The one year incidence of postoperative myocardial infarction in an orthopedic population.
The diagnosis of a postoperative myocardial infarction (PMI) is important in the orthopedic population because these events can be associated with significant cardiac morbidity. Plasma troponin I (cTnI) analysis has markedly increased our ability to detect myocardial damage. Using cTnI analysis for evidence of a PMI, we prospectively assessed all of our patients for (1) the 1-year incidence of PMI, (2) the clinical consequences of a PMI in relation to the level of the cTnI release, and (3) 6-month follow-up for cardiac complications. During a 12-month period, patients at risk for perioperative myocardial ischemia were assessed for a PMI by serum cTnI levels and daily serial ECGs. Patients with cTnI levels above the reference level (> or = 0.4 ng/ml) were also assessed for new cardiac regional wall motion abnormalities with an echocardiogram and 6-month postdischarge adverse cardiac events. Of the 758 patients who were assessed for a PMI, 49 patients had detectable cTnI levels (> or = 0.4 ng/ml); the incidence of a PMI was 0.6% of all surgical cases and 6.5% of those patients were at risk for a cardiac event. A PMI was more common after hip arthroplasty than other orthopedic procedures. Twenty-three patients had a cTnI level >3.0 ng/ml, and 74% these patients (17/23) had anginal symptoms and/or ischemic ECG changes. Nine of these patients (9/23) had new postoperative echocardiographic changes, five (5/23) required emergency transfer to a cardiac care unit, and 10 (10/23) had postoperative cardiac complications. In contrast, 15 patients with levels of cTnI <3.0 ng/ml and without ischemic ECG changes and/or anginal symptoms had no postoperative cardiac complications. Fourteen patients (14/47) had cardiac complications 6 months after discharge, including four cardiac deaths, one fatal stroke, and four patients with unstable anginal episodes that required a change in medical management, and six patients required coronary revascularization. Orthopedic surgical patients with cTnI level <3 ng/ml and without symptoms or ECG changes suggestive of myocardial ischemia (15/49) may have different risks than those with higher-level cTn1.


Correlations in the Electronic Structure of van der Waals NiPS3 Crystals: An X-ray Absorption and Resonant Photoelectron Spectroscopy Study.
The electronic structure of high-quality van der Waals NiPS3 crystals was studied using near-edge X-ray absorption spectroscopy (NEXAFS) and resonant photoelectron spectroscopy (ResPES) in combination with density functional theory (DFT) approach. The experimental spectroscopic methods, being element specific, allow one to discriminate between atomic contributions in the valence and conduction band density of states and give direct comparison with the results of DFT calculations. Analysis of the NEXAFS and ResPES data allows one to identify the NiPS3 material as a charge-transfer insulator. Obtained spectroscopic and theoretical data are very important for the consideration of possible correlated-electron phenomena in such transition-metal layered materials, where the interplay between different degrees of freedom for electrons defines their electronic properties, allowing one to understand their optical and transport properties and to propose further possible applications in electronics, spintronics, and catalysis.


Genetic and pharmacologic identification of Akt as a mediator of brain-derived neurotrophic factor/TrkB rescue of neuroblastoma cells from chemotherapy-induced cell death.
Patients whose neuroblastoma tumors express high levels of brain-derived neurotrophic factor (BDNF) and TrkB have an unfavorable prognosis. Our previous studies indicated that BDNF activation of the TrkB signal transduction pathway blocked the cytotoxic effects of chemotherapeutic drugs via the phosphatidylinositol 3-kinase pathway. Akt is an important downstream target of phosphatidylinositol 3-kinase and functions to regulate cell survival, proliferation, and protein synthesis. In this study, we examined whether Akt is required and sufficient to mediate BDNF/TrkB protection of neuroblastoma cells from chemotherapy. Transient transfection of a constitutively active Akt (Akt-Myr) into TrkB-expressing SY5Y cells (TB8 cells) increases Akt activation and attenuates the cell death induced by chemotherapeutic reagents in the absence of BDNF. Furthermore, expression of a dominant-negative Akt (Akt-K179A) blocks the ability of BDNF to rescue TB8 cells from chemotherapy-induced cell death. Pharmacologic inhibition of Akt, with PIA6, a phosphatidylinositol ether lipid analogue (PIA), blocks BDNF-induced phosphorylation of Akt and the downstream target of Akt. PIA6 sensitizes neuroblastoma cells to chemotherapy and attenuates BDNF protection of neuroblastoma cells from chemotherapy-induced cell death. These results indicate that Akt is a key signaling component by which BDNF activation of the TrkB signal transduction pathway protects neuroblastoma cells from chemotherapy-induced cell death. This study raises the possibility that novel pharmacologic inhibitors of Akt may enhance the effectiveness of chemotherapeutic agents in the treatment of neuroblastoma tumors.


Fall rates in hospital rehabilitation units after individualised patient and staff education programmes: a pragmatic, stepped-wedge, cluster-randomised controlled trial.
Falls are the most frequent adverse events that are reported in hospitals. We examined the effectiveness of individualised falls-prevention education for patients, supported by training and feedback for staff, delivered as a ward-level programme. Eight rehabilitation units in general hospitals in Australia participated in this stepped-wedge, cluster-randomised study, undertaken during a 50 week period. Units were randomly assigned to intervention or control groups by use of computer-generated, random allocation sequences. We included patients admitted to the unit during the study with a Mini-Mental State Examination (MMSE) score of more than 23/30 to receive individualised education that was based on principles of changes in health behaviour from a trained health professional, in addition to usual care. We provided information about patients' goals, feedback about the ward environment, and perceived barriers to engagement in falls-prevention strategies to staff who were trained to support the uptake of strategies by patients. The coprimary outcome measures were patient rate of falls per 1000 patient-days and the proportion of patients who were fallers. All analyses were by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials registry, number ACTRN12612000877886). Between Jan 13, and Dec 27, 2013, 3606 patients were admitted to the eight units (n=1983 control period; n=1623 intervention period). There were fewer falls (n=196, 7·80/1000 patient-days vs n=380, 13·78/1000 patient-days, adjusted rate ratio 0·60 [robust 95% CI 0·42-0·94], p=0·003), injurious falls (n=66, 2·63/1000 patient-days vs 131, 4·75/1000 patient-days, 0·65 [robust 95% CI 0·42-0·88], p=0·006), and fallers (n=136 [8·38%] vs n=248 [12·51%] adjusted odds ratio 0·55 [robust 95% CI 0·38 to 0·81], p=0·003) in the intervention compared with the control group. There was no significant difference in length of stay (intervention median 11 days [IQR 7-19], control 10 days [6-18]). Individualised patient education programmes combined with training and feedback to staff added to usual care reduces the rates of falls and injurious falls in older patients in rehabilitation hospital-units. State Health Research Advisory Council, Department of Health, Government of Western Australia.


South African dyslipidaemia guideline consensus statement.
The European Society of Cardiology together with the European Atherosclerosis Society published updated dyslipidaemia guidelines in 2011. SA Heart and the Lipid and Atherosclerosis Society of Southern Africa officially adopt these guidelines. This statement adapts aspects of the guidelines to the South African situation. Using the updated Framingham risk charts, interventional strategies are based according to the cardiovascular risk score and low-density lipoprotein cholesterol (LDL-C) levels. The Framingham risk score refers to the 10-year risk of any cardiovascular event, and includes four categories of risk. Treatment targets are those of the European guidelines. The LDL-C goal is 1.8 mmol/l for the very high-risk group (>30%), 2.5 mmol/l for the high-risk group (15-30%), and 3 mmol/l for those below 15% risk. Intensive management of dyslipidaemia in South Africa will significantly reduce the cardiovascular disease health burden.


Cranberry impairs selected behaviors essential for virulence in Proteus mirabilis HI4320.
Proteus mirabilis is an etiological agent of complicated urinary tract infections. North American cranberries (Vaccinium macrocarpon) have long been considered to have protective properties against urinary tract infections. This work reports the effects of cranberry powder (CP) on the motility of P. mirabilis HI4320 and its expression of flaA, flhD, and ureD. Our results show that swimming and swarming motilities and swarmer-cell differentiation were inhibited by CP. Additionally, transcription of the flagellin gene flaA and of flhD, the first gene of the flagellar master operon flhDC, decreased during exposure of P. mirabilis to various concentrations of CP. Moreover, using ureD-gfp, a fusion of the urease accessory gene ureD with gfp, we show that CP inhibits urease expression. Because we demonstrate that CP does not inhibit the growth of P. mirabilis, the observed effects are not attributable to toxicity. Taken together, our results demonstrate that CP hinders motility of P. mirabilis and reduces the expression of important virulence factors.


Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2 via RNA-dependent RNA polymerase (RdRp) inhibition: an in-silico analysis.
The sudden outburst of Coronavirus disease (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a massive threat to global public health. Currently, no therapeutic drug or vaccine exists to treat COVID-19. Due to the time taking process of new drug development, drug repurposing might be the only viable solution to tackle COVID-19. RNA-dependent RNA polymerase (RdRp) catalyzes SARS-CoV-2 RNA replication and hence, is an obvious target for antiviral drug design. Interestingly, several plant-derived polyphenols effectively inhibit the RdRp of other RNA viruses. More importantly, polyphenols have been used as dietary supplementations for a long time and played beneficial roles in immune homeostasis. We were curious to study the binding of polyphenols with SARS-CoV-2 RdRp and assess their potential to treat COVID-19. Herein, we made a library of polyphenols that have shown substantial therapeutic effects against various diseases. They were successfully docked in the catalytic pocket of RdRp. The investigation reveals that EGCG, theaflavin (TF1), theaflavin-3'-O-gallate (TF2a), theaflavin-3'-gallate (TF2b), theaflavin 3,3'-digallate (TF3), hesperidin, quercetagetin, and myricetin strongly bind to the active site of RdRp. Further, a 150-ns molecular dynamic simulation revealed that EGCG, TF2a, TF2b, TF3 result in highly stable bound conformations with RdRp. The binding free energy components calculated by the MM-PBSA also confirm the stability of the complexes. We also performed a detailed analysis of ADME prediction, toxicity prediction, and target analysis for their druggability. Overall, our results suggest that EGCG, TF2a, TF2b, TF3 can inhibit RdRp and represent an effective therapy for COVID-19.Communicated by Ramaswamy H. Sarma.


Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure.
Premature ovarian failure (POF) is characterized by elevated gonadotropins and amenorrhea in women aged <40 years. In a Lebanese family with five sisters who received the diagnosis of POF, we established linkage to the long arm of the X chromosome (between Xq21.1 and Xq21.3.3), using whole-genome SNP typing and homozygosity-by-descent mapping. By sequencing one candidate gene within that region, POF1B, we identified a point mutation localized in exon 10. This substitution of a nucleotide (G-->A), at position 1123, results in an arginine-->glutamine mutation of the protein sequence at position 329 (mutation R329Q). All the affected family members were homozygous for the mutation, whereas the unaffected members were heterozygous. Because POF1B shares high homology with the tail portion of the human myosin, we assessed the ability of both wild-type and mutant POF1B proteins to bind nonmuscle actin filaments in vitro. We found that the capacity of the mutant protein to bind nonmuscle actin filaments was diminished fourfold compared with the wild type, suggesting a function of POF1B in germ-cell division. Our study suggests that a homozygous point mutation in POF1B influences the pathogenesis of POF by altering POF1B binding to nonmuscle actin filaments.


Raman microspectroscopy as a biomarking tool for in vitro diagnosis of cancer: a feasibility study.
To elucidate whether Raman spectroscopy aided by extensive spectral database and neural network analysis can be a fast and confident biomarking tool for the diagnosis of various types of cancer. Study included 27 patients with 11 different malignant tumors. Using Raman microscopy (RM) a total of 540 Raman spectra were recorded from histology specimens of both tumors and surrounding healthy tissues. Spectra were analyzed using the principal component analysis (PCA) and results, along with histopathology data, were used to train the neural network (NN) learning algorithm. Independent sets of spectra were used to test the accuracy of PCA/NN tissue classification. The confident tumor identification for the purpose of medical diagnosis has to be performed by taking into account the whole spectral shape, and not only particular spectral bands. The use of PCA/NN analysis showed overall sensitivity of 96% with 4% false negative tumor classification. The specificity of distinguishing tumor types was 80%. These results are comparable to previously published data where tumors of only one tissue type were examined and can be regarded satisfactorily for a relatively small database of Raman spectra used here. In vitro RM combined with PCA/NN is an almost fully automated method for histopathology at the level of macromolecules. Supported by an extensive tumor spectra database, it could become a customary histological analysis tool for fast and reliable diagnosis of different types of cancer in clinical settings.


Have we underestimated the kinematic and kinetic benefits of non-ballistic motion?
Explosive upper-body movements, with which the load is not thrown (non-ballistic), may comprise a phase during which forces are produced in opposition to the motion of the load. Thirty men completed three test sessions (free weight, ballistic, and pneumatic), each consisting of a one-repetition maximum (1-RM) and four explosive repetitions of a bench press at six loads (15, 30, 45, 60, 75, and 90% 1-RM). The end of the lifting phase for the non-ballistic conditions (free weight and pneumatic) was defined by: the point of peak barbell displacement and the point at which the vertical force became negative (positive work). When analysed by peak displacement, the ballistic condition elicited significantly greater mean velocity, force, and power at loads of 15-60% 1-RM compared with the free weight condition. When the period of negative work was removed, the mean free weight velocity, force, and power at loads below 60% 1-RM increased. Consequently, the only differences between the free weight and ballistic conditions were found at loads of 15% and 30% 1-RM. Including a period of negative work may underestimate all kinematic and kinetic variables dependent on the time to, or position of, the end of the lifting phase, for non-ballistic efforts.


Risk factors associated with persistence of Salmonella shedding in finishing pigs.
The objective of this study was to identify risk factors associated with persistence of Salmonella shedding in finishing swine. A longitudinal study was conducted in 18 cohorts of pigs from three finishing sites of one swine production company. Among the 446 Salmonella isolates (isolated from 187 pigs), there were 18 distinct serovars. The six most common serovars were S. enterica serovar Derby (47.3%), S. Agona (27.4%), S. Johannesburg (10.5%), S. Schwarzengrund (2.7%), S. Litchfield (2.5%) and S. Mbandaka (2.2%). Survival analysis techniques, Kaplan-Meier methods and Log-rank test were used to estimate the duration of Salmonella shedding in days and to evaluate differences in shedding associated with risk factors at different organizational levels: isolate (serovar), pig, cohort and site. The risk factors at the pig-level were: sex, age and individual health status; and the risk factors at the cohort-level were: health risk, treatment and "at risk pigs" proportions, nursery and barn environment Salmonella status and prior exposure to the same serovar in the nursery or barn environment. Survival analysis using acceleration failure time models, with a log-normal distribution, was applied to investigate risk factors associated with Salmonella persistence (175 pigs) and serovar-specific persistence (151 pigs) during the study period. Pigs detected Salmonella positive for the first time at 10 weeks of age had a longer duration of shedding, than pigs first detected at an older age. The duration of shedding was shorter among pigs infected with S. Derby, S. Johannesburg and other serovars as compared to pigs infected with S. Agona. A significant difference was observed among sites. Cohorts with pig treatment proportions greater than the median were more likely to have a shorter duration of Salmonella shedding. Pigs from cohorts with nursery positive pools greater than the overall mean had a longer duration of Salmonella shedding as compared to pigs from cohorts with nursery pools less than or equal to the mean. These results suggest that the duration of Salmonella shedding may depend on Salmonella serovar, pig age at the time of infection, farm site and cohort-level risk factors. Identification of risk factors associated with the duration of shedding may allow more targeted interventions for the control Salmonella by evaluation of control measures not only for prevalence reduction, but also to decrease the duration of shedding. Such measures may decrease the risk of contamination of pork and subsequent risk of foodborne illness.


Ion-specific self-assembly of a lipophilic guanosine derivative in thin surface films.
We investigated the effect of various ions on the surface assembly of a guanosine derivative with one hexadecanoyl chain at the air-water interface. The ions were added to the water subphase prior to spreading of the surface film. Like in bulk water, also at the air-water interface, K(+) ions exhibit the strongest influence on the assembly features as they induce structural transformation from lamellar to mosaic-like assembly. In contrast, Li(+) and Na(+) ions only slightly modify the properties of the assembled film with respect to those observed on pure water. The nature of anions plays an important role in the surface self-assembly as well. We found that (Pic(-)) is 2 orders of magnitude more effective for assembly regulation than Cl(-). All surface assemblies observed in our study are very stable and robust, and consequently they remain practically unperturbed after Langmuir-Blodgett transfer onto a solid support.


Urine Arsenic and Arsenic Metabolites in U.S. Adults and Biomarkers of Inflammation, Oxidative Stress, and Endothelial Dysfunction: A Cross-Sectional Study.
Arsenic (As) exposure has been associated with increased risk for cardiovascular disease (CVD) and with biomarkers of potential CVD risk and inflammatory processes. However, few studies have evaluated the effects of As on such biomarkers in U.S. populations, which are typically exposed to low to moderate As concentrations. We investigated associations between As exposures and biomarkers relevant to inflammation, oxidative stress, and CVD risk in a subset of participants from the New Hampshire Health Study, a population with low to moderate As exposure (n=418). Associations between toenail As, total urine As (uAs), and %uAs metabolites [monomethyl (%uMMAV), dimethyl (%uDMAV), and inorganic (%iAs) species] and plasma biomarkers, including soluble plasma vascular and cellular adhesion molecules (VCAM-1 and ICAM-1, respectively), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-α, plasminogen activator inhibitor-1 (PAI-1), and urinary oxidative stress marker 15-F2t-isoprostane (15-F2t-IsoP), were evaluated using linear regression models. Covariate-adjusted estimates of associations with a doubling of urinary As suggested an 8.8% increase in 15-F2t-IsoP (95% CI: 3.2, 14.7), and a doubling of toenail As was associated with a 1.7% increase in VCAM-1 (95% CI: 0.2, 3.2). Additionally, a 5% increase in %uMMA was associated with a 7.9% increase in 15-F2t-IsoP (95% CI: 2.1, 14.1), and a 5% increase in %uDMA was associated with a 2.98% decrease in 15-F2t-IsoP [(95% CI: -6.1, 0.21); p=0.07]. However, in contrast with expectations, a doubling of toenail As was associated with a 2.3% decrease (95% CI: -4.3, -0.3) in MMP-9, and a 5% increase in %uMMA was associated with a 7.7% decrease (95% CI: -12.6, -2.5) in PAI-1. In a cross-sectional study of U.S. adults, we observed some positive associations of uAs and toenail As concentrations with biomarkers potentially relevant to CVD pathogenesis and inflammation, and evidence of a higher capacity to metabolize inorganic As was negatively associated with a marker of oxidative stress. https://doi.org/10.1289/EHP2062.


Initiation factor 2 crystal structure reveals a different domain organization from eukaryotic initiation factor 5B and mechanism among translational GTPases.
The initiation of protein synthesis uses initiation factor 2 (IF2) in prokaryotes and a related protein named eukaryotic initiation factor 5B (eIF5B) in eukaryotes. IF2 is a GTPase that positions the initiator tRNA on the 30S ribosomal initiation complex and stimulates its assembly to the 50S ribosomal subunit to make the 70S ribosome. The 3.1-Å resolution X-ray crystal structures of the full-length Thermus thermophilus apo IF2 and its complex with GDP presented here exhibit two different conformations (all of its domains except C2 domain are visible). Unlike all other translational GTPases, IF2 does not have an effecter domain that stably contacts the switch II region of the GTPase domain. The domain organization of IF2 is inconsistent with the "articulated lever" mechanism of communication between the GTPase and initiator tRNA binding domains that has been proposed for eIF5B. Previous cryo-electron microscopy reconstructions, NMR experiments, and this structure show that IF2 transitions from being flexible in solution to an extended conformation when interacting with ribosomal complexes.


Interfacial assembly and hydrolysis for synthesizing a TiO2/metal-organic framework composite.
Herein we propose an interfacial assembly and hydrolysis route for fabricating TiO2/UiO-67 composites. The UiO-67 assembles at the water-oil interface serving as a stabilizer of the emulsion. TiO2 nanoparticles are loaded on UiO-67 by hydrolysis of the precursor TBT (tetra-n-butyl titanate) at the water-oil interface. By such a strategy, hollow capsules structured by UiO-67 and decorated by ultra-small TiO2 nanoparticles were produced. The newly-constructed composite combines the CO2 adsorption properties of UiO-67 and the photocatalytic activity of TiO2, showing high activity for the photocatalytic reduction of CO2 to formic acid. Such a composite with a novel structure provides a promising route for the preparation of new compound materials.


Engaging multi-stakeholder perspectives to identify dementia care research priorities.
The purpose of this study was to partner with stakeholders to identify gaps in care for persons living with dementia and their family caregivers and from this list, identify priorities for dementia care research. Using a community-engaged research approach, a Stakeholder Advisory Council (SAC) consisting of diverse membership including persons living with dementia and family caregivers was convened. Through our work with the SAC, along with input from the wider network through a symposium, webinars, and an online learning community, gaps in dementia care and a list of topics for dementia care research was generated. This list was reduced to 46 topics for dementia care research and sent to stakeholders (persons living with dementia, family caregivers, and health/social care professionals in dementia care) to be prioritized by rating each of the 46 topics as "Not so important," "Important," or "Very important." Priorities for dementia care were summarized by frequencies and proportions. A total of 186 participants completed the survey from August through October 2020, including 23 (12.4%) persons living with dementia, 101 (54.3%) family caregivers, and 62 (33.3%) health/social care professionals. Consistent across stakeholder groups was the focus on research on how best to support families following a diagnosis of dementia. Among persons living with dementia, research focused on support for continuing to live in their own homes was ranked as the highest priority, rated by 91.3% as "Very Important". High priority research areas for family caregivers included interventions to slow cognitive decline (76.3%) as well as non-pharmacological approaches to manage behavioral symptoms (74.7%). The highest priority research topics for health/social care professionals were focused on the diagnosis including benefits of an early diagnosis (71.4%), how best to deliver the diagnosis (70.9%), and supports needed following a diagnosis (78.6%). This project draws on the strengths of its multi-stakeholder perspective to support patient-centered outcomes research. Findings are intended to inform those who conduct research and those who fund research about which research topics stakeholders believe are most important and thus have greatest potential to improve the quality of life among people living with dementia and their families.


Longitudinal relations between children's exposure to TV violence and their aggressive and violent behavior in young adulthood: 1977-1992.
Although the relation between TV-violence viewing and aggression in childhood has been clearly demonstrated, only a few studies have examined this relation from childhood to adulthood, and these studies of children growing up in the 1960s reported significant relations only for boys. The current study examines the longitudinal relations between TV-violence viewing at ages 6 to 10 and adult aggressive behavior about 15 years later for a sample growing up in the 1970s and 1980s. Follow-up archival data (N = 450) and interview data (N = 329) reveal that childhood exposure to media violence predicts young adult aggressive behavior for both males and females. Identification with aggressive TV characters and perceived realism of TV violence also predict later aggression. These relations persist even when the effects of socioeconomic status, intellectual ability, and a variety of parenting factors are controlled.


Static Clathrin Assemblies at the Peripheral Vacuole-Plasma Membrane Interface of the Parasitic Protozoan Giardia lamblia.
Giardia lamblia is a parasitic protozoan that infects a wide range of vertebrate hosts including humans. Trophozoites are non-invasive but associate tightly with the enterocyte surface of the small intestine. This narrow ecological specialization entailed extensive morphological and functional adaptations during host-parasite co-evolution, including a distinctly polarized array of endocytic organelles termed peripheral vacuoles (PVs), which are confined to the dorsal cortical region exposed to the gut lumen and are in close proximity to the plasma membrane (PM). Here, we investigated the molecular consequences of these adaptations on the Giardia endocytic machinery and membrane coat complexes. Despite the absence of canonical clathrin coated vesicles in electron microscopy, Giardia possesses conserved PV-associated clathrin heavy chain (GlCHC), dynamin-related protein (GlDRP), and assembly polypeptide complex 2 (AP2) subunits, suggesting a novel function for GlCHC and its adaptors. We found that, in contrast to GFP-tagged AP2 subunits and DRP, CHC::GFP reporters have no detectable turnover in living cells, indicating fundamental differences in recruitment to the membrane and disassembly compared to previously characterized clathrin coats. Histochemical localization in electron tomography showed that these long-lived GlCHC assemblies localized at distinctive approximations between the plasma and PV membrane. A detailed protein interactome of GlCHC revealed all of the conserved factors in addition to novel or highly diverged proteins, including a putative clathrin light chain and lipid-binding proteins. Taken together, our data provide strong evidence for giardial CHC as a component of highly stable assemblies at PV-PM junctions that likely have a central role in organizing continuities between the PM and PV membranes for controlled sampling of the fluid environment. This suggests a novel function for CHC in Giardia and the extent of molecular remodeling of endocytosis in this species.


Rational use of Xpert testing in patients with presumptive TB: clinicians should be encouraged to use the test-treat threshold.
A recently published Ugandan study on tuberculosis (TB) diagnosis in HIV-positive patients with presumptive smear-negative TB, which showed that out of 90 patients who started TB treatment, 20% (18/90) had a positive Xpert MTB/RIF (Xpert) test, 24% (22/90) had a negative Xpert test, and 56% (50/90) were started without Xpert testing. Although Xpert testing was available, clinicians did not use it systematically. Here we aim to show more objectively the process of clinical decision-making. First, we estimated that pre-test probability of TB, or the prevalence of TB in smear-negative HIV infected patients with signs of presumptive TB in Uganda, was 17%. Second, we argue that the treatment threshold, the probability of disease at which the utility of treating and not treating is the same, and above which treatment should be started, should be determined. In Uganda, the treatment threshold was not yet formally established. In Rwanda, the calculated treatment threshold was 12%. Hence, one could argue that the threshold was reached without even considering additional tests. Still, Xpert testing can be useful when the probability of disease is above the treatment threshold, but only when a negative Xpert result can lower the probability of disease enough to cross the treatment threshold. This occurs when the pre-test probability is lower than the test-treat threshold, the probability of disease at which the utility of testing and the utility of treating without testing is the same. We estimated that the test-treatment threshold was 28%. Finally, to show the effect of the presence or absence of arguments on the probability of TB, we use confirming and excluding power, and a log10 odds scale to combine arguments. If the pre-test probability is above the test-treat threshold, empirical treatment is justified, because even a negative Xpert will not lower the post-test probability below the treatment threshold. However, Xpert testing for the diagnosis of TB should be performed in patients for whom the probability of TB was lower than the test-treat threshold. Especially in resource constrained settings clinicians should be encouraged to take clinical decisions and use scarce resources rationally.


Non-Pharmacological Interventions to Prevent or Treat Delirium in Older Patients: Clinical Practice Recommendations The SENATOR-ONTOP Series.
The ONTOP project aims to undertake a literature search of systematic reviews concerning evidence-based non-pharmacological interventions of prevalent medical conditions affecting older people, including delirium. To develop explicit and transparent recommendations for non-pharmacological interventions in older subjects at risk of developing delirium, as well as in older subjects with delirium, based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to rating the quality of evidence and the strength of recommendations. A multidisciplinary panel was constituted comprising geriatricians, research nurse and a clinical epidemiologist. The panel developed a systematic overview of non-pharmacological interventions to prevent or treat delirium. The GRADE approach was used to rate the evidence and to formulate recommendations. The critical outcomes were delirium incidence, for delirium prevention, and delirium improvement and functional status, for delirium treatment. The non-pharmacological interventions were identified and categorized as multicomponent and single component. Strong recommendations in favor of multicomponent interventions to prevent delirium, in surgical or medicals wards, were formulated. In the latter case the evidence applied to older patients at intermediate - high risk of developing delirium. Weak recommendations, to prevent delirium, were formulated for multicomponent interventions provided by family members (medical ward), staff education (medical ward), ear plugs (intensive care unit), reorientation protocol (intensive care unit), and the use of a software to perform drug review. Weak recommendations were provided for the use of multicomponent interventions to prevent delirium in medical wards in patients not selected according to the risk of delirium. Strong recommendations not to use bright light therapy to prevent delirium in intensive care unit settings were articulated. Weak recommendations not to use music therapy to prevent delirium for patients undergoing surgical interventions were specified. The ability to make strong recommendations was limited by the low quality of evidence and the presence of uncertainty. Moreover, weak recommendations were provided for the use of multicomponent interventions to treat delirium of older patients (medical wards). Overall, the panel developed 12 recommendations for the delivery of non-pharmacological interventions to older patients at risk of developing or, with delirium.


Structural and functional analysis of the DEAF-1 and BS69 MYND domains.
DEAF-1 is an important transcriptional regulator that is required for embryonic development and is linked to clinical depression and suicidal behavior in humans. It comprises various structural domains, including a SAND domain that mediates DNA binding and a MYND domain, a cysteine-rich module organized in a Cys(4)-Cys(2)-His-Cys (C4-C2HC) tandem zinc binding motif. DEAF-1 transcription regulation activity is mediated through interactions with cofactors such as NCoR and SMRT. Despite the important biological role of the DEAF-1 protein, little is known regarding the structure and binding properties of its MYND domain.Here, we report the solution structure, dynamics and ligand binding of the human DEAF-1 MYND domain encompassing residues 501-544 determined by NMR spectroscopy. The structure adopts a ββα fold that exhibits tandem zinc-binding sites with a cross-brace topology, similar to the MYND domains in AML1/ETO and other proteins. We show that the DEAF-1 MYND domain binds to peptides derived from SMRT and NCoR corepressors. The binding surface mapped by NMR titrations is similar to the one previously reported for AML1/ETO. The ligand binding and molecular functions of the related BS69 MYND domain were studied based on a homology model and mutational analysis. Interestingly, the interaction between BS69 and its binding partners (viral and cellular proteins) seems to require distinct charged residues flanking the predicted MYND domain fold, suggesting a different binding mode. Our findings demonstrate that the MYND domain is a conserved zinc binding fold that plays important roles in transcriptional regulation by mediating distinct molecular interactions with viral and cellular proteins.


Localisation of a gene implicated in a severe speech and language disorder.
Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.


Acute coronary syndrome due to bare metal stent fracture in the right coronary artery.
Stent fracture (SF) has been suggested to be an unusual cause of restenosis after drug eluting-stent implantation. However, angiographically visible SF after bare metal stent (BMS) implantation is extremely rare. We present a case of a 58 year-old male patient who presented with unstable angina secondary to a SF of a BMS within two months of elective percutaneous coronary intervention for right coronary artery associated with a muscle bridge and atherosclerotic stenosis.


Risk factors for under-nutrition among children aged one to five years in Udupi taluk of Karnataka, India: A case control study.
Despite her apparent economic success, India is plagued by a high burden of under-nutrition among children under five. This study was aimed at understanding some of the risk factors for under-nutrition in a region with favourable maternal and child health indicators. A case control study was carried out among children aged one to five years attending the paediatric outpatient department in six rural health care centres in Udupi taluk of Karnataka in Southern India. A total of 162 children were included in the study, of which 56 were cases. A semi-structured questionnaire was used to interview the caregivers of the children and the nutritional status was graded according to the Indian Academy of Paediatrics (IAP) grading of protein-energy malnutrition. Under-nutrition was associated with illness in the last one month [OR- 4.78 (CI: 1.83 -12.45)], feeding diluted milk [OR-14.26 (CI: 4.65 - 43.68)] and having more than two children with a birth interval ≤2 years [OR- 4.93 (CI: 1.78 - 13.61)]. Lack of exclusive breast feeding, level of education of the caregiver and environmental factors like source of water did not have an association. Childhood illness, short birth interval and consumption of diluted milk were some of the significant contributory factors noted among this population. Information, Education, Communication (IEC) campaigns alleviating food fads and promoting birth spacing is needed.


Alcohol Consumption and Risk of Parkinson's Disease: Data From a Large Prospective European Cohort.
Parkinson's disease (PD) etiology is not well understood. Reported inverse associations with smoking and coffee consumption prompted the investigation of alcohol consumption as a risk factor, for which evidence is inconclusive. To assess the associations between alcohol consumption and PD risk. Within NeuroEPIC4PD, a prospective European population-based cohort, 694 incident PD cases were ascertained from 209,998 PD-free participants. Average alcohol consumption at different time points was self-reported at recruitment. Cox regression hazard ratios were estimated for alcohol consumption and PD occurrence. No associations between baseline or lifetime total alcohol consumption and PD risk were observed. Men with moderate lifetime consumption (5-29.9 g/day) were at ~50% higher risk compared with light consumption (0.1-4.9 g/day), but no linear exposure-response trend was observed. Analyses by beverage type also revealed no associations with PD. Our data reinforce previous findings from prospective studies showing no association between alcohol consumption and PD risk. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Cellular and molecular requirements for association of the murine cytomegalovirus protein m4/gp34 with major histocompatibility complex class I molecules.
The murine cytomegalovirus (MCMV) protein m4/gp34 is unique among known viral genes that target the major histocompatibility complex (MHC) class I pathway of antigen presentation in the following two ways: it is found in association with class I MHC molecules at the cell surface, and it inhibits antigen presentation without reducing cell surface class I levels. The current study was undertaken to define more clearly the structural and cellular requirements for m4/gp34 association with the MHC class I molecule K(b). We first assessed the role of the peptide-loading complex in m4/gp34-K(b) association, using cell lines lacking TAP, tapasin, or beta(2)m. m4/gp34-K(b) complexes formed in the absence of TAP or tapasin, although not as efficiently as in wild-type cells. The expression of full-length and truncation mutants of m4/gp34 in a gutless adenovirus vector revealed that the transmembrane region of m4/gp34 was required for efficient association with the K(b) heavy chain. However, the peptide-loading complex was not absolutely required for the association, since m4/gp34 readily formed complexes with K(b) in detergent lysates. The addition of K(b)-binding peptide to the detergent lysates facilitated but was not essential for the formation of the complexes. The ease of complex formation in detergent lysates contrasted with the small fractions of m4/gp34 and K(b) that form complexes in infected cells, suggesting that the endoplasmic reticulum (ER) environment restricts access of m4/gp34 to K(b). Finally, although m4/gp34-K(b) complexes could form when m4 was carried either by MCMV or by the adenovirus vector, they were only efficiently exported from the ER in MCMV-infected cells, suggesting that MCMV provides additional factors needed for transport of the complexes.


Collection of food and dietary supplement intake data: What We Eat in America-NHANES.
This paper describes the collection process for the integrated dietary component of the National Health and Nutrition Examination Survey(NHANES) 2002 (entitled What We Eat in America-NHANES), referred to here as the integrated survey. The dietary components of previous NHANES cycles and the Continuing Survey of Food Intake in Individuals (CSFII) are also described. The collection process for foods in the integrated survey consists of an in-person 24-h recall using a computerized 5-step method and a second nonconsecutive 24-h recall via telephone. A food frequency questionnaire is being pilot-tested to provide information on the propensity to consume certain foods. Dietary supplement intakes over the past 30 d are assessed for all persons during the household interview. Other diet-related data are also obtained. Strengths of the integrated survey include information on food and supplement intakes in a representative sample of the civilian noninstitutionalized population of the United States that can be linked to anthropometric, biochemical, clinical and disease history information in NHANES. After reviewing the current state of the art on dietary and dietary supplement data collection, discussion groups consisting of members of key stakeholder community concluded that, although the most advanced methods for dietary data collection available are being used, the differences between how information on food and dietary supplement intakes is collected make it challenging to combine data describing nutrients from both sources to obtain estimates of total nutrient intakes. The discussion groups concluded that more research is needed on these issues and provided key recommendations for future efforts in this important area of public health surveillance.


Scale-dependent controls on the area burned in the boreal forest of Canada, 1980-2005.
In the boreal forest of North America, as in any fire-prone biome, three environmental factors must coincide for a wildfire to occur: an ignition source, flammable vegetation, and weather that is conducive to fire. Despite recent advances, the relative importance of these factors remains the subject of some debate. The aim of this study was to develop models that identify the environmental controls on spatial patterns in area burned for the period 1980-2005 at several spatial scales in the Canadian boreal forest. Boosted regression tree models were built to relate high-resolution data for area burned to an array of explanatory variables describing ignitions, vegetation, and long-term patterns in fire-conducive weather (i.e., fire climate) at four spatial scales (10(2) km2, 10(3) km2, 10(4) km2, and 10(5) km2). We evaluated the relative contributions of these controls on area burned, as well as their functional relationships, across spatial scales. We also assessed geographic patterns of the influence of wildfire controls. The results indicated that extreme temperature during the fire season was a top control at all spatial scales, followed closely by a wind-driven index of ease of fire spread. However, the contributions of some variables differed substantially among the spatial scales, as did their relationship to area burned. In fact, for some key variables the polarity of relationships was inverted from the finest to the broadest spatial scale. It was difficult to unequivocally attribute values of relative importance to the variables chosen to represent ignitions, vegetation, and climate, as the interdependence of these factors precluded clear partitioning. Furthermore, the influence of a variable on patterns of area burned often changed enormously across the biome, which supports the idea that fire-environment relationships in the boreal forest are complex and nonstationary.


Freeze-fracture study of filipin binding in photoreceptor outer segments and pigment epithelium of dystrophic and normal retinas.
We have studied sterol distribution in the retinal pigment epithelial (RPE) microvillous and outer segment disc membranes of rats with inherited retinal degeneration (RCS; RCS-p/+) and of normal genetic controls (RCS-rdy+, RCS-rdy+-p/+) by using the polyene antibiotic filipin, which binds specifically to 3-B-hydroxy-sterols, and freeze-fracture techniques. Retinas were perfusion-fixed, incubated with filipin in the same fixative, and prepared routinely for freeze-fracture electron microscopy. In the normal retina, the distribution of filipin binding sites on both RPE microvillous and outer segment disc membranes changes during development. Prior to outer segment elongation and the onset of phagocytosis (10 days postnatal), filipin sterol complexes are homogeneously distributed in both microvillous and outer segment membranes. With the onset of phagocytosis (2 weeks postnatal and later) filipin binding in both tissues forms a proximal-to-distal gradient, and binding sites decrease as distance from the cell body increases. In the normal RPE microvillous membranes, binding sites are numerous proximally and sparse on the distal tips. In the normal outer segment disc membranes, binding sites are often present on the basal discs, but are sparse on the intact apical discs prior to shedding. As the discs are cast off and engulfed by the RPE, however, filipin binding increases on both disc and phagosome membranes. In the dystrophic retina, the distribution of filipin binding sites differs from the normal. First, in the microvillous membranes, the proximal-to-distal gradient in filipin binding is rarely present at 2 weeks postnatal and becomes prominent only after the buildup of membranous debris has begun (3-5 weeks postnatal). Second, as the photoreceptors degenerate and the membrane debris disappears (4 months postnatal), filipin binding on the microvillous membranes becomes relatively sparse and homogeneous. Third, filipin binding on the intact disc membranes does not change with outer segment elongation, and numerous filipin binding sites are present on both apical and basal outer segment disc membranes. Fourth, large aggregates of filipin binding sites occupy the vast expanses of particle-free areas of debris membranes which accumulate between the photoreceptors and the RPE. These changes in the amount and distribution of filipin binding sites in the dystrophic retina add to the evidence that the disease process involves outer segment as well as RPE membranes and suggest that alterations in cholesterol distribution could contribute to the phagocytic defect.


The effects of fluoride on bone and implant histomorphometry in growing rats.
The effects of fluoride at concentrations of 2.0 and 4.5 mM in drinking water on growth rate, vitamin D, water and mineral metabolism, bone histomorphometry, and osteoinduction of demineralized allogenic bone matrix (DABM) were compared in the rat. Whereas fluoride did not influence fluid intake or growth rate at the lower concentration, it increased fluid intake and inhibited growth rate at the higher concentration. Fluoride produced dose-related increases in serum fluoride and alkaline phosphatase but did not alter serum 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D. Serum calcium and phosphate were reduced by fluoride at concentrations of 2.0 mM but not 4.5 mM. Cancellous bone fractional area was increased by fluoride at 2.0 mM and was reduced by fluoride at 4.5 mM. Fluoride had no effect on cancellous bone surface length or the percentage surface lined by osteoblasts and osteoclasts. Fluoride increased medullary area and decreased the endosteal bone formation rate. Fluoride increased periosteal bone formation and apposition rates at concentrations of 2.0 mM but not 4.5 mM. Fluoride inhibited mineralization in DABM implants, and at the higher concentration, fluoride increased the formation of new bone matrix. These results indicate that in the rat, fluoride increases cortical and trabecular bone at therapeutic doses and reduces trabecular bone at toxic doses. The serum concentration of fluoride at therapeutic doses in the rat is similar to that in patients with osteoporosis who are on treatment with fluoride. In the rat, there is a narrow range between toxic and therapeutic doses.


Magnetoelectric charge trap memory.
It is demonstrated that a charge-trapping layer placed in proximity to a ferromagnetic metal enables efficient electrical and optical control of the metal's magnetic properties. Retention of charge trapped inside the charge-trapping layer provides nonvolatility to the magnetoelectric effect and enhances its efficiency by an order of magnitude. As such, an engineered charge-trapping layer can be used to realize the magnetoelectric equivalent to today's pervasive charge trap flash memory technology. Moreover, by supplying trapped charges optically instead of electrically, a focused laser beam can be used to imprint the magnetic state into a continuous metal film.


Attention, predictive learning, and the inverse base-rate effect: evidence from event-related potentials.
We report the first electrophysiological investigation of the inverse base-rate effect (IBRE), a robust non-rational bias in predictive learning. In the IBRE, participants learn that one pair of symptoms (AB) predicts a frequently occurring disease, whilst an overlapping pair of symptoms (AC) predicts a rarely occurring disease. Participants subsequently infer that BC predicts the rare disease, a non-rational decision made in opposition to the underlying base rates of the two diseases. Error-driven attention theories of learning state that the IBRE occurs because C attracts more attention than B. On the basis of this account we predicted and observed the occurrence of brain potentials associated with visual attention: a posterior Selection Negativity, and a concurrent anterior Selection Positivity, for C vs. B in a post-training test phase. Error-driven attention theories further predict no Selection Negativity, Selection Positivity or IBRE, for control symptoms matched on frequency to B and C, but for which there was no shared symptom (A) during training. These predictions were also confirmed, and this confirmation discounts alternative explanations of the IBRE based on the relative novelty of B and C. Further, we observed higher response accuracy for B alone than for C alone; this dissociation of response accuracy (B>C) from attentional allocation (C>B) discounts the possibility that the observed attentional difference was caused by the difference in response accuracy.


Assessment of DNA oxidation and antioxidant activity in hypertensive patients with chronic kidney disease.
The aim of this study was to evaluate the oxidative DNA damage, antioxidant activity, and effects of antihypertensive drugs on oxidative stress in hypertensive patients with different stages of chronic kidney disease (CKD). Fifty-three non-dialyzed hypertensive CKD patients were included by the study. Serum and urinary 8-hydroxydeoxy guanosine (8-OHdG) levels (as a marker of oxidative DNA damage), serum superoxide dismutase (SOD), and glutathione peroxidase (G-Px) activities (as antioxidant enzymes) were measured. SOD activity was higher and G-Px activity was lower in the patient group as compared to control group. Serum and urinary 8-OHdG levels were found to be higher in the patients with proteinuria greater than 3 g/day than those in the patients with proteinuria less than 3 g/day. It has been determined that G-Px activity and urinary 8-OHdG level were lower in the patients treated with angiotensin-converting enzyme (ACE) inhibitor compared to patients treated with calcium channel blocker. The present data show oxidative DNA damage at a higher level in the patients with proteinuria greater than 3 g/day. In comparison to a calcium channel blocker, an ACE inhibitor seems much more protective against oxidative DNA damage in hypertensive patients with different stages of CKD.


Occurrence of bifidobacteria in the stool of multiple sclerosis patients.
Stool specimens from 17 multiple sclerosis (MS) patients were examined for bifidobacteria. The count of colony forming units (CFU)/g faeces and the differentiation and typing of species, especially of Bifidobacterium adolescentis biotypes were performed. The pH of the samples was also measured. Stool specimens from 17 healthy volunteers were examined as a control by the same methods (a modified medium, suitable for the detection and recognition of bifidobacteria in adults is given). The results demonstrate a significant deficiency in bifidobacteria of the adolescentis group in MS patients. In 3 patients, no bifidobacteria could be detected (less than 10(7]. In comparison with the samples from healthy donors, B. adolescentis "c" was reduced and B. adolescentis "a" could not be detected at all in MS patients' stool specimens. The occurrence of B. adolescentis "b" and B. adolescentis "d" as well as the species B. bifidum and B. longum did not significantly differ within both groups. The pH was only slightly increased in the MS group.


Systematic review and meta-analysis of biosimilar for the treatment of rheumatoid arthritis informing the 2020 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.
To evaluate the efficacy and safety of biosimilars compared with reference biological disease modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) as a part of the process of developing the 2020 update of the Japan College of Rheumatology guidelines for the management of RA. PubMed, Cochrane Library, and Japan Centra Revuo Medicina were searched for articles to conduct a systematic review (SR). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. Twenty randomized controlled trials were included (biosimilars of infliximab, etanercept, and adalimumab). A meta-analysis revealed that the risk ratios (RRs) and 95% confidence intervals (CIs) of achieving the American College of Rheumatology 50% response (ACR50) at week 24 and serious adverse events (SAEs) for biosimilars compared with the reference bDMARDs were 1.04 (0.98-1.10) and 0.84 (0.61-1.18), respectively. The RRs of achieving ACR50 and SAEs at week 24 were respectively 0.93 (0.69-1.26) and 2.15 (0.55-8.35) in the patients who switched to biosimilars from the reference bDMARDs and 0.92 (0.76-1.12) and 1.41 (0.32-6.15) in those who continued the reference bDMARDs. Biosimilars and reference bDMARDs were equally useful for the management of RA.


Synthetic Chemical Inducers and Genetic Decoupling Enable Orthogonal Control of the rhaBAD Promoter.
External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly used inducible expression systems, but is marred by transient expression caused by degradation of the native inducer, l-rhamnose. To address this problem, 35 analogues of l-rhamnose were screened for induction of the rhaBAD promoter, but no strong inducers were identified. In the native configuration, an inducer must bind and activate two transcriptional activators, RhaR and RhaS. Therefore, the expression system was reconfigured to decouple the rhaBAD promoter from the native rhaSR regulatory cascade so that candidate inducers need only activate the terminal transcription factor RhaS. Rescreening the 35 compounds using the modified rhaBAD expression system revealed several promising inducers. These were characterized further to determine the strength, kinetics, and concentration-dependence of induction; whether the inducer was used as a carbon source by E. coli; and the modality (distribution) of induction among populations of cells. l-Mannose was found to be the most useful orthogonal inducer, providing an even greater range of induction than the native inducer l-rhamnose, and crucially, allowing sustained induction instead of transient induction. These findings address the key limitation of the rhaBAD expression system and suggest it may now be the most suitable system for many applications.


Trends in age at AIDS diagnosis in Europe and the United States: evidence of pronounced "ageing' among injecting drug users.
To analyse trends in age at diagnosis for adult AIDS cases reported in Europe and the United States. We used AIDS surveillance data for the seven European countries with the highest cumulative number of AIDS cases reported through June 1994 and for the United States through June 1993. Mean age at AIDS diagnosis over time was calculated by sex, transmission category and country. Linear regression yielded annual increase in age and permitted statistical evaluation of the trends observed. Annual AIDS incidence was calculated for homo-/bisexual men and injecting drug users (IDU) by 5-year age groups over time. We found an overall increase in age at AIDS diagnosis among the main transmission categories in Europe and the United States. The epidemiologic profiles of the two regions were highly similar, despite the lower average age among IDU in Europe compared with the United States (30.6 versus 36.7 years) and lower annual increases in age in the United States. In contrast to homo-/bisexual men, the increase in age at diagnosis is strikingly uniform and pronounced among IDU. Between 1986 and 1993, IDU in all countries exhibited at least a 6-month increase in age at diagnosis per annum. Although annual AIDS incidence remains consistent between various age groups of homo-/bisexual men, IDU aged 30-49 years show continuing increase, whereas their younger counterparts show signs of stabilization or decrease. Despite different epidemic profiles and prevention policies, the age trends for the European countries examined and the United States were strikingly similar. The meaning of this general increase in age among the main transmission categories and the especially high increase among IDU may provide important insight into epidemic dynamics and intervention assessment.


Low-dose 6-bromoindirubin-3'-oxime induces partial dedifferentiation of endothelial cells to promote increased neovascularization.
Endothelial cell (EC) dedifferentiation in relation to neovascularization is a poorly understood process. In this report, we addressed the role of Wnt signaling in the mechanisms of neovascularization in adult tissues. Here, we show that a low-dose of 6-bromoindirubin-3'-oxime (BIO), a competitive inhibitor of glycogen synthase kinase-3β, induced the stabilization of β-catenin and its subsequent direct interaction with the transcription factor NANOG in the nucleus of ECs. This event induced loss of VE-cadherin from the adherens junctions, increased EC proliferation accompanied by asymmetric cell division (ACD), and formed cellular aggregates in hanging drop assays indicating the acquisition of a dedifferentiated state. In a chromatin immunoprecipitation assay, nuclear NANOG protein bound to the NANOG- and VEGFR2-promoters in ECs, and the addition of BIO activated the NANOG-promoter-luciferase reporter system in a cell-based assay. Consequently, NANOG-knockdown decreased BIO-induced NOTCH-1 expression, thereby decreasing cell proliferation, ACD, and neovascularization. In a Matrigel plug assay, BIO induced increased neovascularization, secondary to the presence of vascular endothelial growth factor (VEGF). Moreover, in a mouse model of hind limb ischemia, BIO augmented neovascularization that was coupled with increased expression of NOTCH-1 in ECs and increased smooth muscle α-actin(+) cell recruitment around the neovessels. Thus, these results demonstrate the ability of a low-dose of BIO to augment neovascularization secondary to VEGF, a process that was accompanied by a partial dedifferentiation of ECs via β-catenin and the NANOG signaling pathway.


NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli.
We found that cells of Vibrio parahaemolyticus possess an energy-dependent efflux system for norfloxacin. We cloned a gene for a putative norfloxacin efflux protein from the chromosomal DNA of V. parahaemolyticus by using an Escherichia coli mutant lacking the major multidrug efflux system AcrAB as the host and sequenced the gene (norM). Cells of E. coli transformed with a plasmid carrying the norM gene showed elevated energy-dependent efflux of norfloxacin. The transformants showed elevated resistance not only to norfloxacin and ciprofloxacin but also to the structurally unrelated compounds ethidium, kanamycin, and streptomycin. These results suggest that this is a multidrug efflux system. The hydropathy pattern of the deduced amino acid sequence of NorM suggested the presence of 12 transmembrane domains. The deduced primary structure of NorM showed 57% identity and 88% similarity with that of a hypothetical E. coli membrane protein, YdhE. No reported drug efflux protein in the sequence databases showed significant sequence similarity with NorM. Thus, NorM seems to be a novel type of multidrug efflux protein. We cloned the ydhE gene from E. coli. Cells of E. coli transformed with the cloned ydhE gene showed elevated resistance to norfloxacin, ciprofloxacin, acriflavine, and tetraphenylphosphonium ion, but not to ethidium, when MICs were measured. Thus, it seems that NorM and YdhE differ somehow in substrate specificity.


Gallstone ileus: case report and literature review.
Gallstone ileus (GI) is characterized by occlusion of the intestinal lumen as a result of one or more gallstones. GI is a rare complication of gallstones that occurs in 1%-4% of all cases of bowel obstruction. The mortality associated with GI ranges between 12% and 27%. Classical findings on plain abdominal radiography include: (1) pneumobilia; (2) intestinal obstruction; (3) an aberrantly located gallstone; and (4) change of location of a previously observed stone. The optimal management of acute GI is controversial and can be: (1) enterotomy with stone extraction alone; (2) enterotomy, stone extraction, cholecystectomy and fistula closure; (3) bowel resection alone; and (4) bowel resection with fistula closure. We describe a case to highlight some of the pertinent issues involved in GI management, and propose a scheme to minimize recurrent disease and postoperative complications. We conclude that GI is a rare condition affecting mainly the older population with a female predominance. The advent of computed tomography and magnetic resonance imaging has made it easier to diagnose GI. Enterotomy with stone extraction alone remains the most common surgical method because of its low incidence of complications.


Population-specific screening by mutation analysis for diseases frequent in Ashkenazi Jews.
We describe a partially automated DNA mutation assay for detecting the most frequent mutations in the alpha-subunit of beta-hexosaminidase A, the acid beta-glucosidase and the cystic fibrosis transmembrane conductance regulator genes for the Ashkenazi Jewish population. The assay detects carriers for Tay-Sachs disease, Gaucher disease, and cystic fibrosis with sensitivities of at least 92%, 96%, and 97%, respectively. Among 1,364 young adults of Ashkenazic ancestry in the Dor Yeshurim community who were tested, 52 were Tay-Sachs carriers, 110 were Gaucher carriers, and 62 were cystic fibrosis carriers. Ten individuals were carriers for two diseases, and three unsuspected cases were diagnosed with Gaucher disease based on mutation test results. In addition to Tay-Sachs mutation data, results for hexosaminidase A activity were also available. All of 1,254 samples normal by enzyme quantitation were also negative for the three alpha-subunit mutations tested, and all of 43 samples with 'inconclusive' enzyme results were negative by DNA. Only 52 of 67 samples positive by enzyme assay were also positive for one of the three mutations tested for Tay-Sachs disease. The data suggest a high degree of false positivity inherent in enzyme identification of carriers. There are no correlative methods to assess the sensitivity of Gaucher and CF carrier testing. The results show that population screening can be carried out efficiently by DNA analysis, with the accrual of carrier information for three separate diseases conducted as a single test. Furthermore, the DNA method for Tay-Sachs screening appears to exceed the specificity of hexosaminidase A enzyme testing.


Uninsurance among children whose parents are losing Medicaid coverage: Results from a statewide survey of Oregon families.
Thousands of adults lost coverage after Oregon's Medicaid program implemented cost containment policies in March 2003. Despite the continuation of comprehensive public health coverage for children, the percentage of uninsured children in the state rose from 10.1 percent in 2002 to 12.3 percent in 2004 (over 110,000 uninsured children). Among the uninsured children, over half of them were likely eligible for public health insurance coverage. To examine barriers low-income families face when attempting to access children's health insurance. To examine possible links between Medicaid cutbacks in adult coverage and children's loss of coverage. Statewide primary data from low-income households enrolled in Oregon's food stamp program. Cross-sectional analysis. The primary predictor variable was whether or not any adults in the household recently lost Medicaid coverage. The main outcome variables were children's current insurance status and children's insurance coverage gaps. A mail-return survey instrument was designed to collect information from a stratified, random sample of households with children presumed eligible for publicly funded health insurance programs. Over 10 percent of children in the study population eligible for publicly funded health insurance programs were uninsured, and over 25 percent of these children had gaps in insurance coverage during a 12-month period. Low-income children who were most likely to be uninsured or have coverage gaps were Hispanic; were teenagers older than 14; were in families at the higher end of the income threshold; had an employed parent; or had a parent who was uninsured. Fifty percent of the uninsured children lived in a household with at least one adult who had recently lost Medicaid coverage, compared with only 40 percent of insured children (p=.040). Similarly, over 51 percent of children with a recent gap in insurance coverage had an adult in the household who lost Medicaid, compared with only 38 percent of children without coverage gaps (p<.0001). After adjusting for ethnicity, age, household income, and parental employment, children living in a household with an adult who lost Medicaid coverage after recent cutbacks had a higher likelihood of having no current health insurance (OR 1.44, 95 percent CI 1.02, 2.04), and/or having an insurance gap (OR 1.79, 95 percent CI 1.36, 2.36). Uninsured children and those with recent coverage gaps were more likely to have adults in their household who lost Medicaid coverage after recent cutbacks. Although current fiscal constraints prevent many states from expanding public health insurance coverage to more parents, states need to be aware of the impact on children when adults lose coverage. It is critical to develop strategies to keep parents informed regarding continued eligibility and benefits for their children and to reduce administrative barriers to children's enrollment and retention in public health insurance programs.


Ca(2+)-regulated expression of steroid hydroxylases in H295R human adrenocortical cells.
Although changes in the expression of key steroidogenic enzymes such as cytochrome P450 cholesterol side-chain cleavage, 17 alpha-hydroxylase (P450c17), aldosterone synthase, and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) in the human adrenal cortex are known to be controlled by factors activating the protein kinase A or protein kinase C signaling pathways, little is known concerning the effects of increased intracellular Ca2+. In this study we describe the effects of K+, an agent known to increase intracellular Ca2+ through the opening of voltage-sensitive Ca2+ channels, on steroidogenesis in H295R human adrenocortical cells and corresponding changes in expression of these vital steroidogenic enzymes. Treatment of cells for 48 h with K+ (14 mM) resulted in an increase in aldosterone (3.5-fold) as well as the 17 alpha-hydroxylated steroids cortisol (2.9-fold) and dehydroepiandrosterone (DHEA; 3.7-fold). This action of K+ was accompanied by a dose-dependent (P < 0.05 at 6 mM K+ or above) and time-dependent (P < 0.05 at 24 h and beyond) increase in expression of P450c17 and, to a lesser extent, cytochrome P450 cholesterol side-chain cleavage messenger RNA (mRNA). Treatment with K+ also caused a time-dependent increase in aldosterone synthase mRNA levels, which were detectable by 12 h. Treatment with K+, however, was without effect on 3 beta HSD expression. These effects contrast with those of (Bu)2cAMP, which stimulated a greater increase in cortisol and DHEA secretion as well as P450c17 expression. The effects of K+ treatment also differ from those of AII, which promoted a greater aldosterone secretory response (5.7-fold), but a lesser effect on DHEA secretion (2.2-fold) and P450c17 expression. Although AII and TPA (known activators of protein kinase C) as well as forskolin and (Bu)2cAMP (known activators of protein kinase A) increased the expression of 3 beta HSD mRNA, K+ treatment was without effect, suggesting that elevation of [Ca2+]i in response to K+ did not activate the protein kinase C or protein kinase A signaling pathways. Furthermore, the effects of K+ on steroid secretion and 17 alpha-hydroxylase activity were reproduced by the voltage-sensitive Ca2+ channel activator BAYK 8644, and increases in P450c17 mRNA in response to K+ were reversed by the Ca2+ channel antagonist, nifedipine. We conclude that K+ can modulate the expression of key steroidogenic enzymes in H295R cells through the Ca2+ signaling pathway without involvement of the protein kinase A or protein kinase C pathways.(ABSTRACT TRUNCATED AT 250 WORDS)


Short-term CFTR inhibition reduces islet area in C57BL/6 mice.
Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.


Restructuring the principle of medical futility.
This essay surveys the need for a clear and objective definition of medical futility. It is urged that once agreement is obtained for structuring operational guidelines for determining futility, a three-tier decisional structure can be developed for testing whether a given treatment falls within the scope of these guidelines. Under the first tier, the treating physician would be given the primary responsibility for making the determination to withhold treatment on the grounds of futility. While the physician would be under a duty not to prescribe treatment deemed futile, he would be obliged to inform the patient and his family of this decision, including the reasons for it, in order to allow, under the second tier, for an appeal to be taken by the patient or family to the hospital ethics committee. The third tier recognizes a right of limited appeal to the courts.


Efficacy of gonadotropin-releasing hormone agonist (buserelin) in the treatment of endometriosis.
In a multicenter study, the efficacy of and tolerance of 6 months' intranasal gonadotropin-releasing hormone agonist (buserelin) treatment (300 micrograms x 3/day) on laparoscopically verified endometriosis was evaluated in 25 patients. At second-look laparoscopy at the end of medication, the mean endometriosis score had fallen by 82.2%. All endometriosis-associated symptoms and physical findings decreased or almost disappeared during buserelin administration. After discontinuing therapy, they showed a tendency to reappear, but nevertheless they were milder after one year of follow-up, than before treatment. Seven (54%) of the 13 women wishing pregnancy actually conceived. Vaginal irregular spotting bleedings during the first 2 months occurred in 7 patients. No patient withdrew from the trial because of side effects, although almost all women developed symptoms of estrogen deficiency (serum estradiol concentrations fell to menopausal levels).


Edge clustered fitting grids for φ-polynomial characterization of freeform optical surfaces.
With the recent emergence of slow-servo diamond turning, optical designs with surfaces that are not intrinsically rotationally symmetric can be manufactured. In this paper, we demonstrate some important limitations to Zernike polynomial representation of optical surfaces in describing the evolving freeform surface descriptions that are effective for optical design and encountered during optical fabrication. Specifically, we show that the ray grids commonly used in sampling a freeform surface to form a database from which to perform a φ-polynomial fit is limiting the efficacy of computation. We show an edge-clustered fitting grid that effectively suppresses the edge ringing that arises as the polynomial adapts to the fully nonsymmetric features of the surface.


The genetic architecture of type 2 diabetes.
The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.


The impact of rural residence on medically serious medicinal self-poisonings.
Suicide rates are often high in rural areas. Despite the strong association between deliberate self-harm (DSH) and suicide, few have studied rural residence and DSH. Self-poisonings dominate DSH hospital presentations. We investigate a previously reported association between rural residence and medical severity (defined as a subsequent medical/surgical inpatient stay) among emergency department presentations for medicinal self-poisoning (SP) to determine whether differences in agents taken, mental health service use or hospital-level resources explain the relationship. A cohort of n=16,294 12-64-year olds presenting with SP to hospital emergency departments in Ontario, Canada, in 2001/2002 was linked to their service records over time. The rural-medical severity association was best explained by differences in hospital resources; presenting to hospitals providing inpatient psychiatric services appeared to reduce medical/surgical inpatient stays in favor of psychiatric ones. Among those with a recent psychiatric admission, more intensive ambulatory psychiatric contact may be protective of a psychiatric inpatient stay subsequent to the SP presentation. Compared to nonrural residents, deliberate intent was identified less often in rural residents, particularly males. The rural-medical severity association was best explained by disparities in the delivery systems serving rural and nonrural residents, important to rural suicide prevention efforts.


Cerebral autoregulation.
Autoregulation of blood flow denotes the intrinsic ability of an organ or a vascular bed to maintain a constant perfusion in the face of blood pressure changes. Alternatively, autoregulation can be defined in terms of vascular resistance changes or simply arteriolar caliber changes as blood pressure or perfusion pressure varies. While known in almost any vascular bed, autoregulation and its disturbance by disease has attracted particular attention in the cerebrovascular field. The basic mechanism of autoregulation of cerebral blood flow (CBF) is controversial. Most likely, the autoregulatory vessel caliber changes are mediated by an interplay between myogenic and metabolic mechanisms. Influence of perivascular nerves and most recently the vascular endothelium has also been the subject of intense investigation. CBF autoregulation typically operates between mean blood pressures of the order of 60 and 150 mm Hg. These limits are not entirely fixed but can be modulated by sympathetic nervous activity, the vascular renin-angiotensin system, and any factor (notably changes in arterial carbon dioxide tension) that decreases or increases CBF. Disease states of the brain may impair or abolish CBF autoregulation. Thus, autoregulation is lost in severe head injury or acute ischemic stroke, leaving surviving brain tissue unprotected against the potentially harmful effect of blood pressure changes. Likewise, autoregulation may be lost in the surroundings of a space-occupying brain lesion, be it a tumor or a hematoma. In many such disease states, autoregulation may be regained by hyperventilatory hypocapnia. Autoregulation may also be impaired in neonatal brain asphyxia and infections of the central nervous system, but appears to be intact in spreading depression and migraine, despite impairment of chemical and metabolic control of CBF. In chronic hypertension, the limits of autoregulation are shifted toward high blood pressure. Acute hypertensive encephalopathy, on the other hand, is thought to be due to autoregulatory failure at very high pressure. In long-term diabetes mellitus there may be chronic impairment of CBF autoregulation, probably due to diabetic microangiopathy.


[Pulmonary tuberculosis: association between extent of the residual pulmonary lesion and alteration in the lung function].
To describe alterations in spirometric variables and its disturbances and to study the existence of a relationship between extent of the residual lung lesion at the end of treatment for tuberculosis and alteration of the lung function measured by spirometry. Analyzed were 96 patients with diagnosis of pulmonary tuberculosis, treated in three health centers in the metropolitan area of Recife, from January, 2003 to November, 2005. Patients of both genders, 15 years of age or older were included, whose chest x-rays at end of the treatment were classified according to criteria of the National Tuberculosis Association (NTA) for extent of lung lesion. Patients replied to a questionnaire at the beginning of the survey, and were submitted to spirometry after conclusion of treatment. Of the 96 patients, 89.6% presented with radiographic sequels. About 54% had moderate to severe sequels. These radiographic alterations correspond to 24.6% and 73.8% respectively of alterations in the pulmonary function. The large number of residual radiographic lesionss (89.6%) and breathing dysfunction (66,7%) identified in this survey call attention to the fact that treatment of a patient with pulmonary tuberculosis must not be restricted to bacteriological healing of the disease. Identification of the residual lung lesions and of the breathing dysfunction in patients who conclude treatment will promote early actions to treat these sequels, improving the quality of life of these patients.


Form-from-motion: MEG evidence for time course and processing sequence.
The neural mechanisms and role of attention in the processing of visual form defined by luminance or motion cues were studied using magnetoencephalography. Subjects viewed bilateral stimuli composed of moving random dots and were instructed to covertly attend to either left or right hemifield stimuli in order to detect designated target stimuli that required a response. To generate form-from-motion (FFMo) stimuli, a subset of the dots could begin to move coherently to create the appearance of a simple form (e.g., square). In other blocks, to generate form-from-luminance (FFLu) stimuli that served as a control, a gray stimulus was presented superimposed on the randomly moving dots. Neuromagnetic responses were observed to both the FFLu and FFMo stimuli and localized to multiple visual cortical stages of analysis. Early activity in low-level visual cortical areas (striate/early extrastriate) did not differ for FFLu versus FFMo stimuli, nor as a function of spatial attention. Longer latency responses elicited by the FFLu stimuli were localized to the ventral-lateral occipital cortex (LO) and the inferior temporal cortex (IT). The FFMo stimuli also generated activity in the LO and IT, but only after first eliciting activity in the lateral occipital cortical region corresponding to MT/V5, resulting in a 50-60 msec delay in activity. All of these late responses (MT/V5, LO, and IT) were significantly modulated by spatial attention, being greatly attenuated for ignored FFLu and FFMo stimuli. These findings argue that processing of form in IT that is defined by motion requires a serial processing of information, first in the motion analysis pathway from V1 to MT/V5 and thereafter via the form analysis stream in the ventral visual pathway to IT.


The influence of diabetes distress on digital interventions for diabetes management in vulnerable people with type 2 diabetes: A qualitative study of patient perspectives.
Digital interventions for improving diabetes management in Type 2 diabetes mellitus (T2DM) are used universally. Digital interventions are defined as any intervention accessed and taking input from people with T2DM in the form of a web-based or mobile phone-based app to improve diabetes self-management. However, the current confidence in digital interventions threatens to augment social inequalities in health, also known as the "digital divide". To counteract dissemination of the digital divide, we aimed to assess the potential of a tailored digital intervention for improving diabetes management in vulnerable people with T2DM. A qualitative design using semi-structured in-depth interviews to explore the perspectives of 12 vulnerable people with T2DM. Interviews were analyzed using inductive content analysis. Vulnerability was defined by the presence of one or more comorbidities, one or more lifestyle risk factors, poor diabetes management, low educational level and low health literacy. The main themes identified were: "Dealing with diabetes distress" characterized by psychological avoidance mechanisms; "Suffering informational confusion" dealing with inconsistent information; "Experiencing digital alienation" dealing with loss of freedom when technology invades the private sphere; and "Missing the human touch" preferring human interaction over digital contact. Vulnerable people with T2DM are unprepared for digital interventions for disease management. Experiencing diabetes distress may be an intermediate mechanism leading to nonadherence to digital interventions and the preference for human interaction in vulnerable people with T2DM. Future interventions could include a designated caregiver and an allocated buddy to provide support and assist uptake of digital interventions for diabetes management.


The nest architecture of three species of north Florida Aphaenogaster ants.
The architecture of the subterranean nests of Aphaenogaster floridana Smith (Hymenoptera: Formicidae), A. treatae Forel and A. ashmeadi (Emery), was studied from plaster, wax, or metal casts. After structural features were quantified from digital images, the entombed ants were retrieved from the plaster by dissolution or wax casts by melting and counted. Nests of all three species were rather simple, small and vertical, with horizontal chambers connected by vertical shafts. Shafts descending to lower chambers tended to arise from chamber edges, whereas those connecting to a chamber above tended to arise from chamber centers. A. floridana had the largest nests and colonies, and multiple shafts commonly connected upper chambers, a feature lacking in the other two species. In A. floridana nests a higher proportion of chamber area and greater spacing between chambers occurred in the deeper parts of the nest, regardless of nest size. The other two species showed no vertical differentiation of any size-free measure at any nest size. In all three species, nest size increased more slowly than the worker population, so crowding was greater in large colonies than in small, in contrast to the situation in three other ant species for which data were available. An appendix with stereo images of all casts is provided.


Patients with rib fractures do not develop delayed pneumonia: a prospective, multicenter cohort study of minor thoracic injury.
Patients admitted to emergency departments (EDs) for minor thoracic injuries are possibly at risk of delayed pneumonia. We aimed to evaluate the incidence of delayed pneumonia post-minor thoracic injury and the associated risk factors. A prospective, multicenter cohort study was conducted in 4 Canadian EDs, from November 2006 to November 2010. All consecutive patients aged 16 years and older with minor thoracic injury who were discharged from the ED were screened for eligibility. Uniform clinical and radiologic evaluations were performed on the initial ED visit and were repeated at weeks 1 and 2. Relative risk analyses quantified incidence with comparison by age, sex, smoking status, alcohol intoxication, pulmonary comorbidity, ability to cough atelectasis, pain level, and number of rib fractures. Of the 1,057 participants recruited, 347 (32.8%) had at least 1 rib fracture, 87 (8.2%) had asthma, and 36 (3.4%) had chronic obstructive pulmonary disease. Only 6 patients (0.6%; 95% confidence interval 0.24% to 1.17%) developed pneumonia during the follow-up period. The relative risk for patients with preexistent pulmonary disease and radiologically proven rib fractures was 8.6 (P=.045; 95% confidence interval 1.05 to 70.9). Sex, smoking habit, initial atelectasis, ability to cough, and alcohol intoxication were not significantly associated with delayed pneumonia. This prospective cohort study of nonhospitalized patients with minor thoracic injuries revealed a low incidence of delayed pneumonia. Nonetheless, our results support tailored follow-up for asthmatic or chronic obstructive pulmonary disease patients with rib fracture.


What is Important in E-health Interventions for Stroke Rehabilitation? A Survey Study among Patients, Informal Caregivers and Health Professionals.
Incorporating user requirements in the design of e-rehabilitation interventions facilitates their implementation. However, insight into requirements for e-rehabilitation after stroke is lacking. This study investigated which user requirements for stroke e-rehabilitation are important to stroke patients, informal caregivers, and health professionals. The methodology consisted of a survey study amongst stroke patients, informal caregivers, and health professionals (physicians, physical therapists and occupational therapists). The survey consisted of statements about requirements regarding accessibility, usability and content of a comprehensive stroke e-health intervention (4-point Likert scale, 1=unimportant/4=important). The mean with standard deviation was the metric used to determine the importance of requirements. Patients (N=125), informal caregivers (N=43), and health professionals (N=105) completed the survey. The mean score of user requirements regarding accessibility, usability and content for stroke e-rehabilitation was 3.1 for patients, 3.4 for informal caregivers and 3.4 for health professionals. Data showed that a large number of user requirements are important and should be incorporated into the design of stroke e-rehabilitation to facilitate their implementation.


Data based medicine and clinical judgement.
Randomized controlled trials (RCTs) are a useful tool to check the effectiveness of drugs but have come to shape the culture of medicine in a manner that increasingly compromises medical care. Dependence on RCT evidence is compromised by the well-known problems stemming non-publication of trials, lack of access to trial data, ghostwriting of those trials that are published and a variety of coding and other strategies to hide harms. But what is less appreciated is that whenever a drug and an illness can produce the same benefit or harm that the outcomes of RCTs can be profoundly misleading. This article gives examples of how RCTs can produce the wrong answer.


Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes.
Mutations in the RAS family of oncogenes are highly prevalent in human cancer and, amongst its manifold effects, oncogenic RAS impairs the expression of components of the antigen presentation pathway. This allows evasion of cytotoxic T lymphocytes (CTL). CTL and natural killer (NK) cells are reciprocally regulated by MHC class I molecules and any gain in CTL recognition obtained by therapeutic inactivation of oncogenic RAS may be offset by reduced NK cell activation. We have investigated the consequences of targeted inactivation of oncogenic RAS on the recognition by both CTL and NK cells. Inactivation of oncogenic RAS, either by genetic deletion or inactivation with an inducible intracellular domain antibody (iDAb), increased MHC class I expression in human colorectal cell lines. The common RAS mutations, at codons 12, 13 and 61, all inhibited antigen presentation. Although MHC class I modulates the activity of both CTL and NK cells, the enhanced MHC class I expression resulting from inactivation of mutant KRAS did not significantly affect the in vitro recognition of these cell lines by either class of cytotoxic lymphocyte. These results show that oncogenic RAS and its downstream signalling pathways modulate the antigen presentation pathway and that this inhibition is reversible. However, the magnitude of these effects was not sufficient to alter the in vitro recognition of tumour cell lines by either CTL or NK cells.


[Underreporting of maternal deaths in Paraná State, Brazil: 1991-2005].
The objective of this article was to analyze the underreporting of maternal deaths in Paraná State, Brazil, from 1991 to 2005, identifying details on the basic causes that keep maternal deaths hidden and problems with completing items 43 and 44 on death certificates during a recent period (2003-2005). Data were obtained from the database of the Paraná State Committees for the Prevention of Maternal Mortality, which investigate maternal deaths using the Reproductive Age Mortality Survey (RAMOS). According to the data, maternal mortality decreased by 26% in 15 years, but the level of underreporting remained the same, generating adjustment factors ranging from 1.6 to 1.8. In conclusion, medical schools and the State medical board should provide more incisive and comprehensive orientation on completing death certificates in order to minimize this underreporting. The Paraná State Committees for the Prevention of Maternal Mortality help correct underreporting of maternal deaths by identifying their real causes and determinants and defining strategies to reduce them. More effective measures to reduce avoidable maternal deaths are still needed in the State.


Actin-binding proteins from Drosophila embryos: a complex network of interacting proteins detected by F-actin affinity chromatography.
By using F-actin affinity chromatography columns to select proteins solely by their ability to bind to actin filaments, we have identified and partially purified greater than 40 proteins from early Drosophila embryos. These proteins represent approximately 0.5% of the total protein present in soluble cell extracts, and 2 mg are obtained by chromatography of an extract from 10 g of embryos. As judged by immunofluorescence of fixed embryos, 90% of the proteins that we have detected in F-actin column eluates are actin-associated in vivo (12 of 13 proteins tested). The distributions of antigens observed suggest that groups of these proteins cooperate in generating unique actin structures at different places in the cell. These structures change as cells progress through the cell cycle and as they undergo the specializations that accompany development. The variety of different spatial localizations that we have observed in a small subset of the total actin-binding proteins suggests that the actin cytoskeleton is a very complex network of interacting proteins.


The 3rd DBCLS BioHackathon: improving life science data integration with Semantic Web technologies.
BioHackathon 2010 was the third in a series of meetings hosted by the Database Center for Life Sciences (DBCLS) in Tokyo, Japan. The overall goal of the BioHackathon series is to improve the quality and accessibility of life science research data on the Web by bringing together representatives from public databases, analytical tool providers, and cyber-infrastructure researchers to jointly tackle important challenges in the area of in silico biological research. The theme of BioHackathon 2010 was the 'Semantic Web', and all attendees gathered with the shared goal of producing Semantic Web data from their respective resources, and/or consuming or interacting those data using their tools and interfaces. We discussed on topics including guidelines for designing semantic data and interoperability of resources. We consequently developed tools and clients for analysis and visualization. We provide a meeting report from BioHackathon 2010, in which we describe the discussions, decisions, and breakthroughs made as we moved towards compliance with Semantic Web technologies - from source provider, through middleware, to the end-consumer.