, and "outside," as measured by perceived age, an indicator of declining tissue integrity. A better understanding of mechanisms underlying perinatal programming of adult aging is needed.


Genetic analysis of glucosinolate variability in broccoli florets using genome-anchored single nucleotide polymorphisms.
The identification of genetic factors influencing the accumulation of individual glucosinolates in broccoli florets provides novel insight into the regulation of glucosinolate levels in Brassica vegetables and will accelerate the development of vegetables with glucosinolate profiles tailored to promote human health. Quantitative trait loci analysis of glucosinolate (GSL) variability was conducted with a B. oleracea (broccoli) mapping population, saturated with single nucleotide polymorphism markers from a high-density array designed for rapeseed (Brassica napus). In 4 years of analysis, 14 QTLs were associated with the accumulation of aliphatic, indolic, or aromatic GSLs in floret tissue. The accumulation of 3-carbon aliphatic GSLs (2-propenyl and 3-methylsulfinylpropyl) was primarily associated with a single QTL on C05, but common regulation of 4-carbon aliphatic GSLs was not observed. A single locus on C09, associated with up to 40 % of the phenotypic variability of 2-hydroxy-3-butenyl GSL over multiple years, was not associated with the variability of precursor compounds. Similarly, QTLs on C02, C04, and C09 were associated with 4-methylsulfinylbutyl GSL concentration over multiple years but were not significantly associated with downstream compounds. Genome-specific SNP markers were used to identify candidate genes that co-localized to marker intervals and previously sequenced Brassica oleracea BAC clones containing known GSL genes (GSL-ALK, GSL-PRO, and GSL-ELONG) were aligned to the genomic sequence, providing support that at least three of our 14 QTLs likely correspond to previously identified GSL loci. The results demonstrate that previously identified loci do not fully explain GSL variation in broccoli. The identification of additional genetic factors influencing the accumulation of GSL in broccoli florets provides novel insight into the regulation of GSL levels in Brassicaceae and will accelerate development of vegetables with modified or enhanced GSL profiles.


The fusion of tissue spheroids attached to pre-stretched electrospun polyurethane scaffolds.
Effective cell invasion into thick electrospun biomimetic scaffolds is an unsolved problem. One possible strategy to biofabricate tissue constructs of desirable thickness and material properties without the need for cell invasion is to use thin (<2 µm) porous electrospun meshes and self-assembling (capable of tissue fusion) tissue spheroids as building blocks. Pre-stretched electrospun meshes remained taut in cell culture and were able to support tissue spheroids with minimal deformation. We hypothesize that elastic electrospun scaffolds could be used as temporal support templates for rapid self-assembly of cell spheroids into higher order tissue structures, such as engineered vascular tissue. The aim of this study was to investigate how the attachment of tissue spheroids to pre-stretched polyurethane scaffolds may interfere with the tissue fusion process. Tissue spheroids attached, spread, and fused after being placed on pre-stretched polyurethane electrospun matrices and formed tissue constructs. Efforts to eliminate hole defects with fibrogenic tissue growth factor-β resulted in the increased synthesis of collagen and periostin and a dramatic reduction in hole size and number. In control experiments, tissue spheroids fuse on a non-adhesive hydrogel and form continuous tissue constructs without holes. Our data demonstrate that tissue spheroids attached to thin stretched elastic electrospun scaffolds have an interrupted tissue fusion process. The resulting tissue-engineered construct phenotype is a direct outcome of the delicate balance of the competing physical forces operating during the tissue fusion process at the interface of the pre-stretched elastic scaffold and the attached tissue spheroids. We have shown that with appropriate treatments, this process can be modulated, and thus, a thin pre-stretched elastic polyurethane electrospun scaffold could serve as a supporting template for rapid biofabrication of thick tissue-engineered constructs without the need for cell invasion.


The endocrine and metabolic evaluation of benign symmetrical lipomatosis: a case report and literature review.
Benign symmetrical lipomatosis (BSL) is a rare disease characterized by the presence of multiple, symmetric and nonencapsulated fat masses. Alcoholism is observed in nearly 90% patients. However the etiology of this disease is still unclarified. BSL is very rare in Chinese people. Herein we described the endocrine and metabolic status of a patient with typical BSL. We also discussed the clinical manifestation, etiology, diagnosis and treatment for BSL. Hyperuricemia and abnormal liver enzyme levels were observed in this case. However insulin sensitivity and function of the thyroid, adrenal glands and pituitary were all normal. The insulin sensitivity was assessed by the hyperinsulinemic euglycemic clam. Although an association had been found between BSL and some endocrinological or metabolic disorders including abnormal glucose tolerance, excessive secretion of insulin, hyperuricemia, and so on, they were not specific for BSL. It is necessary to develop into the pathogenesis of BSL further.


An assessment of the impact of the NHS Health Technology Assessment Programme.
To consider how the impact of the NHS Health Technology Assessment (HTA) Programme should be measured. To determine what models are available and their strengths and weaknesses. To assess the impact of the first 10 years of the NHS HTA programme from its inception in 1993 to June 2003 and to identify the factors associated with HTA research that are making an impact. Main electronic databases from 1990 to June 2005. The documentation of the National Coordinating Centre for Health Technology Assessment (NCCHTA). Questionnaires to eligible researchers. Interviews with lead investigators. Case study documentation. A literature review of research programmes was carried out, the work of the NCCHTA was reviewed, lead researchers were surveyed and 16 detailed case studies were undertaken. Each case study was written up using the payback framework. A cross-case analysis informed the analysis of factors associated with achieving payback. Each case study was scored for impact before and after the interview to assess the gain in information due to the interview. The draft write-up of each study was checked with each respondent for accuracy and changed if necessary. The literature review identified a highly diverse literature but confirmed that the 'payback' framework pioneered by Buxton and Hanney was the most widely used and most appropriate model available. The review also confirmed that impact on knowledge generation was more easily quantified than that on policy, behaviour or especially health gain. The review of the included studies indicated a higher level of impact on policy than is often assumed to occur. The survey showed that data pertinent to payback exist and can be collected. The completed questionnaires showed that the HTA Programme had considerable impact in terms of publications, dissemination, policy and behaviour. It also showed, as expected, that different parts of the Programme had different impacts. The Technology Assessment Reports (TARs) for the National Institute for Health and Clinical Excellence (NICE) had the clearest impact on policy in the form of NICE guidance. Mean publications per project were 2.93 (1.98 excluding the monographs), above the level reported for other programmes. The case studies revealed the large diversity in the levels and forms of impacts and the ways in which they arise. All the NICE TARs and more than half of the other case studies had some impact on policy making at the national level whether through NICE, the National Screening Committee, the National Service Frameworks, professional bodies or the Department of Health. This underlines the importance of having a customer or 'receptor' body. A few case studies had very considerable impact in terms of knowledge production and in informing national and international policies. In some of these the principal investigator had prior expertise and/or a research record in the topic. The case studies confirmed the questionnaire responses but also showed how some projects led to further research. This study concluded that the HTA Programme has had considerable impact in terms of knowledge generation and perceived impact on policy and to some extent on practice. This high impact may have resulted partly from the HTA Programme's objectives, in that topics tend to be of relevance to the NHS and have policy customers. The required use of scientific methods, notably systematic reviews and trials, coupled with strict peer reviewing, may have helped projects publish in high-quality peer-reviewed journals. Further research should cover more detailed, comprehensive case studies, as well as enhancement of the 'payback framework'. A project that collated health research impact studies in an ongoing manner and analysed them in a consistent fashion would also be valuable.


Protein hydrolysate versus standard formula for preterm infants.
When human milk is not available for feeding preterm infants, protein hydrolysate, rather than standard cow's milk formulas (with intact proteins), is often used because it is perceived as being tolerated better and less likely to lead to complications. However, protein hydrolysate formulas are more expensive than standard formulas, and concern exists that their use in practice is not supported by high-quality evidence. To assess the effects of feeding preterm infants hydrolysed formula (vs standard cow's milk formula) on risk of feed intolerance, necrotising enterocolitis, and other morbidity and mortality. We used the standard Cochrane Neonatal search strategy including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1), in the Cochrane Library; Ovid MEDLINE (1966 to 28 January 2019); Ovid Embase (1980 to 28 January 2019); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (28 January 2019), as well as conference proceedings and previous reviews. Randomised and quasi-randomised controlled trials that compared feeding preterm infants protein hydrolysate versus standard (non-hydrolysed) cow's milk formula. Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios and risk differences for dichotomous data, and mean differences for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in sensitivity analyses. We assessed quality of evidence at the outcome level using the GRADE approach. We identified 11 trials for inclusion in the review. All trials were small (total participants 665) and had various methodological limitations including uncertainty about methods to ensure allocation concealment and blinding. Most participants were clinically stable preterm infants of less than about 34 weeks' gestational age or with birth weight less than about 1750 g. Fewer participants were extremely preterm, extremely low birth weight, or growth restricted. Most trials found no effects on feed intolerance, assessed variously as mean pre-feed gastric residual volume, incidence of abdominal distension or other gastrointestinal signs of concern, or time taken to achieve full enteral feeds (meta-analysis was limited because studies used different measures). Meta-analysis showed no effect on the risk of necrotising enterocolitis (typical risk ratio 1.10, 95% CI 0.36 to 3.34; risk difference 0.00, 95% CI -0.03 to 0.04; 5 trials, 385 infants) (low-certainty evidence; downgraded for imprecision and design weaknesses). The identified trials provide only low-certainty evidence about the effects of feeding preterm infants protein hydrolysate versus standard formula. Existing data do not support conclusions that feeding protein hydrolysate affects the risk of feed intolerance or necrotising enterocolitis. Additional large, pragmatic trials are needed to provide more reliable and precise estimates of effectiveness and cost-effectiveness.


Action myoclonus-renal failure syndrome: diagnostic applications of activity-based probes and lipid analysis.
Lysosomal integral membrane protein-2 (LIMP2) mediates trafficking of glucocerebrosidase (GBA) to lysosomes. Deficiency of LIMP2 causes action myoclonus-renal failure syndrome (AMRF). LIMP2-deficient fibroblasts virtually lack GBA like the cells of patients with Gaucher disease (GD), a lysosomal storage disorder caused by mutations in the GBA gene. While GD is characterized by the presence of glucosylceramide-laden macrophages, AMRF patients do not show these. We studied the fate of GBA in relation to LIMP2 deficiency by employing recently designed activity-based probes labeling active GBA molecules. We demonstrate that GBA is almost absent in lysosomes of AMRF fibroblasts. However, white blood cells contain considerable amounts of residual enzyme. Consequently, AMRF patients do not acquire lipid-laden macrophages and do not show increased plasma levels of macrophage markers, such as chitotriosidase, in contrast to GD patients. We next investigated the consequences of LIMP2 deficiency with respect to plasma glycosphingolipid levels. Plasma glucosylceramide concentration was normal in the AMRF patients investigated as well as in LIMP2-deficient mice. However, a marked increase in the sphingoid base, glucosylsphingosine, was observed in AMRF patients and LIMP2-deficient mice. Our results suggest that combined measurements of chitotriosidase and glucosylsphingosine can be used for convenient differential laboratory diagnosis of GD and AMRF.


Hyperimmune immunoglobulin for people with COVID-19.
Hyperimmune immunoglobulin (hIVIG) contains polyclonal antibodies, which can be prepared from large amounts of pooled convalescent plasma or prepared from animal sources through immunisation. They are being investigated as a potential therapy for coronavirus disease 2019 (COVID-19). This review was previously part of a parent review addressing convalescent plasma and hIVIG for people with COVID-19 and was split to address hIVIG and convalescent plasma separately. To assess the benefits and harms of hIVIG therapy for the treatment of people with COVID-19, and to maintain the currency of the evidence using a living systematic review approach. To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Research Database, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform and Medline and Embase from 1 January 2019 onwards. We carried out searches on 31 March 2022. We included randomised controlled trials (RCTs) that evaluated hIVIG for COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies that evaluated standard immunoglobulin. We followed standard Cochrane methodology. To assess bias in included studies, we used RoB 2. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), quality of life, adverse events, and serious adverse events. We included five RCTs with 947 participants, of whom 688 received hIVIG prepared from humans, 18 received heterologous swine glyco-humanised polyclonal antibody, and 241 received equine-derived processed and purified F(ab')2 fragments. All participants were hospitalised with moderate-to-severe disease, most participants were not vaccinated (only 12 participants were vaccinated). The studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern. There are no data for people with COVID-19 with no symptoms (asymptomatic) or people with mild COVID-19. We identified a further 10 ongoing studies evaluating hIVIG. Benefits of hIVIG prepared from humans We included data on one RCT (579 participants) that assessed the benefits and harms of hIVIG 0.4 g/kg compared to saline placebo. hIVIG may have little to no impact on all-cause mortality at 28 days (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.43 to 1.44; absolute effect 77 per 1000 with placebo versus 61 per 1000 (33 to 111) with hIVIG; low-certainty evidence). The evidence is very uncertain about the effect on worsening of clinical status at day 7 (RR 0.85, 95% CI 0.58 to 1.23; very low-certainty evidence). It probably has little to no impact on improvement of clinical status on day 28 (RR 1.02, 95% CI 0.97 to 1.08; moderate-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if hIVIG has any impact on quality of life. Harms of hIVIG prepared from humans hIVIG may have little to no impact on adverse events at any grade on day 1 (RR 0.98, 95% CI 0.81 to 1.18; 431 per 1000; 1 study 579 participants; low-certainty evidence). Patients receiving hIVIG probably experience more adverse events at grade 3-4 severity than patients who receive placebo (RR 4.09, 95% CI 1.39 to 12.01; moderate-certainty evidence). hIVIG may have little to no impact on the composite outcome of serious adverse events or death up to day 28 (RR 0.72, 95% CI 0.45 to 1.14; moderate-certainty evidence). We also identified additional results on the benefits and harms of other dose ranges of hIVIG, not included in the summary of findings table, but summarised in additional tables. Benefits of animal-derived polyclonal antibodies We included data on one RCT (241 participants) to assess the benefits and harms of receptor-binding domain-specific polyclonal F(ab´)2 fragments of equine antibodies (EpAbs) compared to saline placebo. EpAbs may reduce all-cause mortality at 28 days (RR 0.60, 95% CI 0.26 to 1.37; absolute effect 114 per 1000 with placebo versus 68 per 1000 (30 to 156) ; low-certainty evidence). EpAbs may reduce worsening of clinical status up to day 28 (RR 0.67, 95% CI 0.38 to 1.18; absolute effect 203 per 1000 with placebo versus 136 per 1000 (77 to 240); low-certainty evidence). It may have some effect on improvement of clinical status on day 28 (RR 1.06, 95% CI 0.96 to 1.17; low-certainty evidence). We did not identify any studies that reported quality-of-life outcomes, so we do not know if EpAbs have any impact on quality of life. Harms of animal-derived polyclonal antibodies EpAbs may have little to no impact on the number of adverse events at any grade up to 28 days (RR 0.99, 95% CI 0.74 to 1.31; low-certainty evidence). Adverse events at grade 3-4 severity were not reported. Individuals receiving EpAbs may experience fewer serious adverse events than patients receiving placebo (RR 0.67, 95% CI 0.38 to 1.19; low-certainty evidence). We also identified additional results on the benefits and harms of other animal-derived polyclonal antibody doses, not included in the summary of findings table, but summarised in additional tables. We included data from five RCTs that evaluated hIVIG compared to standard therapy, with participants with moderate-to-severe disease. As the studies evaluated different preparations (from humans or from various animals) and doses, we could not pool them. hIVIG prepared from humans may have little to no impact on mortality, and clinical improvement and worsening. hIVIG may increase grade 3-4 adverse events. Studies did not evaluate quality of life. RBD-specific polyclonal F(ab´)2 fragments of equine antibodies may reduce mortality and serious adverse events, and may reduce clinical worsening. However, the studies were conducted before or during the emergence of several SARS-CoV-2 variants of concern and prior to widespread vaccine rollout. As no studies evaluated hIVIG for participants with asymptomatic infection or mild disease, benefits for these individuals remains uncertain. This is a living systematic review. We search monthly for new evidence and update the review when we identify relevant new evidence.


Long-term durable response to lenalidomide in a patient with hepatic epithelioid hemangioendothelioma.
Epithelioid hemangioendothelioma (EH) is a rare tumor arising from the vascular endothelial cells of soft tissue or visceral organs. The most common visceral site is the liver, where it is often involved in a multifocal manner known as hepatic EH (HEH). Surgical resection with curative intent represents the gold standard therapy. When surgery is not feasible, or in cases of metastatic disease, no standard medical treatment is currently indicated. In small series, drugs with anti-angiogenic activity (such as bevacizumab, sorafenib, thalidomide, and lenalidomide) have been proposed with promising results. We describe a 73-year-old man with multifocal non-resectable HEH treated with lenalidomide. Disease status was evaluated by abdominal ultrasound and magnetic resonance every four months. The patient was treated for a total of 39 mo with prolonged disease stabilization and, at the time of writing, is still under treatment with a good tolerance profile. During a short period of treatment discontinuation, the disease showed slight progression that immediately resolved after the reintroduction of lenalidomide. Lenalidomide may represent a valid treatment option for HEH due to its anti-angiogenic and antineoplastic activities. This preliminary result merits further study in a large series.


Development of the Assessment of Belief Conflict in Relationship-14 (ABCR-14).
Nurses and other healthcare workers frequently experience belief conflict, one of the most important, new stress-related problems in both academic and clinical fields. In this study, using a sample of 1,683 nursing practitioners, we developed The Assessment of Belief Conflict in Relationship-14 (ABCR-14), a new scale that assesses belief conflict in the healthcare field. Standard psychometric procedures were used to develop and test the scale, including a qualitative framework concept and item-pool development, item reduction, and scale development. We analyzed the psychometric properties of ABCR-14 according to entropy, polyserial correlation coefficient, exploratory factor analysis, confirmatory factor analysis, average variance extracted, Cronbach's alpha, Pearson product-moment correlation coefficient, and multidimensional item response theory (MIRT). The results of the analysis supported a three-factor model consisting of 14 items. The validity and reliability of ABCR-14 was suggested by evidence from high construct validity, structural validity, hypothesis testing, internal consistency reliability, and concurrent validity. The result of the MIRT offered strong support for good item response of item slope parameters and difficulty parameters. However, the ABCR-14 Likert scale might need to be explored from the MIRT point of view. Yet, as mentioned above, there is sufficient evidence to support that ABCR-14 has high validity and reliability. The ABCR-14 demonstrates good psychometric properties for nursing belief conflict. Further studies are recommended to confirm its application in clinical practice.


Bayesian surprise attracts human attention.
We propose a formal Bayesian definition of surprise to capture subjective aspects of sensory information. Surprise measures how data affects an observer, in terms of differences between posterior and prior beliefs about the world. Only data observations which substantially affect the observer's beliefs yield surprise, irrespectively of how rare or informative in Shannon's sense these observations are. We test the framework by quantifying the extent to which humans may orient attention and gaze towards surprising events or items while watching television. To this end, we implement a simple computational model where a low-level, sensory form of surprise is computed by simple simulated early visual neurons. Bayesian surprise is a strong attractor of human attention, with 72% of all gaze shifts directed towards locations more surprising than the average, a figure rising to 84% when focusing the analysis onto regions simultaneously selected by all observers. The proposed theory of surprise is applicable across different spatio-temporal scales, modalities, and levels of abstraction.


Methamphetamine Consumption Inhibits Pair Bonding and Hypothalamic Oxytocin in Prairie Voles.
Methamphetamine (MA) abuse has been linked to violence, risk-taking behaviors, decreased sexual inhibition, and criminal activity. It is important to understand mechanisms underlying these drug effects for prevention and treatment of MA-associated social problems. Previous studies have demonstrated that experimenter-administered amphetamine inhibits pair bonding and increases aggression in monogamous prairie voles. It is not currently known whether similar effects on social behaviors would be obtained under conditions during which the drug is voluntarily (actively) administered. The current study investigated whether MA drinking affects pair bonding and what neurocircuits are engaged. In Experiment 1, we exposed male and female voles to 4 days each of 20 and 40 mg/L MA under a continuous 2-bottle choice (2BC) procedure. Animals were housed either singly or in mesh-divided cages with a social partner. Voles consumed MA in a drinking solution, but MA drinking was not affected by either sex or housing condition. In Experiment 2, we investigated whether MA drinking disrupts social bonding by measuring aggression and partner preference formation following three consecutive days of 18-hour/day access to 100 mg/L MA in a 2BC procedure. Although aggression toward a novel opposite-sex animal was not affected by MA exposure, partner preference was inhibited in MA drinking animals. Experiment 3 examined whether alterations in hypothalamic neuropeptides provide a potential explanation for the inhibition of partner preference observed in Experiment 2. MA drinking led to significant decreases in oxytocin, but not vasopressin, in the paraventricular nucleus of the hypothalamus. These experiments are the first investigation into how voluntary pre-exposure to MA affects the development of social attachment in a socially monogamous species and identify potential neural circuits involved in these effects.


Risk assessment of staphylococcal poisoning due to consumption of informally-marketed milk and home-made yoghurt in Debre Zeit, Ethiopia.
The objectives of the study were twofold: to prove that participatory risk assessment can be applied to informally-marketed foods, and to assess the risk of staphylococcal poisoning through consumption of raw milk and home-made yoghurt in Debre Zeit, Ethiopia. Rapid urban appraisals were combined with conventional interviews to identify and quantify formal and informal milk value chains and to collect information on consumers' food preparation and consumption behavior. Milk was sampled in 170 dairy farms and 5 milk collection centers and microbiological tests were conducted. Published data on milk fermentation in Ethiopia was combined with a growth model of Staphylococcus aureus to develop a stochastic risk model. The annual incidence rate of staphylococcal poisoning was estimated to be 20.0 (90% CI: 13.9-26.9) per 1000 people. When the effect of fermentation was removed from the model, the annual incidence rate increased to 315.8 (90% CI: 224.3-422.9) per 1000 people, showing the importance of traditional food preparation methods in risk mitigation; traditional milk fermentation reduced the risk by 93.7%. Improving the safety of milk and dairy products could be achieved through supporting appropriate traditional food preparation and consumption where an industrial risk mitigation system is not feasible. Participatory risk assessment was shown to be applicable to informal food value chain.


Identification and characterization of a new Escherichia coli gene that is a dosage-dependent suppressor of a dnaK deletion mutation.
We report the isolation and characterization of a previously unidentified Escherichia coli gene that suppresses the temperature-sensitive growth and filamentation of a dnaK deletion mutant strain. Introduction of a multicopy plasmid carrying this wild-type gene into a dnaK deletion mutant strain rescued the temperature-sensitive growth of the dnaK deletion mutant strain at 40.5 degrees C and the filamentation, fully at 37 degrees C and partially at 40.5 degrees C. However, the inability of dnaK mutant cells to support bacteriophage lambda growth was not suppressed. This gene was also able to suppress the temperature-sensitive growth of a grpE280 mutant strain at 41 degrees C. Filamentation of the grpE280 mutant strain was suppressed at 37 degrees C but not at 41 degrees C. The dnaK suppressor gene, designated dksA, maps near the mrcB gene (3.7 min on the E. coli chromosome). DNA sequence analysis and in vivo experiments showed that dksA encodes a 17,500-Mr polypeptide. Gene disruption experiments indicated that dksA is not an essential gene.


Early gene expression divergence between allopatric populations of the house mouse (Mus musculus domesticus).
Divergence of gene expression is known to contribute to the differentiation and separation of populations and species, although the dynamics of this process in early stages of population divergence remains unclear. We analyzed gene expression differences in three organs (brain, liver, and testis) between two natural populations of Mus musculus domesticus that have been separated for at most 3000 years. We used two different microarray platforms to corroborate the results at a large scale and identified hundreds of genes with significant expression differences between the populations. We find that although the three tissues have similar number of differentially expressed genes, brain and liver have more tissue-specific genes than testis. Most genes show changes in a single tissue only, even when expressed in all tissues, supporting the notion that tissue-specific enhancers act as separable targets of evolution. In terms of functional categories, in brain and to a smaller extent in liver, we find transcription factors and their targets to be particularly variable between populations, similar to previous findings in primates. Testis, however, has a different set of differently expressed genes, both with respect to functional categories and overall correlation with the other tissues, the latter indicating that gene expression divergence of potential importance might be present in other datasets where no differences in fraction of differentially expressed genes were reported. Our results show that a significant amount of gene expression divergence quickly accumulates between allopatric populations.


Close packing of Listeria monocytogenes ActA, a natively unfolded protein, enhances F-actin assembly without dimerization.
Studies of the biochemistry of Listeria monocytogenes virulence protein ActA have typically focused on the behavior of bacteria in complex systems or on the characterization of the protein after expression and purification. Although prior in vivo work has proposed that ActA forms dimers on the surface of L. monocytogenes, dimerization has not been demonstrated in vitro, and little consideration has been given to the surface environment where ActA performs its pivotal role in bacterial actin-based motility. We have synthesized and characterized an ActA dimer and provide evidence that the two ActA molecules do not interact with each other even when tethered together. However, we also demonstrate that artificial dimers provide superior activation of actin nucleation by the Arp2/3 complex compared with monomers and that increased activation of the Arp2/3 complex by dimers may be a general property of Arp2/3 activators. It appears that the close packing ( approximately 19 nm) of ActA molecules on the surface of L. monocytogenes is so dense that the kinetics of actin nucleation mimic that of synthetic ActA dimers. We also present observations indicating that ActA is a natively unfolded protein, largely random coil that is responsible for many of the unique physical properties of ActA including its extended structure, aberrant mobility during SDS-PAGE, and ability to resist irreversible denaturation upon heating.


Dynamic metabolic models in context: biomass backtracking.
Mathematical modeling has proven to be a powerful tool to understand and predict functional and regulatory properties of metabolic processes. High accuracy dynamic modeling of individual pathways is thereby opposed by simplified but genome scale constraint based approaches. A method that links these two powerful techniques would greatly enhance predictive power but is so far lacking. We present biomass backtracking, a workflow that integrates the cellular context in existing dynamic metabolic models via stoichiometrically exact drain reactions based on a genome scale metabolic model. With comprehensive examples, for different species and environmental contexts, we show the importance and scope of applications and highlight the improvement compared to common boundary formulations in existing metabolic models. Our method allows for the contextualization of dynamic metabolic models based on all available information. We anticipate this to greatly increase their accuracy and predictive power for basic research and also for drug development and industrial applications.


Cholera deaths in Soho, London, 1854: Risk Terrain Modeling for epidemiological investigations.
Risk Terrain Modeling (RTM) is a spatial analysis technique used to diagnose environmental conditions that lead to hazardous outcomes. Originally developed for applications to violent crime analysis, RTM is utilized here to analyze Dr. John Snow's data from the 1854 cholera outbreak in London to demonstrate its potential value to contemporary epidemiological investigations. Dr. Snow saved countless lives when he traced the source of the cholera outbreak to a specific water pump through inductive reasoning, which he communicated through maps and spatial evidence. His methods have since inspired several fields of scientific inquiry. Informed by the extant research on RTM, we speculated that it could have helped test Dr. Snow's hypothesis about cholera and empirically identified the sole source of contaminated well water. We learned that it could and, although it was not available to Dr. Snow in the 1800s, we discuss RTM's implications for present-day research and practice as it relates to the analysis, prevention and treatment of cholera and other public health threats around the world.


Understanding the Economic Benefit Associated with Research and Services at the National Institute for Occupational Safety and Health: An Approach and Three Case Studies.
The National Institute for Occupational Safety and Health (NIOSH) asked the RAND Corporation to develop an approach, reported here, for estimating the economic benefit of NIOSH research, using three case studies. The cases provide concrete illustrations of the ways in which NIOSH research could affect worker health and safety practices and outcomes, as well as some initial estimates of the economic benefit associated with those impacts. The authors selected the case studies to illustrate variation in types of NIOSH research and in intended users. The first case study examines research to develop, test, and support implementation of engineering control measures to limit exposure to silica among road construction workers. This case study offers an example of NIOSH's intervention and surveillance research and provision of technical assistance. The second case study involves two NIOSH studies that strengthened the evidence base about the linkage between firefighting activities and increased risk of certain cancers among firefighters. This case study provides an example of etiological and exposure surveillance research, coupled with an intervention study. The third case study involves a NIOSH evaluation of the effectiveness of Ohio's Safety Intervention Grant Program in reducing the prevalence and costs of workplace injuries. This case study illustrates intervention research targeting government organizations. The first and second case studies led to the development of control technologies, and all three case studies involved dissemination and stakeholder engagement efforts that promoted the adoption of risk-reducing technologies and practices.


The single-cell pathology landscape of breast cancer.
Single-cell analyses have revealed extensive heterogeneity between and within human tumours1-4, but complex single-cell phenotypes and their spatial context are not at present reflected in the histological stratification that is the foundation of many clinical decisions. Here we use imaging mass cytometry5 to simultaneously quantify 35 biomarkers, resulting in 720 high-dimensional pathology images of tumour tissue from 352 patients with breast cancer, with long-term survival data available for 281 patients. Spatially resolved, single-cell analysis identified the phenotypes of tumour and stromal single cells, their organization and their heterogeneity, and enabled the cellular architecture of breast cancer tissue to be characterized on the basis of cellular composition and tissue organization. Our analysis reveals multicellular features of the tumour microenvironment and novel subgroups of breast cancer that are associated with distinct clinical outcomes. Thus, spatially resolved, single-cell analysis can characterize intratumour phenotypic heterogeneity in a disease-relevant manner, with the potential to inform patient-specific diagnosis.


Controlling the Formation of Phospholipid Monolayer, Bilayer, and Intact Vesicle Layer on Graphene.
Exciting progress has been made in the use of graphene for bio- and chemical sensing applications. In this regard, interfacing lipid membranes with graphene provides a high-sealing interface that is resistant to nonspecific protein adsorption and suitable for measuring biomembrane-associated interactions. However, a controllable method to form well-defined lipid bilayer coatings remains elusive, and there are varying results in the literature. Herein, we demonstrate how design strategies based on molecular self-assembly and surface chemistry can be employed to coat graphene surface with different classes of lipid membrane architectures. We characterize the self-assembly of lipid membranes on CVD-graphene using quartz crystal microbalance with dissipation, field-effect transistor, and Raman spectroscopy. By employing the solvent-assisted lipid bilayer (SALB) method, a lipid monolayer and bilayer were formed on pristine and oxygen-plasma-treated CVD-graphene, respectively. On these surfaces, vesicle fusion method resulted in formation of a lipid monolayer and intact vesicle layer, respectively. Collectively, these findings provide the basis for improved surface functionalization strategies on graphene toward bioelectronic applications.


Uncertainty in 1D heat-flow analysis to estimate groundwater discharge to a stream.
Temperature measurements have been used by a variety of researchers to gain insight into groundwater discharge patterns. However, much of this research has reduced the problem to heat and fluid flow in one dimension for ease of analysis. This approach is seemingly at odds with the goal of determining spatial variability in specific discharge, which implies that the temperature field will vary in more than one dimension. However, it is unclear how important the resulting discrepancies are in the context of determining groundwater discharge to surface water bodies. In this study, the importance of these variations is examined by testing two popular one-dimensional analytical solutions with stochastic models of heat and fluid flow in a two-dimensional porous medium. For cases with low degrees of heterogeneity in hydraulic conductivity, acceptable results are possible for specific discharges between 10(-7) and 10(-5) m/s. However, conduction into areas with specific discharges less than 10(-7) m/s from adjacent areas can lead to significant errors. In some of these cases, the one-dimensional solutions produced estimates of specific discharge of nearly 10(-6) m/s. This phenomenon is more likely in situations with greater degrees of heterogeneity.


Heterogeneity and Risk Sharing in Village Economies.
We show how to use panel data on household consumption to directly estimate households' risk preferences. Specifically, we measure heterogeneity in risk aversion among households in Thai villages using a full risk-sharing model, which we then test allowing for this heterogeneity. There is substantial, statistically significant heterogeneity in estimated risk preferences. Full insurance cannot be rejected. As the risk sharing, as-if-complete-markets theory might predict, estimated risk preferences are unrelated to wealth or other characteristics. The heterogeneity matters for policy: Although the average household would benefit from eliminating village-level risk, less-risk-averse households who are paid to absorb that risk would be worse off by several percent of household consumption.


Shared learning from national to international contexts: a research and innovation collaboration to enhance education for patient safety.
Patient safety is key for healthcare across the world and education is critical in improving practice. We drew on existing links to develop the Shared LearnIng from Practice to improve Patient Safety (SLIPPS) group. The group incorporates expertise in education, research, healthcare, healthcare organisation and computing from Norway, Spain, Italy, the UK and Finland. In 2016 we received co-funding from the Erasmus + programme of the European Union for a 3-year project. SLIPPS aims to develop a tool to gather learning events related to patient safety from students in each country, and to use these both for further research to understand practice, and to develop educational activities (virtual seminars, simulation scenarios and a game premise). The SLIPPS project is well underway. It is underpinned by three main theoretical bodies of work: the notion of diverse knowledge contexts existing in academia, practice and at an organisational level; the theory of reflective practice; and experiential learning theory. The project is based on recognition of the unique position of students as they navigate between contexts, experience and reflect on important learning events related to patient safety. To date, we have undertaken the development of the SLIPPS Learning Event Recording Tool (SLERT) and have begun to gather event descriptions and reflections. Key to the ongoing success of SLIPPS are relationships and reciprocal openness to view things from diverse perspectives and cultures.