Trends of Suicidal Behaviors Among High School Students in the United States: 1991-2017.
To determine if racial and ethnic subgroups of adolescents are at high risk for engagement in suicidal behaviors. Using the nationally representative school-based Youth Risk Behavior Survey from the years 1991 to 2017, we conducted logistic regression analyses to examine trends by different racial and ethnic groups, with each suicide indicator serving as a dichotomous outcome. Participants included 198 540 high school students. Across all sex and race and ethnic groups, there were significant linear decreases in self-reported suicidal ideation and suicide plans from 1991 to 2017. Female adolescents (odds ratio [OR], 0.98; P < .001) had significant decreases in attempts over time. Black adolescents had positive linear trends for suicide attempts among both boys (OR, 1.04; P < .001) and girls (OR, 1.02; P = .003). Black adolescent boys (OR, 1.04; P = .048) had a significant linear increase in injury by attempt. The results suggest that, over time, black youth have experienced an increase in suicide attempts, which is troubling because attempts are the most prominent risk factor associated with suicide death. For black boys, a significant increase in injury by attempt occurred, which suggests that black boys may be engaging in increasingly lethal means when attempting suicide. Examining trends of suicidal thoughts and behaviors over time by sex and race and ethnicity allow us to determine where to focus prevention and intervention efforts. Future research should examine the underlying reasons for these changes observed in US high school students.


Spatiotemporal linear mixed effects modeling for the mass-univariate analysis of longitudinal neuroimage data.
We present an extension of the Linear Mixed Effects (LME) modeling approach to be applied to the mass-univariate analysis of longitudinal neuroimaging (LNI) data. The proposed method, called spatiotemporal LME or ST-LME, builds on the flexible LME framework and exploits the spatial structure in image data. We instantiated ST-LME for the analysis of cortical surface measurements (e.g. thickness) computed by FreeSurfer, a widely-used brain Magnetic Resonance Image (MRI) analysis software package. We validate the proposed ST-LME method and provide a quantitative and objective empirical comparison with two popular alternative methods, using two brain MRI datasets obtained from the Alzheimer's disease neuroimaging initiative (ADNI) and Open Access Series of Imaging Studies (OASIS). Our experiments revealed that ST-LME offers a dramatic gain in statistical power and repeatability of findings, while providing good control of the false positive rate.


Development of a definition for Rapid Progression (RP) of renal function in HIV-positive persons: the D:A:D study.
No consensus exists on how to define abnormally rapid deterioration in renal function (Rapid Progression, RP). We developed an operational definition of RP in HIV-positive persons with baseline estimated glomerular filtration rate (eGFR) >90 ml/min/1.73 m2 (using Cockcroft Gault) in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study from 2004 to 2011. Two definitions were evaluated; RP definition A: An average eGFR decline (slope) ≥5 ml/min/1.73 m2/year over four years of follow-up with ≥3 eGFR measurements/year, last eGFR <90 ml/min/1.73 m2 and an absolute decline ≥5 ml/min/1.73 m2/year in two consecutive years. RP definition B: An absolute annual decline ≥5 ml/min/1.73 m2/year in each year and last eGFR <90 ml/min/1.73 m2. Sensitivity analyses were performed considering two and three years' follow-up. The percentage with and without RP who went on to subsequently develop incident chronic kidney disease (CKD; 2 consecutive eGFRs <60 ml/min/1.73 m2 and 3 months apart) was calculated. 22,603 individuals had baseline eGFR ≥90 ml/min/1.73 m2. 108/3655 (3.0%) individuals with ≥4 years' follow-up and ≥3 measurements/year experienced RP under definition A; similar proportions were observed when considering follow-up periods of three (n=195/6375; 3.1%) and two years (n=355/10756; 3.3%). In contrast under RP definition B, greater proportions experienced RP when considering two years (n=476/10756; 4.4%) instead of three (n=48/6375; 0.8%) or four (n=15/3655; 0.4%) years' follow-up. For RP definition A, 13 (12%) individuals who experienced RP progressed to CKD, and only (21) 0.6% of those without RP progressed to CKD (sensitivity 38.2% and specificity 97.4%); whereas for RP definition B, fewer RP individuals progressed to CKD. Our results suggest using three years' follow-up and at least two eGFR measurements per year is most appropriate for a RP definition, as it allows inclusion of a reasonable number of individuals and is associated with the known risk factors. The definition does not necessarily identify all those that progress to incident CKD, however, it can be used alongside other renal measurements to early identify and assess those at risk of developing CKD. Future analyses will use this definition to identify other risk factors for RP, including the role of antiretrovirals.


Structure of Semliki Forest virus core protein.
Alphaviruses are enveloped, insect-borne viruses, which contains a positive-sense RNA genome. The protein capsid is surrounded by a lipid membrane, which is penetrated by glycoprotein spikes. The structure of the Sindbis virus (SINV) (the type virus) core protein (SCP) was previously determined and found to have a chymotrypsin-like structure. SCP is a serine proteinase which cleaves itself from a polyprotein. Semliki Forest virus (SFV) is among the most distantly related alphaviruses to SINV. Similar to SCP, autocatalysis is inhibited in SFCP after cleavage of the polyprotein by leaving the carboxy-terminal tryptophan in the specificity pocket. The structures of two different crystal forms (I and II) of SFV core protein (SFCP) have been determined to 3.0 A and 3.3 A resolution, respectively. The SFCP monomer backbone structure is very similar to that of SCP. The dimeric association between monomers, A and B, found in two different crystal forms of SCP is also present in both crystal forms of SFCP. However, a third monomer, C, occurs in SFCP crystal form I. While monomers A and B make a tail-to-tail dimer contact, monomers B and C make a head-to-head dimer contact. A hydrophobic pocket on the surface of the capsid protein, the proposed site of binding of the E2 glycoprotein, has large conformational differences with respect to SCP and, in contrast to SCP, is found devoid of bound peptide. In particular, Tyr184 is pointing out of the hydrophobic pocket in SFCP, whereas the equivalent tyrosine in SCP is pointing into the pocket. The conformation of Tyr184, found in SFCP, is consistent with its availability for iodination, as observed in the homologous SINV cores. This suggests, by comparison with SCP, that E2 binding to cores causes major conformational changes, including the burial of Tyr184, which would stabilize the intact virus on budding from an infected cell. The head-to-tail contacts found in the pentameric and hexameric associations within the virion utilize in the same monomer surface regions as found in the crystalline dimer interfaces.


Underwater working times in two groups of traditional apnea divers in Asia: the Ama and the Bajau.
Traditional apnea diving for sea harvesting for a living continues in some communities in Asia, the outcome being dependent on the total underwater working time. We studied dive and surface interval durations and daily time spent submerged by Japanese Ama and the Phillipine Bajau. Diving and surface interval durations were timed, and daily in-water working time noted for 14 female Ama (mean age 60 years) during sea-mollusc collection, and five male Bajau divers (mean age 38 years) during spearfishing, using direct observations and depth-time recorders. In the Ama, mean (SD) dive duration was 38 (8) s, with mean surface interval duration of 38 (8) s, at depths of 5-12 metres' sea water (msw), and diving constituted 50 (4)% of the total immersed working time, which was limited to 4 h per day by fishing regulations. In the Bajau, mean dive duration was 28 (9) s, with surface intervals of 19 (8) s, at depths of 5-7 msw, and diving was 60 (6)% of the total working time. Diving patterns in Hegura-Ama were similar to those previously reported, with up to 2 h per day spent under water. The Bajau total working time of 2-9 h per day suggests that some divers may spend more than 5 h per day submerged, which is the greatest daily apnea diving time reported in humans. We conclude that natural human diving ability in these two groups of traditional apnea divers allows efficient sea harvesting at shallow depths and that the outcome does not seem to be limited by total daily apnea time.


Proapoptotic effect of endocannabinoids in prostate cancer cells.
In the early stages, prostate cancer is androgen‑ dependent; therefore, medical castration has shown significant results during the initial stages of this pathology. Despite this early effect, advanced prostate cancer is resilient to such treatment. Recent evidence shows that derivatives of Cannabis sativa and its analogs may exert a protective effect against different types of oncologic pathologies. The purpose of the present study was to detect the presence of cannabinoid receptors (CB1 and CB2) on cancer cells with a prostatic origin and to evaluate the effect of the in vitro use of synthetic analogs. In order to do this, we used a commercial cell line and primary cultures derived from prostate cancer and benign prostatic hyperplasia. The presence of the CB1 and CB2 receptors was determined by immunohistochemistry where we showed a higher expression of these receptors in later stages of the disease (samples with a high Gleason score). Later, treatments were conducted using anandamide, 2-arachidonoyl glycerol and a synthetic analog of anandamide, methanandamide. Using the MTT assay, we proved that the treatments produced a cell growth inhibitory effect on all the different prostate cancer cultures. This effect was demonstrated to be dose-dependent. The use of a specific CB1 receptor blocker (SR141716) confirmed that this effect was produced primarily from the activation of the CB1 receptor. In order to understand the MTT assay results, we determined cell cycle distribution by flow cytometry, which showed no variation at the different cell cycle stages in all the cultures after treatment. Treatment with endocannabinoids resulted in an increase in the percentage of apoptotic cells as determined by Annexin V assays and caused an increase in the levels of activated caspase-3 and a reduction in the levels of Bcl-2 confirming that the reduction in cell viability noted in the MTT assay was caused by the activation of the apoptotic pathway. Finally, we observed that endocannabinoid treatment activated the Erk pathway and at the same time, produced a decrease in the activation levels of the Akt pathway. Based on these results, we suggest that endocannabinoids may be a beneficial option for the treatment of prostate cancer that has become nonresponsive to common therapies.


TnBP⁄Triton X-45 treatment of plasma for transfusion efficiently inactivates hepatitis C virus.
Risk of transmission of hepatitis C virus (HCV) by clinical plasma remains high in countries with a high prevalence of hepatitis C, justifying the implementation of viral inactivation treatments. In this study, we assessed the extent of inactivation of HCV during minipool solvent/detergent (SD; 1% TnBP / 1% Triton X-45) treatment of human plasma. Luciferase-tagged infectious cell culture-derived HCV (HCVcc) particles were used to spike human plasma prior to treatment by SD at 31 ± 0.5°C for 30 min. Samples were taken before and after SD treatment and filtered on a Sep-Pak Plus C18 cartridge to remove the SD agents. Risk of cytotoxicity was assessed by XTT cell viability assay. Viral infectivity was analyzed based on the luciferase signals, 50% tissue culture infectious dose viral titer, and immunofluorescence staining for HCV NS5A protein. Total protein, cholesterol, and triglyceride contents were determined before and after SD treatment and C18 cartridge filtration. Binding analysis, using patient-derived HCV clinical isolates, was also examined to validate the efficacy of the inactivation by SD. SD treatment effectively inactivated HCVcc within 30 min, as demonstrated by the baseline level of reporter signals, total loss of viral infectivity, and absence of viral protein NS5A. SD specifically targeted HCV particles to render them inactive, with essentially no effect on plasma protein content and hemostatic function. More importantly, the efficacy of the SD inactivation method was confirmed against various genotypes of patient-derived HCV clinical isolates and against HCVcc infection of primary human hepatocytes. Therefore, treatment by 1% TnBP / 1% Triton X-45 at 31°C is highly efficient to inactivate HCV in plasma for transfusion, showing its capacity to enhance the safety of therapeutic plasma products. We propose that the methodology used here to study HCV infectivity can be valuable in the validation of viral inactivation and removal processes of human plasma-derived products.


Toxicoproteomics -- a new preclinical tool.
The publication of the human genome has presented the scientific community with an unprecedented amount of genetic information with the potential to revolutionize the drug discovery process. This information could be used to identify novel drug targets and disease markers or could aid in the development of personalized medicines. The realization that genetic changes must ultimately influence protein function has pushed the field of proteomics further into the limelight. In this review the applications of proteomics to the field of toxicology will be discussed. It is anticipated that, in the future, toxicologists will apply a range of genomic and proteomic techniques to address issues in toxicity.


Chiral edge fluctuations of colloidal membranes.
We study edge fluctuations of a flat colloidal membrane comprised of a monolayer of aligned filamentous viruses. Experiments reveal that a peak in the spectrum of the in-plane edge fluctuations arises for sufficiently strong virus chirality. Accounting for internal liquid crystalline degrees of freedom by the length, curvature, and geodesic torsion of the edge, we calculate the spectrum of the edge fluctuations. The theory quantitatively describes the experimental data, demonstrating that chirality couples in-plane and out-of-plane edge fluctuations to produce the peak.


The Transition to "Patienthood," the Contribution of the Nursing Assistant: A Grounded Theory Study.
The face of nursing is changing, as health-care organizations are looking to new assistant roles to support the registered nurse and potentially provide a source for apprenticeship toward registration. These developments are within a context of an existing assistant staff group, delivering much of the bedside care. Few studies have explored the dyadic relationship between nursing assistant and patient, despite the potential for their interactions to contribute to the patient experience. This study aimed to gain an understanding of patients' perceptions of the nursing assistant role using constructivist grounded theory. Constant comparison guided data collection and analysis, and 4 core categories emerged: expectation, observation, meaningful connections, and adaptation. Within these core categories, we suggest the assistant plays a part in how participants adapt from the known self to a self of patienthood and the overall patient experience. We conclude that there is a necessity to understand more fully the dyadic relationship between patients and nursing assistants.


The Use of VTE prophylaxis in relatioN to patiEnt risk profiling (TUNE-IN) Wave 2 study.
The TUNE-IN (The Use of VTE prophylaxis in relatioN to patiEnt risk profiling) study evaluated venous thrombo-embolism (VTE) risk assessment and prophylaxis in private medical and surgical inpatients in Gauteng Province, South Africa. The study concluded that of the 608 patients enrolled, 54.1% were clinically evaluated to be at risk for VTE. A VTE risk assessment model (RAM), the Caprini score, increased the rate to 74.6%. TUNE-IN Wave 2, an extension of TUNE-IN, was conducted on a national level including the public sector, focusing on surgical inpatients. The study was a national, prospective, non-interventional, multisite, epidemiological disease registry enrolling 453 surgical inpatients. The perceived clinical VTE risk, VTE risk score on Caprini RAM, VTE prophylaxis and clinical details were documented during a baseline visit. A bleeding risk score was provided. Of the cohort, 269 patients (59.4%) were assessed to be at risk for VTE before applying the RAM. All patients (100%), however, were at risk on the RAM score. Early mobilisation and assessment of the VTE risk as low were the most frequent reasons for non-prescription of prophylaxis. Only 15 patients in the private and 2 in the public sector were assessed as having a bleeding risk. Chemoprophylaxis differed between the healthcare sectors, with low-molecular-weight heparin predominating in the private sector and unfractionated heparin being prescribed only in the public sector. VTE risk assessment and prophylaxis need to improve in both the public and the private sectors. A formal RAM will improve identification of patients at risk of VTE.


Comparison of residual oil cluster size distribution, morphology and saturation in oil-wet and water-wet sandstone.
We imaged an oil-wet sandstone at residual oil saturation (S(or)) conditions using X-ray micro-tomography with a nominal voxel size of (9 μm)(3) and monochromatic light from a synchrotron source. The sandstone was rendered oil-wet by ageing with a North Sea crude oil to represent a typical wettability encountered in hydrocarbon reservoirs. We measured a significantly lower S(or) for the oil-wet core (18.8%) than for an analogue water-wet core (35%). We analysed the residual oil cluster size distribution and find consistency with percolation theory that predicts a power-law cluster size distribution. We measure a power-law exponent τ=2.12 for the oil-wet core which is higher than τ for the water-wet system (τ=2.05), indicating fewer large clusters in the oil-wet case. The clusters are rough and sheet-like consistent with connectivity established through layers in the pore space and occupancy of the smaller pores; in contrast the clusters for water-wet media occupy the centres of the larger pores. These results imply less trapping of oil, but with a greater surface area for dissolution. In carbon storage applications, this suggests that in CO(2)-wet systems, capillary trapping is less significant, but that there is a large surface area for dissolution and reaction.


[Anti- NMDA- receptor encephalitis; a neuropsychiatric illness requiring further study].
We describe the case of a 17-year-old girl with anti-NMDA-receptor encephalitis. She had the characteristic psychiatric symptoms such as hallucinations, delirious and bizarre behaviour, and catatonic symptoms. She later also displayed neurological symptoms such as epileptic seizures, dyskinesias and sensitivity disturbances. After treatment with corticosteroids and immunoglobulins patient recovered completely. Potentially lethal symptoms can arise from the autonomic dysregulation. The incidence of this disorder has not yet been established. The catatonic features should be treated adequately with high doses of benzodiazepines. Because patients usually present with psychiatric symptoms, treatment often starts in a psychiatric setting. In view of the serious somatic complications it is desirable that the patient be treated in a general hospital. Early diagnosis and treatment are very important because the chances of recovery are thereby enhanced.


The relative antimicrobial effect of blue 405 nm LED and blue 405 nm laser on methicillin-resistant Staphylococcus aureus in vitro.
It has long been argued that light from a laser diode is superior to light from a light-emitting diode (LED) in terms of its effect on biological tissues. In order to shed light on this ongoing debate, we compared the antimicrobial effect of light emitted from a 405-nm LED with that of a 405-nm laser on methicillin-resistant Staphylococcus aureus (MRSA) at comparable fluences. We cultured 5 × 10(6) CFU/ml MRSA on tryptic soy agar and then irradiated culture plates once, twice, or thrice with either LED or laser light using 40, 54, 81, or 121 J/cm(2) fluence at 15-, 30-, or 240-min time interval between irradiation. Cultures were incubated immediately after irradiation at 37 °C for 24 h before imaging and counting remnant bacterial colonies. Regardless of the device used, LED or laser, irradiation at each fluence resulted in statistically significant bacterial growth suppression compared to non-irradiated controls (p < 0.0001). The antimicrobial effect of both light sources, LED and laser, was not statistically different at each fluence in 35 of the 36 experimental trials. Bacterial growth suppression achieved with either source of light increased with repeated irradiation, particularly at the 15- or 30-min treatment time interval. Thus, we conclude that the antimicrobial effect of 405-nm laser and 405-nm LED on MRSA is similar; neither has a superior antimicrobial effect when compared to the other.


Perceptions of active and inactive prototypes are associated with objective measures of physical activity in adolescents.
The benefits of physical activity are known, but the proportion of adolescents meeting daily activity guidelines remains low. The Theory of Planned Behaviour (TPB), which assumes reasoned intentions explain actions, is a useful framework for predicting activity, but it leaves variance unexplained. The Prototype Willingness Model (PWM) which builds on the TPB, proposes a reasoned action pathway and a second social reactive pathway in which perceptions of social images, or prototypes, explain actions via behavioural willingness. We explored whether variables in the PWM's social reactive pathway explained variance in an objective measure of daily activity, over and above the reasoned action path. Participants aged 12-13 (n = 205) were invited to complete measures of constructs in the PWM and to wear an accelerometer for the next seven days. Overall, 126 students (65 males) participated. Reasoned intentions, attitudes and subjective norms explained 12.8% of variance in activity. Prototype perceptions and willingness explained an additional 13.1% of variance. Participants' perceived similarity to active prototypes, and unfavourable perceptions of inactive prototypes, significantly predicted activity. There were no significant differences between sexes on psychological variables. These findings highlight the importance of targeting prototype perceptions to encourage physical activity in this age group.


A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.
The incidence of lung cancer is declining following a drop in smoking rates, but it is still the leading cause of death from cancer in England and Wales, with about 30,000 deaths a year. Survival rates for lung cancer are poor everywhere, but they appear to be better in the rest of the European Community and the USA than in the UK. Only about 5 per cent of people with lung cancer survive for 5 years, and nearly all of these are cured by surgery after fortuitously early diagnosis. At present, only a small proportion of patients (probably about 5 per cent) with non-small-cell lung cancer are being given chemotherapy. Some centres treat a greater proportion. This review examines the clinical effectiveness and cost-effectiveness of four of the newer drugs - vinorelbine, gemcitabine, paclitaxel and docetaxel - used for treating the most common type of lung cancer (non-small-cell lung cancer). The first three drugs are used for first-line treatment, but at present docetaxel is used only after first-line chemotherapy has failed. This report was based on a systematic literature review and economic modelling, supplemented by cost data. RESULTS - NUMBER AND QUALITY OF STUDIES: A reasonable number of randomised trials were found - three for docetaxel, six for gemcitabine, five for paclitaxel and 13 for vinorelbine. The quality of the trials was variable but good overall. There was a wide range of comparators. Some trials compared chemotherapy with best supportive care (BSC), which involves care that aims to control symptoms, with palliative radiotherapy if needed, but not to prolong life. Others compared the newer drugs against previous drugs or combinations. RESULTS - SUMMARY OF BENEFITS: The gains in duration of survival with the new drugs are modest - a few months - but worthwhile in a condition for which the untreated survival is only about 5 months. There are also gains in quality of life compared with BSC, because on balance the side-effects of some forms of chemotherapy have less effect on quality of life than the effects of uncontrolled spread of cancer. RESULTS - COSTS: The total cost to the NHS of using these new drugs in England and Wales might be about GBP 10 million per annum, but is subject to a number of factors. There would be non-financial constraints on any increase in chemotherapy for the next few years, such as staffing; the number of patients choosing to have the newer forms of chemotherapy is not yet known; and the costs of the drugs may fall, for example, as generic forms appear. RESULTS - COST PER LIFE-YEAR GAINED: The available data did not provide an entirely satisfactory basis for cost-effectiveness calculations. The main problem was the lack of direct comparisons of the new drugs. In order to strengthen the analysis, three different modelling approaches were used: pairwise comparisons using trial data; cost-minimisation analysis, as if all the new regimens were of equal efficacy; and cost-effectiveness analysis pooling the results of several trials with different comparators, giving indirect comparisons of the new drugs by using BSC as the common comparator. A number of different scenarios were explored through extensive sensitivity analysis in each model. Outcomes were expressed in incremental cost per life-year saved or incremental cost, versus BSC. There was insufficient evidence from which to derive cost per quality-adjusted life-year. In first-line treatment, vinorelbine, gemcitabine, and the lower-dose paclitaxel plus cisplatin combinations generally performed well against BSC under a range of different scenarios and especially when given as a maximum of 3 cycles. Incremental cost per life-year gained (LYG) versus BSC varied depending on scenario, but baseline figures based on trial data and protocols were: single-agent vinorelbine, pound 2194 per LYG; vinorelbine plus cisplatin, pound 5206; single-agent gemcitabine, pound 5690; gemcitabine plus cisplatin, pound 10,041; and paclitaxel plus cisplatin, pound 8537. In second-line chemotherapy, docetaxel gave a cost per LYG of pound 17,546, again well within the range usually accepted as cost-effective. However, in routine care, the impact of therapy would be regularly reviewed, and continuation would depend on response, side-effects, patient choice and clinical judgement. Chemotherapy would be stopped in non-responders, making chemotherapy more cost-effective. A 'real-life' scenario in which 60 per cent of patients receive only 1 or 2 cycles of chemotherapy gives much lower costs per LYG, with single-agent gemcitabine, single-agent vinorelbine, and paclitaxel plus platinum appearing to be cost-saving compared with BSC; the incremental cost of gemcitabine plus cisplatin would be pound 2478 per LYG, and of vinorelbine plus cisplatin, pound 2808. At the very least, gains in duration of survival were achieved without diminution of quality of life (at best, they improved quality) and with relatively low incremental cost. Comparisons among the individual drugs should be viewed with caution because they have had to be based on indirect comparisons. RESULTS - LIMITATIONS OF THE ANALYSIS: Each of the three models had limitations. The cost-effectiveness estimates from the pairwise comparisons were based on single studies. The cost-minimisation analysis assumed that the regimens have equal efficacy in practice. The cost-effectiveness analysis had to be based on pooling data from individual trials. The costs of BSC, inpatient stay and outpatient visits were from Scottish data. Median rather than mean data on duration of survival have been used in the analysis, because most of the trials reported only median data. Median survival and number of drug cycles were calculated by averaging across a number of studies, rather than being reliant on one particular study. The costs of the less expensive antiemetics cited in the trials were omitted. The use of more modern and costly antiemetics would have a modest detrimental effect on cost-effectiveness. In the absence of published data, an estimate was made of the cost of side-effects of chemotherapy, in particular hospital admissions, and applied to all the new regimens. In practice, admissions related to side-effects and their respective costs are likely to vary by regimen. The new drugs for non-small-cell lung cancer extend life by only a few months compared with BSC, but appear to do so without net loss in quality of life and at a cost per LYG that is much lower than for many other NHS activities. Depending on assumptions used, these new drugs range from being cost-effective, as conventionally accepted, to being cost-saving. CONCLUSIONS - IMPLICATIONS OF THE NEWER DRUGS: One of the present constraints on chemotherapy is availability of inpatient beds. The advent of newer and gentler forms of chemotherapy given on an outpatient basis would not only overcome this, but it would allow more patients to be treated. This might apply particularly to older patients. The treatment of more patients would increase workload for oncologists, cancer nurses and pharmacists. The Government has already announced increased expenditure on staff for cancer care. The previously pessimistic attitudes to chemotherapy in non-small-cell lung cancer are changing in the wake of the newer agents, and this shift is likely to increase referral. CONCLUSIONS - NEED FOR FURTHER RESEARCH: Recent advances in chemotherapy are welcome, but their effects remain small for patients with non-small-cell lung cancer. Much more research is needed into better drugs, better combinations, new ways of assessing the likelihood of response and especially direct comparisons between the new regimens. This research would be aided by having a greater proportion of patients involved in trials, but there will be infrastructure implications of increased participation.


The association between under-nutrition, school performance and perceptual motor functioning in first-grade South African learners: The North-West Child Health Integrated with Learning and Development study.
Early childhood is characterised by an immense spurt of growing and learning where under-nutrition can have adverse effects on the neuro-developmental health and school performance of children. A full understanding of the relationship between school performance and motor functioning skills and malnourishment in school beginners is still lacking. To determine the association between indices of under-nutrition and how it relates to school performance and motor functioning skills of first-grade learners. North West province (NWP) of South Africa (SA). The baseline data of the stratified, randomised North-West Child Health Integrated with Learning and Development (NW-CHILD) longitudinal study were used. Grade 1 learners (N = 816, 420 boys, 396 girls, mean age 6.78+ years) from four school districts in the NWP of SA took part in the study. Indices of under-nutrition were determined by Z-scores (-2 standard deviation [s.d.]) for stunting (height-for-age [HAZ]) and wasting and underweight (Z-score for body mass index) using the 2007 World Health Organization reference sample. The Bruininks-Oseretsky Test of Motor Proficiency Short Form and the Visual Motor Integration fourth edition were used to assess different aspects of motor functioning, while school performance in mathematics, reading and writing was assessed by teachers according to the National South African standards of assessments. Both HAZ and Z-score for weight-for-age correlated significantly with school performance and motor functioning skills (r > 2.0, p < 0.05), while visual perception was moderately associated (r < 0.30) with mathematics in HAZ and Z-score for weight-for-height (WHZ) children. Motor functioning of HAZ and WHZ children was significantly poorer (p < 0.05) compared to typical children, while underweight was not associated with any outcome variables. Moderate forms of stunting and wasting influence school performance and motor functioning of school beginners negatively, while an association between visual perceptual abilities and inferior mathematics, reading and writing suggests a close link with inferior cognitive information processing in stunted and wasted children. These barriers should be addressed as poor scholastic success in Grade 1 may influence future school performance and the subsequent well-being of children.


Comparative Study on the Performance of Anaerobic and Aerobic Biotrickling Filter for Removal of Chloroform.
Use of biotrickling filter (BTF) for gas phase treatment of volatile trihalomethanes (THMs) stripped from water treatment plants could be an attractive treatment option. The aim of this study is to use laboratory-scale anaerobic BTF to treat gaseous chloroform (recalcitrant to biological transformation) as a model THM and compare results with aerobic BTF. Additional investigations were conducted to determine the microbial diversity present within the BTFs. Chloroform is a hydrophobic volatile THM known to be difficult to biodegrade. To improve the degradation process, ethanol was used as a cometabolite at a different ratio to chloroform. The experimental plan was designed to operate one BTF under anaerobic condition and the other one under aerobic acidic condition. Higher elimination capacity (EC) of 0.23 ± 0.01 g/[m3·h] was observed with a removal efficiency of 80.9% ± 4% for the aerobic BTF operating at pH 4 for the concentration ratio of 1:40 chloroform to ethanol. For similar ratio, the anaerobic BTF supported lower removal efficiency of 59% ± 10% with corresponding lower EC of 0.16 ± 0.01 g/[m3·h]. Carbon recovery acquired for anaerobic and aerobic BTFs was 59% and 63%, respectively. The loading rate for chloroform on both BTFs was 0.27 g/[m3·h] (per m3 of filter bed volume). Variations of the microbial community were attributed to degradation of chloroform in each BTF. Azospira oryzae and Azospira restrica were the dominant bacteria and potential candidates for chloroform degradation for the anaerobic BTF, whereas Fusarium sp. and Fusarium solani were the dominant fungi and potential candidates for chloroform degradation in the aerobic BTF.


Likeability of Garden Birds: Importance of Species Knowledge & Richness in Connecting People to Nature.
Interacting with nature is widely recognised as providing many health and well-being benefits. As people live increasingly urbanised lifestyles, the provision of food for garden birds may create a vital link for connecting people to nature and enabling them to access these benefits. However, it is not clear which factors determine the pleasure that people receive from watching birds at their feeders. These may be dependent on the species that are present, the abundance of individuals and the species richness of birds around the feeders. We quantitatively surveyed urban households from towns in southern England to determine the factors that influence the likeability of 14 common garden bird species, and to assess whether people prefer to see a greater abundance of individuals or increased species richness at their feeders. There was substantial variation in likeability across species, with songbirds being preferred over non-songbirds. Species likeability increased for people who fed birds regularly and who could name the species. We found a strong correlation between the number of species that a person could correctly identify and how connected to nature they felt when they watched garden birds. Species richness was preferred over a greater number of individuals of the same species. Although we do not show causation this study suggests that it is possible to increase the well-being benefits that people gain from watching birds at their feeders. This could be done first through a human to bird approach by encouraging regular interactions between people and their garden birds, such as through learning the species names and providing food. Second, it could be achieved through a bird to human approach by increasing garden songbird diversity because the pleasure that a person receives from watching an individual bird at a feeder is dependent not only on its species but also on the diversity of birds at the feeder.


Safety of High-Flow Nasal Cannula Outside the ICU for Previously Healthy Children With Bronchiolitis.
High-flow nasal cannula (HFNC), a form of noninvasive respiratory support, is effective for the treatment of respiratory distress in ICUs. Although HFNC has been used outside of the ICU, there is little research that examines its safety in this less-monitored setting. Children ≤ 24 months old admitted with bronchiolitis to a pediatric floor at a tertiary care center from April 1 2013, to March 31 2015, were identified by using standard diagnostic codes. Exclusion criteria were concomitant pneumonia or complex comorbidities. Demographic and clinical characteristics were abstracted. Outcomes included transfer to the ICU, higher levels of respiratory support, intubation, pneumothorax, or aspiration events. Eighty children admitted with bronchiolitis who were treated with HFNC while on the pediatric floor were examined. The median age was 4.6 months, 45% were girls, and the majority were either Hispanic (41%) or black (36%). Flow ranged from 3 to 10 L/min. Thirty-three subjects (41% of the sample) required subsequent transfer to the ICU. No children were intubated or developed a pneumothorax. Eighty-three percent were fed while on HFNC. No children had an aspiration event. HFNC may be a safe modality of respiratory support outside of the ICU for children ages ≤ 24 months with bronchiolitis and without comorbidities up to a maximum flow of 10 L/min. There were no adverse events among the subjects who were fed while on HFNC.


AAGP position statement: disaster preparedness for older Americans: critical issues for the preservation of mental health.
The Disaster Preparedness Task Force of the American Association for Geriatric Psychiatry was formed after Hurricane Katrina devastated New Orleans to identify and address needs of the elderly after the disaster that led to excess health disability and markedly increased rates of hopelessness, suicidality, serious mental illness (reported to exceed 60% from baseline levels), and cognitive impairment. Substance Abuse and Mental Health Services Administration (SAMHSA) outlines risk groups which fail to address later effects from chronic stress and loss and disruption of social support networks. Range of interventions recommended for Preparation, Early Response, and Late Response reviewed in the report were not applied to elderly for a variety of reasons. It was evident that addressing the needs of elderly will not be made without a stronger mandate to do so from major governmental agencies (Federal Emergency Management Agency [FEMA] and SAMHSA). The recommendation to designate frail elderly and dementia patients as a particularly high-risk group and a list of specific recommendations for research and service and clinical reference list are provided.


Epistasis constrains mutational pathways of hemoglobin adaptation in high-altitude pikas.
A fundamental question in evolutionary genetics concerns the roles of mutational pleiotropy and epistasis in shaping trajectories of protein evolution. This question can be addressed most directly by using site-directed mutagenesis to explore the mutational landscape of protein function in experimentally defined regions of sequence space. Here, we evaluate how pleiotropic trade-offs and epistatic interactions influence the accessibility of alternative mutational pathways during the adaptive evolution of hemoglobin (Hb) function in high-altitude pikas (Mammalia: Lagomorpha). By combining ancestral protein resurrection with a combinatorial protein-engineering approach, we examined the functional effects of sequential mutational steps in all possible pathways that produced an increased Hb-O2 affinity. These experiments revealed that the effects of mutations on Hb-O2 affinity are highly dependent on the temporal order in which they occur: Each of three β-chain substitutions produced a significant increase in Hb-O2 affinity on the ancestral genetic background, but two of these substitutions produced opposite effects when they occurred as later steps in the pathway. The experiments revealed pervasive epistasis for Hb-O2 affinity, but affinity-altering mutations produced no significant pleiotropic trade-offs. These results provide insights into the properties of adaptive substitutions in naturally evolved proteins and suggest that the accessibility of alternative mutational pathways may be more strongly constrained by sign epistasis for positively selected biochemical phenotypes than by antagonistic pleiotropy.


A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.
K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.


Increase in cytosolic free calcium concentration is an intracellular messenger for the production of interleukin 2 but not for expression of the interleukin 2 receptor.
Activation of lymphocytes by mitogenic lectins results in the production of a group of soluble factors, the lymphokines. Proliferation of activated T cells requires interaction of one of these lymphokines, interleukin 2 (IL 2), with its receptor. The induction of IL 2 receptor expression and IL 2 production may involve different activation signals; some mitogens or antigens may activate both, whereas others may activate only one. An increase in cytosolic free calcium concentrations [( Ca++]i) is one of the signals involved in cellular activation by lectins. By using the fluorescent indicator quin-2, we have demonstrated that increases in [Ca++]i accompany phytohemagglutinin induced proliferative responses of human T lymphocytes. Preventing the increase in [Ca++]i also prevents proliferation. We demonstrate that an increase in [Ca++]i is not required for the expression of the IL 2 receptor, which is expressed even in the presence of extremely low external calcium concentrations. In contrast, IL 2 production requires an increase in [Ca++]i and does not occur in the absence of extracellular free calcium. IL 2 production appears to be the critical step requiring transmembrane calcium flux. In the absence of transmembrane calcium flux and subsequent IL 2 production, lectins are not able to trigger DNA synthesis and cell proliferation.


Naturally Occurring Monoclonal Antibodies and Their Therapeutic Potential for Neurologic Diseases.
Modulating the immune system does not reverse long-term disability in neurologic disorders. Better neuroregenerative and neuroprotective treatment strategies are needed for neuroinflammatory and neurodegenerative diseases. To review the role of monoclonal, naturally occurring antibodies (NAbs) as novel therapeutic molecules for treatment of neurologic disorders. Peer-reviewed articles, including case reports, case series, retrospective reviews, prospective randomized clinical trials, and basic science reports, were identified in a PubMed search for articles about NAbs and neurologic disorders that were published from January 1, 1964, through June 30, 2015. We concentrated our review on multiple sclerosis, Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. Many insults, including trauma, ischemia, infection, inflammation, and neurodegeneration, result in irreversible damage to the central nervous system. Central nervous system injury often results in a pervasive inhibitory microenvironment that hinders regeneration. A common targeted drug development strategy is to identify molecules with high potency in animal models. Many approaches often fail in the clinical setting owing to a lack of efficacy in human diseases (eg, less than the response demonstrated in animal models) or a high incidence of toxic effects. An alternative approach is to identify NAbs in humans because these therapeutic molecules have potential physiologic function without toxic effects. NAbs of the IgG, IgA, or IgM isotype contain germline or close to germline sequences and are reactive to self-components, altered self-components, or foreign antigens. Our investigative group developed recombinant, autoreactive, natural human IgM antibodies directed against oligodendrocytes or neurons with therapeutic potential for central nervous system repair. One such molecule, recombinant HIgM22, directed against myelin and oligodendrocytes completed a successful phase 1 clinical trial without toxic effects with the goal of promoting remyelination in multiple sclerosis. Animal studies demonstrate that certain monoclonal NAbs are beneficial as therapeutic agents for neurologic diseases. This class of antibodies represents a unique source from which to develop a new class of disease-modifying therapies.


Alcohol Metabolism in the Progression of Human Nonalcoholic Steatohepatitis.
Alcohol metabolism is a well-characterized biological process that is dominated by the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) families. Nonalcoholic steatohepatitis (NASH) is the advanced inflammatory stage of nonalcoholic fatty liver disease (NAFLD) and is known to alter the metabolism and disposition of numerous drugs. The purpose of this study was to investigate the alterations in alcohol metabolism processes in response to human NASH progression. Expression and function of ADHs, ALDHs, and catalase were examined in normal, steatosis, NASH (fatty) and NASH (not fatty) human liver samples. ALDH4A1 mRNA was significantly decreased in both NASH groups, while no significant changes were observed in the mRNA levels of other alcohol-related enzymes. The protein levels of ADH1A, ADH1B, and ADH4 were each decreased in the NASH groups, which was consistent with a decreased overall ADH activity. The protein level of ALDH2 was significantly increased in both NASH groups, while ALDH1A1 and ALDH1B1 were only decreased in NASH (fatty) samples. ALDH activity represented by oxidation of acetaldehyde was decreased in the NASH (fatty) group. The protein level of catalase was decreased in both NASH groups, though activity was unchanged. Furthermore, the significant accumulation of 4-hydroxynonenal protein adduct in NASH indicated significant oxidative stress and a potential reduction in ALDH activity. Collectively, ADH and ALDH expression and function are profoundly altered in the progression of NASH, which may have a notable impact on ADH- and ALDH-associated cellular metabolism processes and lead to significant alterations in drug metabolism mediated by these enzymes.


Risk factors for tuberculosis among HIV-infected patients in Switzerland. Swiss HIV Cohort Study.
The aim of this study was to determine the risk factors associated with tuberculosis among human immunodeficiency virus (HIV)-infected persons living in Switzerland, a country with low prevalence of tuberculous infection. We performed a nested case-control study and logistic regression. Cases (n = 239) were patients participating in the Swiss-HIV Cohort study (n = 7,103), diagnosed with bacteriologically confirmed tuberculosis. The rest of the cohort population was used as control. Patients from industrialized countries had a risk of tuberculosis similar to those from Switzerland (adjusted odds ratio (OR) 1.1; 95% confidence interval (95% CI) 0.7-1.5); whereas the risk among patients from Eastern Europe (OR 2.8, 95% CI 1.9-3.7), Brazil (OR 10.6; 95% CI 9.6-11.5), and Africa (OR 3.0; 95% CI 2.4-3.6) was markedly higher. Immune suppression, as indicated by low CD4 + cell count, was an independent risk factor for tuberculosis (OR 7.8; 95% CI 7.3-8.3 for patients with CD4 + < 50 cells.mm-3 compared to those with CD4 + > 500 cells.mm-3). Age, sex and HIV-transmission category did not appear to increase the risk of tuberculosis after adjustment for other patient characteristics. In conclusion, in countries of low prevalence of Mycobacterium tuberculosis infection, to originate from a country with high prevalence of tuberculosis infection and to have advanced immunodeficiency are significant risk factors for tuberculosis. They may be used to complement the tuberculin skin test in targeting patients for preventive chemotherapy.


Respiratory hospitalizations in association with fine PM and its components in New York State.
Despite observed geographic and temporal variation in particulate matter (PM)-related health morbidities, only a small number of epidemiologic studies have evaluated the relation between PM2.5 chemical constituents and respiratory disease. Most assessments are limited by inadequate spatial and temporal resolution of ambient PM measurements and/or by their approaches to examine the role of specific PM components on health outcomes. In a case-crossover analysis using daily average ambient PM2.5 total mass and species estimates derived from the Community Multiscale Air Quality (CMAQ) model and available observations, we examined the association between the chemical components of PM (including elemental and organic carbon, sulfate, nitrate, ammonium, and other remaining) and respiratory hospitalizations in New York State. We evaluated relationships between levels (low, medium, high) of PM constituent mass fractions, and assessed modification of the PM2.5-hospitalization association via models stratified by mass fractions of both primary and secondary PM components. In our results, average daily PM2.5 concentrations in New York State were generally lower than the 24-hr average National Ambient Air Quality Standard (NAAQS). Year-round analyses showed statistically significant positive associations between respiratory hospitalizations and PM2.5 total mass, sulfate, nitrate, and ammonium concentrations at multiple exposure lags (0.5-2.0% per interquartile range [IQR] increase). Primarily in the summer months, the greatest associations with respiratory hospitalizations were observed per IQR increase in the secondary species sulfate and ammonium concentrations at lags of 1-4 days (1.0-2.0%). Although there were subtle differences in associations observed between mass fraction tertiles, there was no strong evidence to support modification of the PM2.5-respiratory disease association by a particular constituent. We conclude that ambient concentrations of PM2.5 and secondary aerosols including sulfate, ammonium, and nitrate were positively associated with respiratory hospitalizations, although patterns varied by season. Exposure to specific fine PM constituents is a plausible risk factor for respiratory hospitalization in New York State. The association between ambient concentrations of PM2.5 components has been evaluated in only a small number of epidemiologic studies with refined spatial and temporal scale data. In New York State, fine PM and several of its constituents, including sulfate, ammonium, and nitrate, were positively associated with respiratory hospitalizations. Results suggest that PM species relationships and their influence on respiratory endpoints are complex and season dependent. Additional work is needed to better understand the relative toxicity of PM species, and to further explore the role of co-pollutant relationships and exposure prediction error on observed PM-respiratory disease associations.


Evaluation of the Glucocorticoid Receptor as a Biomarker of Treatment Response in Vogt-Koyanagi-Harada Disease.
This study is aimed to investigate the role of glucocorticoid receptor (GR) isoforms in peripheral blood mononuclear cells (PBMC) as biomarkers of glucocorticoid (GC) resistance and to validate a set of clinical predictive factors in patients with Vogt-Koyanagi-Harada (VKH) disease. This was a prospective cohort study that included a total of 21 patients with VKH. A complete ophthalmologic evaluation was carried out at baseline that recorded the presence of any clinical predictive factors (visual acuity ≤ 20/200, tinnitus, chronic disease, and fundus depigmentation). Real-time quantitative PCR was performed to measure the mRNA levels of GR alpha (GRα) and beta (GRβ) isoforms at baseline and at 2 weeks after prednisone therapy initiation. There were no differences between GRα and GRβ levels in GC-sensitive and GC-resistant patients at baseline before treatment initiation. After 2 weeks of prednisone treatment, GC-sensitive patients had a median 5.5-fold increase in levels of GRα, whereas GC-resistant patients had a median 0.7-fold decrease in levels of this isoform (P = 0.003). Similarly, GRβ increased in GC-sensitive patients, in comparison with GR-resistant patients (6.49-fold versus 1.01 fold, respectively, I = 0.04). The mRNA levels of GR isoforms were independent of disease activity. Fundus depigmentation and chronic disease at diagnosis were associated with GC resistance (P = 0.03, odds ratio = 21.0; and P = 0.008, odds ratio = 37.8, respectively). However, associations with visual acuity or tinnitus were not confirmed in this study. The evaluation of clinical predictive factors and determination of the change in expression of GR isoforms as potential biomarkers can contribute to the early identification of GC-resistant patients with VKH.


Existing data sources for clinical epidemiology: The Danish National Database of Reimbursed Prescriptions.
The Danish health care system provides partial reimbursement of most prescription medications in Denmark. The dispensation of prescription medications is registered in administrative databases. Each time a prescription is redeemed at a pharmacy, an electronic record is generated with information related to the user, prescriber, the pharmacy, and the dispensed drug. The National Health Service gathers this information for administration of the drug reimbursement plan. Recently, this information became the basis for the establishment of a new research database, the Danish National Database of Reimbursed Prescriptions (DNDRP). In this paper, we review the content, coverage, quality, linkage, access, and research possibilities of this new database. The database encompasses the reimbursement records of all reimbursed drugs sold in community pharmacies and hospital-based outpatient pharmacies in Denmark since 2004. On average, approximately 3.5 million users are recorded in the database each year. During the coverage period, the number of annual prescription redemptions increased by 15%. Most dispensed prescriptions are in the categories "alimentary tract and metabolism", "cardiovascular system", "nervous system", and "respiratory system". Individuals are identified by the unique central personal registration (CPR) number assigned to all persons born in or immigrating to Denmark. The new database fully complies with Denmark's Act on Processing of Personal Data, while avoiding additional restrictions imposed on data use at the Danish National Prescription Registry, administered by Statistics Denmark. Most importantly, CPR numbers are reversibly encrypted, which allows re-identification of drug users; furthermore, the data access is possible outside the servers of Statistics Denmark. These features open additional opportunities for international collaboration, validation studies, studies on adverse drug effects requiring review of medical records, studies involving contact to general practitioners, and linkage of prescription data to other clinical and research databases. The DNDRP thus is a valuable data source for pharmacoepidemiological research.


Optimization of a peptide-based protocol employing IL-7 for in vitro restimulation of human cytotoxic T lymphocyte precursors.
A variety of different methods for the in vitro restimulation of human cytotoxic T lymphocyte (CTL) precursors (CTLp) are in use. Our aim was to enhance the detection of circulating human CTLp in peripheral blood. We have developed a standardized and highly efficient method for restimulating CTLp. Synthetic peptides were used to restimulate cognate CTLp from peripheral blood mononuclear cells (PBMC), and effector CTL capable of lysing peptide-pulsed and virus infected targets were generated. The effects of several parameters on CTL specific for influenza A, EBV and HIV-1 were evaluated, and the optimum peptide concentration for CTL generation was established. Supplementation of initial cultures with IL-7 greatly enhanced peptide-specific lytic activity for all peptides tested and the dose-response relationship for IL-7 was delineated. A novel technique using peptide-MHC class I molecule tetramers to stain T cells bearing cognate T cell receptors permitted enumeration of antigen-specific CD8 + CTL during in vitro restimulation; IL-7 supplementation selectively expanded the population of peptide-specific CD8 + CTL. Importantly, this protocol, whilst enhancing the restimulation and lytic activity of secondary CTL, does not induce primary CTL in vitro. The improved efficiency with which CTL are generated in this system substantially enhances the sensitivity of CTL culture and the 51Cr release assay to detect low levels of CTL activity.


Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials.
To determine the effects of lowering cholesterol concentrations on total and cause specific mortality in randomised primary prevention trials. Qualitative (meta-analytic) evaluation of total mortality from coronary heart disease, cancer, and causes not related to illness in six primary prevention trials of cholesterol reduction (mean duration of treatment 4.8 years). 24,847 Male participants; mean age 47.5 years. Total and cause specific mortalities. Follow up periods totalled 119,000 person years, during which 1147 deaths occurred. Mortality from coronary heart disease tended to be lower in men receiving interventions to reduce cholesterol concentrations compared with mortality in control subjects (p = 0.06), although total mortality was not affected by treatment. No consistent relation was found between reduction of cholesterol concentrations and mortality from cancer, but there was a significant increase in deaths not related to illness (deaths from accidents, suicide, or violence) in groups receiving treatment to lower cholesterol concentrations relative to controls (p = 0.004). When drug trials were analysed separately the treatment was found to reduce mortality from coronary heart disease significantly (p = 0.04). The association between reduction of cholesterol concentrations and deaths not related to illness warrants further investigation. Additionally, the failure of cholesterol lowering to affect overall survival justifies a more cautious appraisal of the probable benefits of reducing cholesterol concentrations in the general population.


The Preventive Role of Angiotensin Converting Enzyme Inhibitors/Angiotensin-II Receptor Blockers and β-Adrenergic Blockers in Anthracycline- and Trastuzumab-Induced Cardiotoxicity.
Anthracycline (doxorubicin) and trastuzumab treatments for cancer patients have been known to cause cardiotoxicity. The current recommendations for prevention of cardiac events from cancer chemotherapies are largely based on opinion. The American Society of Clinical Oncology recommends active screening and prevention of modifiable cardiovascular risk factors. The risk factors are defined as tobacco use, high blood pressure, high cholesterol, alcohol use, obesity, and physical inactivity. Beta-adrenergic blockers and angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) have been the mainstay of treatment for heart failure patients with reduced left ventricular ejection fraction for many years. This review analyzed the use of beta-adrenergic blockers and ACE inhibitors/ARBs as protection against cardiomyopathy caused by anthracyclines and trastuzumab. Although many more studies are warranted, it was concluded that the addition of a beta-blocker early in the treatment of cancer patients who are undergoing anthracycline or trastuzumab treatment can have beneficial effects in preserving left ventricular ejection fraction and preventing chemotherapy-induced cardiotoxicity. The effects are more apparent in the short term. More studies of the long-term effects are warranted, as are the additive effects of using a beta-blocker and ACE inhibitor/ARB together to prevent chemotherapy-induced cardiotoxicity.


Cytogenetic mapping of 5S and 18S rRNAs and H3 histone genes in 4 ancient Proscopiidae grasshopper species: contribution to understanding the evolutionary dynamics of multigene families.
This paper reports on the chromosomal location of 18S rRNA, 5S rRNA and H3 histone multigene families in 4 species of a relatively ancient and diversified group of grasshoppers belonging to the family Proscopiidae. The 5S rRNA and H3 histone genes were highly conserved in the number of sites and chromosomal position in the 4th chromosome pair in all species analyzed, whereas the 18S rRNA genes showed slightly more variation because they were present on one or 2 chromosome pairs, depending on the species. The 5S and 18S rRNA gene families occurred in different chromosomes; in contrast, H3 histone and 5S rRNA genes co-localized in the same chromosomal position, with an apparently interspersed organization. Considering that the Proscopiidae family is a relatively ancient group compared with the Acrididae family, the association of the H3 histone and 5S rRNA multigene families can represent a basal condition for grasshoppers, although more research is needed on other representatives of this insect group to confirm this statement. The presence of such an association of 5S rDNA and H3 histone in mussels and arthropods (beetles, grasshoppers and crustaceans) suggests that this linked configuration could represent an ancestral pattern for invertebrates. These results provide new insights into the understanding of the genome organization and the evolution of multigene families in grasshoppers and in insects as a whole.


Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis.
Loss of heterozygosity (LOH) and K-ras mutation were analyzed in 111 colorectal polyps and 26 invasive carcinomas from 40 patients with familial adenomatous polyposis of distinct histopathological types. LOH, being less than 2% in moderate adenomas, was detected on chromosome 5q (20%) in severe adenomas, on 5q (26%) and 17p (38%) in intramucosal carcinomas, and on 5q (52%), 17p (56%), 18 (46%), and 22q (33%) in invasive carcinomas. LOH on chromosome 5q occurred most frequently in the region close to the APC gene both in adenomas and carcinomas, and a loss of the normal allele of the APC gene was demonstrated in 3 cases. K-ras mutation markedly increased in the step of development from moderate (11%) to severe (36%) adenomas. These results suggest the following mechanisms for the development of colon tumors in patients with familial adenomatous polyposis: (a) the heterozygous mutant/wild-type condition at the APC gene causes formation of mild or moderate adenoma; (b) the loss of the normal allele in the APC gene leads to a change from moderate to severe adenoma; (c) LOH on chromosome 17p contributes to the conversion of adenoma to intramucosal carcinoma; (d) LOH on other chromosomes, such as 18 and 22q, are involved in the progression of intramucosal carcinoma to invasive carcinoma; and (e) K-ras mutation may also affect the development of moderate to severe adenoma.


Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules.
The phosphorylation state of tau changes during neurodevelopment and highly phosphorylated tau accumulates in the paired helical filaments found in Alzheimer's disease. In non-neuronal mammalian cells transiently expressed tau is predominantly not phosphorylated at sites known to be phosphorylated in paired helical filaments. However this pattern of phosphorylation is induced by both glycogen synthase kinase-3 alpha and -3 beta and here we show that this results in a change in the intracellular properties of tau. Within cells tau is bound to cytoskeletal structures and causes changes in cellular cytoarchitecture with the induction of thick and stable microtubule bundles. This morphology is lost when tau is co-expressed with glycogen synthase kinase-3 beta; microtubules become less stable and are not bound by tau. Independently of any direct or indirect effects on tau, glycogen synthase kinase-3 beta induces some but relatively slight changes in microtubule organization with the loss of a prominent centrosomal microtubular origin. The cytoskeleton is critical to cell function and within post-mitotic neurons has a highly specialized structure induced, in part, by the neuronal-specific microtubule-associated proteins such as tau. In vitro studies have suggested that the properties of tau are regulated by phosphorylation as highly phosphorylated tau does not promote tubulin polymer assembly. We have demonstrated, in intact cells, that tau highly phosphorylated in the presence of glycogen synthase kinase-3 beta loses the properties of microtubule binding and stabilization, suggesting that regulation of tau phosphorylation by this enzyme might be an important mechanism whereby cytoskeletal function is modulated during neurodevelopment and lost in neurodegeneration.


T Lymphocyte Myosin IIA is Required for Maturation of the Immunological Synapse.
The role of non-muscle myosin IIA (heavy chain encoded by the non-muscle myosin heavy chain 9 gene, Myh9) in immunological synapse formation is controversial. We have addressed the role of myosin IIA heavy chain protein (MYH9) in mouse T cells responding to MHC-peptide complexes and ICAM-1 in supported planar bilayers - a model for immunological synapse maturation. We found that reduction of MYH9 expression levels using Myh9 siRNA in proliferating mouse CD4(+) AND T cell receptor (TCR) transgenic T cells resulted in increased spreading area, failure to assemble the central and peripheral supramolecular activation clusters (cSMAC and pSMAC), and increased motility. Surprisingly, TCR microcluster speed was reduced marginally, however TCR microclusters dissipated prior to forming a cSMAC. TCR microclusters formed in the Myh9 siRNA-treated T cells showed reduced phosphorylation of the Src family kinase (SFK) activation loop and displayed reduced cytoplasmic calcium ion (Ca(2+)) elevation. In addition, Myh9 siRNA-treated cells displayed reduced phosphorylation of the Cas-L substrate domain - a force-dependent SFK substrate - which was observed in control siRNA-treated cells in foci throughout the immunological synapse except the cSMAC. Cas-L exhibited TCR ligation-dependent induction of phosphorylation. These results provide further evidence that T cell activation is modulated by intrinsic force-generating systems and can be viewed as a mechanically responsive process influenced by MYH9.


Homo floresiensis: a cladistic analysis.
The announcement of a new species, Homo floresiensis, a primitive hominin that survived until relatively recent times is an enormous challenge to paradigms of human evolution. Until this announcement, the dominant paradigm stipulated that: 1) only more derived hominins had emerged from Africa, and 2) H. sapiens was the only hominin since the demise of Homo erectus and Homo neanderthalensis. Resistance to H. floresiensis has been intense, and debate centers on two sets of competing hypotheses: 1) that it is a primitive hominin, and 2) that it is a modern human, either a pygmoid form or a pathological individual. Despite a range of analytical techniques having been applied to the question, no resolution has been reached. Here, we use cladistic analysis, a tool that has not, until now, been applied to the problem, to establish the phylogenetic position of the species. Our results produce two equally parsimonious phylogenetic trees. The first suggests that H. floresiensis is an early hominin that emerged after Homo rudolfensis (1.86Ma) but before H. habilis (1.66Ma, or after 1.9Ma if the earlier chronology for H. habilis is retained). The second tree indicates H. floresiensis branched after Homo habilis.


Confronting the language barrier: Theory of mind in deaf children.
The current study addressed deaf children's Theory of Mind (ToM) development as measured by a battery of first- and second-order belief tasks. Both a chronological age-matched control group and a younger group of pre-school aged hearing children were compared to a group of deaf children born to hearing parents. A hearing native signer enacted each of the tasks, which were pre-recorded in video clips in English (SSE), British Sign Language (BSL) and spoken English, in order to consider all communication preferences of the deaf children. Results revealed no differences in performance between the deaf and the young hearing children. However, despite the inclusion of ToM tasks based on their preferred mode of communication, the deaf children performed significantly worse at the unexpected-content and second-order belief task compared with their age-matched controls. These findings imply a delay rather than a deficit in ToM in deaf children that could be attributed to limited opportunities to converse and overhear conversations about mental states. None.


RCircos: an R package for Circos 2D track plots.
Circos is a Perl language based software package for visualizing similarities and differences of genome structure and positional relationships between genomic intervals. Running Circos requires extra data processing procedures to prepare plot data files and configure files from datasets, which limits its capability of integrating directly with other software tools such as R. Recently published R Bioconductor package ggbio provides a function to display genomic data in circular layout based on multiple other packages, which increases its complexity of usage and decreased the flexibility in integrating with other R pipelines. We implemented an R package, RCircos, using only R packages that come with R base installation. The package supports Circos 2D data track plots such as scatter, line, histogram, heatmap, tile, connectors, links, and text labels. Each plot is implemented with a specific function and input data for all functions are data frames which can be objects read from text files or generated with other R pipelines. RCircos package provides a simple and flexible way to make Circos 2D track plots with R and could be easily integrated into other R data processing and graphic manipulation pipelines for presenting large-scale multi-sample genomic research data. It can also serve as a base tool to generate complex Circos images.


Differing Approaches to Managing the Chronic Breathlessness Syndrome in Advanced COPD: A Multi-National Survey of Specialists.
This study explored the approaches of respiratory and palliative medicine specialists to managing the chronic breathlessness syndrome in patients with severe chronic obstructive pulmonary disease. A voluntary, online survey was emailed to all specialists and trainees in respiratory medicine in Australia and New Zealand (ANZ), and to all palliative medicine specialists and trainees in ANZ and the United Kingdom (UK). Five hundred and seventy-seven (33.0%) responses were received from 1,749 specialists, with 440 (25.2%) complete questionnaires included from 177 respiratory and 263 palliative medicine doctors. Palliative medicine doctors in ANZ and the UK had similar approaches to managing chronic breathlessness, whereas respiratory and palliative medicine doctors had significantly different approaches (p < 0.0001). Both specialties most commonly recommended a combination of non-pharmacological and pharmacological breathlessness management strategies. Respiratory doctors focussed more on pulmonary rehabilitation, whereas palliative medicine doctors recommended breathing techniques, anxiety management and the handheld fan. Palliative medicine doctors (197 (74.9%)) recommended short acting oral morphine for breathlessness, as compared with 73 (41.2%) respiratory doctors (p < 0.0001). Respiratory doctors cited opioid concerns related to respiratory depression and lack of knowledge. Nineteen (10.7%) respiratory doctors made no specific recommendations for managing chronic breathlessness. Both specialties reported actively managing chronic breathlessness, albeit with differing approaches. Integrated services, which combine the complementary knowledge and approaches of both specialities, may overcome current gaps in care and improve the management of distressing, chronic breathlessness.


Client perspectives on an Aboriginal community led oral health service in rural Australia.
An oral health service was implemented, using a unique community development approach, for Northern NSW Australian Aboriginal communities in 2013-14. This study examined the views of children (and parents) who accessed the service, including: the extent of reported dental problems, oral health knowledge, attitudes and behaviour, accessibility of oral health services, satisfaction and cultural sensitivity of the service. A survey of the children who accessed this service was conducted between October 2014 and December 2014. A total of 49 (71%) Aboriginal children aged 4-14 (or parents of), provided responses to the survey. All agreed that healthy teeth were important (100%), but many thought oral disease leading to extraction was normal (68%). High levels of oral pain were reported (66%), half (53%) reported brushing morning and night. Access to the new dental health service was reported as 'easy' (92%). Many walked (47%) or were driven (35%) in <30 min (90%). All respondents were happy with their dental treatment, and that their Aboriginal heritage was respected by the oral health team (100%). The implementation of a new community led oral health service to Northern NSW Aboriginal communities was shown here to be well-utilised, respected and in an area of high need. The collaborative approach could be continued to be utilised to implement targeted, community led health promotion programs to facilitate and encourage better oral health practices for the Aboriginal children in these communities.


The role of genomics in common variable immunodeficiency disorders.
The advent of next-generation sequencing (NGS) and 'omic' technologies has revolutionized the field of genetics, and its implementation in health care has the potential to realize precision medicine. Primary immunodeficiencies (PID) are a group of rare diseases which have benefited from NGS, with a massive increase in causative genes identified in the past few years. Common variable immunodeficiency disorders (CVID) are a heterogeneous form of PID and the most common form of antibody failure in children and adults. While a monogenic cause of disease has been identified in a small subset of CVID patients, a genomewide association study and whole genome sequencing have found that, in the majority, a polygenic cause is likely. Other NGS technologies such as RNA sequencing and epigenetic studies have contributed further to our understanding of the contribution of altered gene expression in CVID pathogenesis. We believe that to unravel further the complexities of CVID, a multi-omic approach, combining DNA sequencing with gene expression, methylation, proteomic and metabolomics data, will be essential to identify novel disease-associated pathways and therapeutic targets.


Canine brucellosis in Costa Rica reveals widespread Brucella canis infection and the recent introduction of foreign strains.
Brucellosis is a prevalent disease in Costa Rica (CR), with an increasing number of human infections. Close to half of homes in CR have one or more dogs, corresponding to ∼1.4 million canines, most of them in the Central Valley within or near the cities of San José, Heredia, and Alajuela. From 302 dog sera collected from this region, 19 were positive for Brucella canis antigens, and five had antibodies against smooth lipopolysaccharide, suggesting infections by both B. canis and other Brucella species. B. canis strains were isolated in the Central Valley from 26 kennel dogs and three pet dogs, all displaying clinical signs of canine brucellosis. We detected three recent introductions of different B. canis strains in kennels: two traced from Mexico and one from Panama. Multiple locus-variable number tandem repeats (MLVA-16) and whole-genome sequencing (WGSA) analyses showed that B. canis CR strains comprise three main lineages. The tree topologies obtained by WGSA and MLVA-16 just partially agreed, indicating that the latter analysis is not suitable for phylogenetic studies. The fatty acid methyl ester analysis resolved five different B. canis groups, showing less resolution power than the MLVA-16 and WGSA. Lactobacillic acid was absent in linages I and II but present in linage III, supporting the recent introductions of B. canis strains from Mexico. B. canis displaying putative functional cyclopropane synthase for the synthesis of lactobacillic acid are phylogenetically intertwined with B. canis with non-functional protein, indicating that mutations have occurred independently in the various lineages.


Thyroid hormone levels and Thyroid Hormone Levels and Ultrasonographic Changes in the Thyroid Gland of Patients on Long-Term Lithium Treatment for Affective Disorders: A Controlled Study.
Although lithium is known to cause thyroid dysfunction and increased thyroid gland volume, clinical examination and biochemical assessment are fundamental to thyroid workup of patients on lithium treatment. We aimed to determine thyroid gland volume and the Thyroid hormone levels of patients who have been receiving lithium treatment for affective disorders in comparison to voluntary healthy controls. This was a cross-sectional, hospital-based observational study which was performed in 43 patients on long-term lithium treatment for bipolar disorder, major depressive and schizoaffective disorders. Patients with documented continuous and adequate serum lithium levels for more than or equal to 6 months recruited consecutively underwent the ultrasonographic examination of the thyroid gland. Ultrasonographic examinations were also done in all gender- and age-matched healthy controls. All cases and controls underwent biochemical thyroid function tests. There were no statistically significant differences in gender (P = 0.198; Chi-square = 1.654) of cases and controls. Most of the cases were married, maximum number of them unemployed and belonged to the lower socioeconomic status. Total thyroid volume was significantly greater in the lithium-treated group than the controls (9.40 ± 1.41 vs. 4.79 ± 0.45). Clinical inspection and palpation only detected goiter in six (n = 6, 13.95%) of patients on lithium and none among controls. The mean triiodothyronine, mean thyroxine, and mean scores for thyroid-stimulating hormone were significantly increased in patients receiving lithium therapy as compared to controls. It would seem wise from a clinical point of view to include ultrasonographic examination of the thyroid gland as part of the standard thyroid workup before initiating lithium treatment.


The PROMIS of QALYs.
Measuring health and health-related quality of life (HRQoL) is important for tracking the health of individuals and populations over time. Generic HRQoL measures allow for comparison across health conditions. One form of generic HRQoL measures are profile measures, which provide a description of health across several different domains (such as physical functioning, depression, and pain). Recent advances in health profile measurement include the development of measures based on item response theory. The Patient-Reported Outcomes Measurement Information System (PROMIS®) has been constructed using this theory. Another form of generic HRQoL measures are utility measures, which assess the value of health states. Multi-attribute utility theory provides a framework for valuing disparate domains of health and aggregating them into a single preference-based score. Such a score provides an overall measure of health outcomes as well as a quality of life weight for use in decision analyses and cost-effectiveness analyses. Developing a utility score for PROMIS® would allow simultaneous estimation of both health profile and utility scores using a single measure. The purpose of this paper is to provide a roadmap of the methodological steps necessary to create such a scoring system.


Anatomic study of the occipital condyle and its surgical implications in transcondylar approach.
Craniovertebral surgeries require the anatomical knowledge of craniovertebral junction. The human occipital condyle (OC) is unique bony structure connecting the cranium and the vertebral column. A lateral approach like transcondylar approach (TA) requires understanding of the relationships between the OC, jugular tubercle, and hypoglossal canal. Hence, the aim of the present study was to analyze the morphological variations in OCs of dry adult human skull. The study was carried out on 142 OC of 71 adult human dry skulls (55 males and 16 females). Morphometric parameters such as length, width, thickness, intercondylar distances, and the distances from the OC to the foramen magnum, hypoglossal canal and jugular foramen were measured. In addition, the different locations of the hypoglossal canal orifices in relation to the OC and different shapes of the OC were also noted. The average length, width and height of the OC were found to be 2.2, 1.1 and 0.9 cm. The anterior and posterior intercondylar distances were 2.1 and 3.9 cm, respectively. Maximum and minimum bicondylar distances were 4.5 and 2.6 cm, respectively. The intra-cranial orifice of the hypoglossal canal was found to be present in middle 1/3(rd) in all skulls (100%), and extra-cranial orifice of the hypoglossal canal was found to be in anterior 1/3(rd) (98%) in relation to OC. The oval shaped OC (22.5%) was the most predominant type of OC observed in these skulls. Occipital condyle is likely to have variations with respect to shape, length, width and its orientation. Therefore, knowledge of the variations in OC along with careful radiological analysis may help in safe TAs during skull base surgery.


Multivalent Cation-Induced Actuation of DNA-Mediated Colloidal Superlattices.
Nanoparticles functionalized with DNA can assemble into ordered superlattices with defined crystal habits through programmable DNA "bonds". Here, we examine the interactions of multivalent cations with these DNA bonds as a chemical approach for actuating colloidal superlattices. Multivalent cations alter DNA structure on the molecular scale, enabling the DNA "bond length" to be reversibly altered between 17 and 3 nm, ultimately leading to changes in the overall dimensions of the micrometer-sized superlattice. The identity, charge, and concentration of the cations each control the extent of actuation, with Ni2+ capable of inducing a remarkable >65% reversible change in crystal volume. In addition, these cations can increase "bond strength", as evidenced by superlattice thermal stability enhancements of >60 °C relative to systems without multivalent cations. Molecular dynamics simulations provide insight into the conformational changes in DNA structure as the bond length approaches 3 nm and show that cations that screen the negative charge on the DNA backbone more effectively cause greater crystal contraction. Taken together, the use of multivalent cations represents a powerful strategy to alter superlattice structure and stability, which can impact diverse applications through dynamic control of material properties, including the optical, magnetic, and mechanical properties.


The structure and histopathology of the "enthesis organ" at the navicular insertion of the tendon of tibialis posterior.
To investigate the structure, histopathology, and molecular composition of tissue specializations of the tibialis posterior enthesis. They collectively reduce stress concentration at the insertion site and are part of an "enthesis organ." This has implications for understanding the basis of enthesopathy. Fifty-two specimens of tibialis posterior and the associated superomedial part of the calcaneonavicular ligament taken from cadavers were sectioned longitudinally and examined by routine histology (42 samples) or immunohistochemistry (10 samples). Serial sections of formalin fixed material were stained with Masson's trichrome, toluidine blue, or hematoxylin, eosin and alcian blue. A panel of antibodies against collagens, glycosaminoglycans, and proteoglycans was used to immunolabel methanol fixed material. The enthesis organ consists of the enthesis itself, the superomedial part of the calcaneonavicular ligament (which may fuse with the tendon), the tendon sheath, and associated accessory bones. The accessory bones lay in a region of fibrocartilage that was present even in specimens where the bones themselves were absent. Degenerative changes were seen at the enthesis, around the accessory bones, and in the walls of the tendon sheath. The navicular and accessory bone entheses, together with the calcaneonavicular ligament, were all rich in fibrocartilage. This immunolabeled for aggrecan, link protein, type II collagen, and versican. The complexity of the enthesis organ, and the diversity of sites showing histopathological changes, suggest that enthesopathy may not be located precisely at the osteotendinous junction. It could target a number of adjacent locations, in accord with what happens at other entheses; e.g., in patients with spondyloarthropathy. The prominence of fibrocartilage in the enthesis organ, and the degenerative changes to which it is subject, support the view that spondyloarthropathy has an underlying biomechanical basis.


Discovery of Synergistic and Antagonistic Drug Combinations against SARS-CoV-2 In Vitro.
COVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide. As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro . Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner. Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2. The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction. Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism. Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections.


Current guidelines for total joint VTE prophylaxis: dawn of a new day.
Venous thromboembolism (VTE) remains an immediate threat to patients following total hip and knee replacement. While there is a strong consensus that steps should be taken to minimise the risk to patients by utilising some forms of prophylaxis for the vast majority of patients, the methods utilised have been extremely variable. Clinical practice guidelines (CPGs) have been published by various professional organisations for over 25 years to provide recommendations to standardise VTE prophylaxis. Historically, these recommendations have varied widely depending in underlying assumptions, goals, and methodology of the various groups. This effort has previously been exemplified by the American College of Chest Physicians (ACCP) and the American Academy of Orthopaedic Surgeons (AAOS). The former group of medical specialists targeted minimising venographically proven deep vein thrombosis (DVT) (the vast majority of which are asymptomatic) as their primary goal prior to 2012. The latter group of surgeons targeted minimising symptomatic VTE. As a result prior to 2012, the recommendations of the two groups were widely divergent. In the past year, both groups have reassessed the current literature with the principal goals of minimising symptomatic VTE events and bleeding complications. As a result, for the first time the CPGs of these two major subspecialty organisations are in close agreement.


Predicting consumer liking and preference based on emotional responses and sensory perception: A study with basic taste solutions.
Traditional methods of sensory testing focus on capturing information about multisensory perceptions, but do not necessarily measure emotions elicited by these food and beverages. The objective of this study was to develop an optimum model of predicting overall liking (rating) and preference (choice) based on taste intensity and evoked emotions. One hundred and two participants (51 females) were asked to taste water, sucrose, citric acid, salt, and caffeine solutions. Their emotional responses toward each sample were measured by a combination of a self-reported emotion questionnaire (EsSense25), facial expressions, and autonomic nervous system (ANS) responses. In addition, their perceived intensity and overall liking were measured. After a break, participants re-tasted the samples and ranked them according to their preference. The results showed that emotional responses measured using self-reported emotion questionnaire and facial expression analysis along with perceived taste intensity performed best to predict overall liking as well as preference, while ANS measures showed limited contribution. Contrary to some previous research, this study demonstrated that not only negative emotions, but also positive ones could help predict consumer liking and preference. In addition, since there were subtle differences in the prediction models of overall liking and preference, both aspects should be taken into account to understand consumer behavior. In conclusion, combination of evoked emotions along with sensory perception could help better understand consumer acceptance as well as preference toward basic taste solutions.


Correlation of office-based cystoscopy and cytology with histologic diagnosis: how good is the reference standard?
To evaluate the accuracy of cystoscopy and cytology in predicting the histopathologic features of suspicious cystoscopic lesions. We reviewed the bladder biopsy records at two institutions from July 2001 to July 2004. Intraoperative biopsies were performed for positive (papillary or sessile) (n = 155) and equivocal (n = 101) lesions found during office cystoscopy. The specimens were submitted for histopathologic analysis, and the results were correlated with the preceding office-based cystoscopy and cytology findings. Malignancy was found in 27 (26.7%) of 101 equivocal lesions and 128 (82.5%) of 155 sessile or papillary lesions. Of the 72 biopsies performed for equivocal lesions in patients with a history of transitional cell carcinoma (TCC), 24 (33%) had malignancy compared with 3 (10.3%) of 29 biopsies performed in patients without a history of TCC. For patients with no history of TCC and equivocal lesions, cytology was able to identify all neoplasms (100% sensitivity) and negative cytology always predicted a normal biopsy result (100% negative predictive value). However, for patients with a history of TCC and equivocal lesions, cytology had a sensitivity and negative predictive value of 81.8% and 88.2%, respectively. Our findings suggest that patients without a history of TCC who have an equivocal lesion at cystoscopy may avoid an unnecessary operation if they have normal cytology findings. A large number of patients with equivocal cystoscopic findings undergo unnecessary biopsies in the operating room, and future studies should be performed to assess the value of other bladder markers in predicting oncologic status in this setting.


Unmet Needs in Managing Myocardial Infarction in Patients With Malignancy.
Patients with cancer face a high short-term risk of arterial thromboembolism. One of the most fatal manifestations of arterial thromboembolism is myocardial infarction (MI), and patients with cancer face a 3-fold greater risk of MI than patients without cancer. The individual risk for arterial thrombotic events in patients with cancer is determined by the complex interaction of baseline cardiovascular risk factors, cancer type and stage, chemotherapeutic regimen, and other general contributing factors for thrombosis. Managing MI in patients with cancer is a clinical challenge, particularly due to cancer's unique pathophysiology, which makes it difficult to balance thrombotic and bleeding risks in this specific patient population. When patients with cancer present with MI, a limited proportion are treated with guideline-recommended therapy, such as antiplatelet therapy or invasive revascularization. Despite the limited evidence, existing reports consistently suggest similar clinical benefits of guideline-recommended therapy when administered to patients with cancer presenting with MI. In this review, we briefly summarize the available evidence, clinical challenges, and future perspectives on simultaneous management of MI and cancer, with a focus on invasive strategy.


Crohn's disease-associated interstitial lung disease mimicking sarcoidosis: a case report and review of the literature.
Respiratory involvement in Crohn's disease (CD) is a rare manifestation known to involve the large and small airways, lung parenchyma, and pleura. The clinical presentation is nonspecific, and diagnostic tests can mimic other pulmonary diseases, posing a diagnostic challenge and delay in treatment. We report a case of a 60-year-old female with a history of CD and psoriatic arthritis who presented with dyspnea, fever, and cough with abnormal radiological findings. Diagnostic testing revealed an elevated CD4:CD8 ratio in the bronchoalveolar lavage fluid, and cryoprobe lung biopsy results showed non-necrotizing granulomatous inflammation. We describe here the second reported case of pulmonary involvement mimicking sarcoidosis in Crohn's disease and a review of the literature on the approaches to making a diagnosis of CD-associated interstitial lung disease.


Counterfactual clinical prediction models could help to infer individualized treatment effects in randomized controlled trials-An illustration with the International Stroke Trial.
Causal treatment effects are estimated at the population level in randomized controlled trials, while clinical decision is often to be made at the individual level in practice. We aim to show how clinical prediction models used under a counterfactual framework may help to infer individualized treatment effects. As an illustrative example, we reanalyze the International Stroke Trial. This large, multicenter trial enrolled 19,435 adult patients with suspected acute ischemic stroke from 36 countries, and reported a modest average benefit of aspirin (vs. no aspirin) on a composite outcome of death or dependency at 6 months. We derive and validate multivariable logistic regression models that predict the patient counterfactual risks of outcome with and without aspirin, conditionally on 23 predictors. The counterfactual prediction models display good performance in terms of calibration and discrimination (validation c-statistics: 0.798 and 0.794). Comparing the counterfactual predicted risks on an absolute difference scale, we show that aspirin-despite an average benefit-may increase the risk of death or dependency at 6 months (compared with the control) in a quarter of stroke patients. Counterfactual prediction models could help researchers and clinicians (i) infer individualized treatment effects and (ii) better target patients who may benefit from treatments.


Little salt spring, Florida: a unique underwater site.
Little Salt Spring in southwest Florida, consisting of a shallow, water-filled basin above a deep, vertical underwater cavern, was a freshwater cenote in the peninsula's drier past. It collected and preserved perishable organic artifacts and other evidence of Paleo-Indian and Archaic Indian origin ranging in age from 12,000 to 9000 and from 6800 to 5200 years ago. An Archaic Period cemetery containing an estimated 1000 burials occupies an adjoining muck-filled slough and presently drowned portions of the basin of the spring. Artifacts and the nature of interment suggest a cultural link between the Archaic people and the much later Glades Tradition of southern Florida.