Bimodal control of Hoxd gene transcription in the spinal cord defines two regulatory subclusters.
The importance of Hox genes in the specification of neuronal fates in the spinal cord has long been recognized. However, the transcriptional controls underlying their collinear expression domains remain largely unknown. Here we show in mice that the correspondence between the physical order of Hoxd genes and their rostral expression boundaries, although respecting spatial collinearity, does not display a fully progressive distribution. Instead, two major anteroposterior boundaries are detected, coinciding with the functional subdivision of the spinal cord. Tiling array analyses reveal two distinct blocks of transcription, regulated independently from one another, that define the observed expression boundaries. Targeted deletions in vivo that remove the genomic fragments separating the two blocks induce ectopic expression of posterior genes. We further evaluate the independent regulatory potential and transcription profile of each gene locus by a tiling array approach using a contiguous series of transgenes combined with locus-specific deletions. Our work uncovers a bimodal type of HoxD spatial collinearity in the developing spinal cord that relies on two separate 'enhancer mini-hubs' to ensure correct Hoxd gene expression levels while maintaining their appropriate anteroposterior boundaries.


Characterization of flounder (Paralichthys olivaceus) FoxD3 and its function in regulating myogenic regulatory factors.
As one member of winged helix domain transcription factors, FoxD3 plays an important role in the regulation of neural crest development and maintenance of mammalian stem cell lineages. A recent study showed that zebrafish FoxD3 is a downstream gene of Pax3 and can mediate the expression of Myf5. To further understand the function of FoxD3 in fish muscle development, we isolated the FoxD3 gene from flounder, and analyzed its expression pattern and function in regulating myogenic regulatory factors, MyoD and Myf5. In situ hybridization showed that flounder FoxD3 was firstly detected in the premigratory neural crest cells at 90% epiboly stage. The FoxD3 was expressed not only in neural crest cells but also in somite cells that will form muscle in the future. When flounder FoxD3 was over-expressed in zebrafish by microinjection, the expressions of zebrafish Myf5 and MyoD were both affected. It is possible that FoxD3 is involved in myogenesis by regulating the expression of Myf5 and MyoD. Also, over-expression of flounder FoxD3 in zebrafish inhibits the expression of zebrafish endogenic FoxD3.


High-resolution volume holographic profilometry using the Viterbi algorithm.
We use the Viterbi decoding algorithm to resolve depth features beyond the nominal resolution limit of a volume holographic profilometry system. The formulation treats the truncated point-spread function as an intersymbol interference and uses surface constraints and transition constraints to reduce the computational complexity. A factor-of-5 improvement in resolution was obtained in our experimental demonstration.


Amino acid sequence in constitutionally isomeric tetrapeptide amphiphiles dictates architecture of one-dimensional nanostructures.
The switching of two adjacent amino acids can lead to differences in how proteins fold thus affecting their function. This effect has not been extensively explored in synthetic peptides in the context of supramolecular self-assembly. Toward this end, we report here the use of isomeric peptide amphiphiles as molecular building blocks to create one-dimensional (1D) nanostructures. We show that four peptide amphiphile isomers, with identical composition but a different sequence of their four amino acids, can form drastically different types of 1D nanostructures under the same conditions. We found that molecules with a peptide sequence of alternating hydrophobic and hydrophilic amino acids such as VEVE and EVEV self-assemble into flat nanostructures that can be either helical or twisted. On the other hand, nonalternating isomers such as VVEE and EEVV result in the formation of cylindrical nanofibers. Furthermore, we also found that when the glutamic acid is adjacent to the alkyl tail the supramolecular assemblies appear to be internally flexible compared to those with valine as the first amino acid. These results clearly demonstrate the significance of peptide side chain interactions in determining the architectures of supramolecular assemblies.


Effects of web-based intervention on risk reduction behaviors in melanoma survivors.
Melanoma is the most severe form of skin cancer, and survivors of melanoma carry increased risk of additional melanoma diagnosis. Multiple methods exist for primary and secondary prevention of melanoma in survivors. This study tested a web-based family communication intervention to improve these preventive behaviors in melanoma families. Families (a survivor, at least one first-degree relative and a parent) were randomized either to receive the intervention package or to serve as comparison families. We assessed melanoma prevention behaviors in each cohort member before and after the intervention. The intervention was a web-based multicomponent intervention focused on increasing family communication and exchange of risk information. Results indicated that, compared to comparison survivors, intervention survivors improved their skin self-examination and their sun protection behaviors significantly from before to after intervention. These data support the use of web-based interventions for behavioral changes in survivors and allow for consideration of dissemination of this successful intervention. These data have implications for interventions that can help cancer families deal with issues of risk and illness. These data indicate that survivors can benefit from exposure to a website that helps direct their future health behaviors.


Neural substrates of cognitive biases during probabilistic inference.
Decision making often requires simultaneously learning about and combining evidence from various sources of information. However, when making inferences from these sources, humans show systematic biases that are often attributed to heuristics or limitations in cognitive processes. Here we use a combination of experimental and modelling approaches to reveal neural substrates of probabilistic inference and corresponding biases. We find systematic deviations from normative accounts of inference when alternative options are not equally rewarding; subjects' choice behaviour is biased towards the more rewarding option, whereas their inferences about individual cues show the opposite bias. Moreover, inference bias about combinations of cues depends on the number of cues. Using a biophysically plausible model, we link these biases to synaptic plasticity mechanisms modulated by reward expectation and attention. We demonstrate that inference relies on direct estimation of posteriors, not on combination of likelihoods and prior. Our work reveals novel mechanisms underlying cognitive biases and contributions of interactions between reward-dependent learning, decision making and attention to high-level reasoning.


Ferroelectric Domain Wall Memristor.
A domain wall-enabled memristor is created, in thin film lithium niobate capacitors, which shows up to twelve orders of magnitude variation in resistance. Such dramatic changes are caused by the injection of strongly inclined conducting ferroelectric domain walls, which provide conduits for current flow between electrodes. Varying the magnitude of the applied electric-field pulse, used to induce switching, alters the extent to which polarization reversal occurs; this systematically changes the density of the injected conducting domain walls in the ferroelectric layer and hence the resistivity of the capacitor structure as a whole. Hundreds of distinct conductance states can be produced, with current maxima achieved around the coercive voltage, where domain wall density is greatest, and minima associated with the almost fully switched ferroelectric (few domain walls). Significantly, this "domain wall memristor" demonstrates a plasticity effect: when a succession of voltage pulses of constant magnitude is applied, the resistance changes. Resistance plasticity opens the way for the domain wall memristor to be considered for artificial synapse applications in neuromorphic circuits.


Curcumin Nanoformulation for Cervical Cancer Treatment.
Cervical cancer is one of the most common cancers among women worldwide. Current standards of care for cervical cancer includes surgery, radiation, and chemotherapy. Conventional chemotherapy fails to elicit therapeutic responses and causes severe systemic toxicity. Thus, developing a natural product based, safe treatment modality would be a highly viable option. Curcumin (CUR) is a well-known natural compound, which exhibits excellent anti-cancer potential by regulating many proliferative, oncogenic, and chemo-resistance associated genes/proteins. However, due to rapid degradation and poor bioavailability, its translational and clinical use has been limited. To improve these clinically relevant parameters, we report a poly(lactic-co-glycolic acid) based curcumin nanoparticle formulation (Nano-CUR). This study demonstrates that in comparison to free CUR, Nano-CUR effectively inhibits cell growth, induces apoptosis, and arrests the cell cycle in cervical cancer cell lines. Nano-CUR treatment modulated entities such as miRNAs, transcription factors, and proteins associated with carcinogenesis. Moreover, Nano-CUR effectively reduced the tumor burden in a pre-clinical orthotopic mouse model of cervical cancer by decreasing oncogenic miRNA-21, suppressing nuclear β-catenin, and abrogating expression of E6/E7 HPV oncoproteins including smoking compound benzo[a]pyrene (BaP) induced E6/E7 and IL-6 expression. These superior pre-clinical data suggest that Nano-CUR may be an effective therapeutic modality for cervical cancer.


Sociotechnical Perspective on Implementing Clinical Video Telehealth for Veterans with Spinal Cord Injuries and Disorders.
Real-time videoconferencing technology such as clinical video telehealth (CVT) offers a means to reach patient populations who face limited access to healthcare. The Veterans Health Administration has invested in CVT to improve care access for U.S. military veterans with spinal cord injuries and disorders (SCI/D); however, no studies have assessed the factors that influence implementation of this technology in clinical practice for individuals with SCI/D. Guided by a sociotechnical perspective, the purpose of this study was to identify factors that influence implementation of CVT for veterans with SCI/D. We conducted semistructured telephone interviews with 40 healthcare providers who use CVT to deliver services to veterans with SCI/D. Factors related to workflow and communication were widely reported as implementation barriers. Coordinating logistics for CVT appointments was challenging, and effective communication between CVT team members across facilities was considered crucial. Providers also cited factors related to technical infrastructure, people, and organizational features, including the need for appropriate equipment, space, personnel, and support for using CVT equipment. The implementation of CVT in the care of veterans with SCI/D was influenced by an interrelated set of social and technical factors. Key among them were social factors related to people, workflow, and communication, given that CVT supports healthcare teams interacting remotely in real time. CVT implementation requires teams working together to negotiate a complex, distributed process across multiple sites. Such complexity places a premium on teamwork and communication among healthcare teams before, during, and after a CVT encounter.


Sensitivity of coral calcification to ocean acidification: a meta-analysis.
To date, meta-analyses of effects of acidification have focused on the overall strength of evidence for statistically significant responses; however, to anticipate likely consequences of ocean acidification, quantitative estimates of the magnitude of likely responses are also needed. Herein, we use random effects meta-analysis to produce a systematically integrated measure of the distribution of magnitudes of the response of coral calcification to decreasing ΩArag . We also tested whether methodological and biological factors that have been hypothesized to drive variation in response magnitude explain a significant proportion of the among-study variation. We found that the overall mean response of coral calcification is ~15% per unit decrease in ΩArag over the range 2 < ΩArag < 4. Among-study variation is large (standard deviation of 8% per unit decrease in ΩArag ). Neither differences in carbonate chemistry manipulation method, study duration, irradiance level, nor study species growth rate explained a significant proportion of the among-study variation. However, studies employing buoyant weighting found significantly smaller decreases in calcification per unit ΩArag (~10%), compared with studies using the alkalinity anomaly technique (~25%). These differences may be due to the greater tendency for the former to integrate over light and dark calcification. If the existing body of experimental work is indeed representative of likely responses of corals in nature, our results imply that, under business as usual conditions, declines in coral calcification by end-of-century will be ~22%, on average, or ~15% if only studies integrating light and dark calcification are considered. These values are near the low end of published projections, but support the emerging view that variability due to local environmental conditions and species composition is likely to be substantial.


PACE-UP (Pedometer and consultation evaluation--UP)--a pedometer-based walking intervention with and without practice nurse support in primary care patients aged 45-75 years: study protocol for a randomised controlled trial.
Most adults do not achieve the 150 minutes weekly of at least moderate intensity activity recommended for health. Adults' most common physical activity (PA) is walking, light intensity if strolling, moderate if brisker. Pedometers can increase walking; however, most trials have been short-term, have combined pedometer and support effects, and have not reported PA intensity. This trial will investigate whether pedometers, with or without nurse support, can help less active 45-75 year olds to increase their PA over 12 months. Primary care-based 3-arm randomized controlled trial with 12-month follow-up and health economic and qualitative evaluations. Less active 45-75 year olds (n = 993) will be recruited by post from six South West London general practices, maximum of two per household and households randomised into three groups. Step-count and time spent at different PA intensities will be assessed for 7 days at baseline, 3 and 12 months by accelerometer. Questionnaires and anthropometric assessments will be completed. The pedometer-alone group will be posted a pedometer (Yamax Digi-Walker SW-200), handbook and diary detailing a 12-week pedometer-based walking programme, using targets from their baseline assessment. The pedometer-plus-support group will additionally receive three practice nurse PA consultations. The handbook, diary and consultations include behaviour change techniques (e.g., self-monitoring, goal-setting, relapse prevention planning). The control group will receive usual care. Changes in average daily step-count (primary outcome), time spent sedentary and in at least moderate intensity PA weekly at 12 months, measured by accelerometry. Other outcomes include change in body mass index, body fat, self-reported PA, quality of life, mood and adverse events. Cost-effectiveness will be assessed by the incremental cost of the intervention to the National Health Service and incremental cost per change in step-count and per quality adjusted life year. Qualitative evaluations will explore reasons for trial non-participation and the interventions' acceptability. The PACE-UP trial will determine the effectiveness and cost-effectiveness of a pedometer-based walking intervention delivered by post or practice nurse to less active primary care patients aged 45-75 years old. Approaches to minimise bias and challenges anticipated in delivery will be discussed. ISRCTN98538934.


Using Vibrating and Cold Device for Pain Relieves in Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
Needle procedures are the most common source of pain, anxiety, and fear among children. A combination of a cooling ice-pack and/or a vibrating motor for pain management in children has been evaluated in trials, but their overall effects await a synthesis of the available evidence. Comprehensive search was conducted using Cochrane, PubMed, EMBASE, PsycINFO, CINAHL and Airiti. We calculated pooled risk ratios (RR), mean difference (MD) and 95% CI using RevMan 5.3. A meta-regression was conducted to investigate the effects of mean age on MD of pain. A total of 1479 children from 16 publications were included. Compared with the control group, using cold-vibrating device significantly decreased pain level above the age of 2 (MD -3.03, 95% CI: -3.38, -2.68), as well as lower anxiety level among parents (MD -1.3, 95% CI: -1.9, -0.7). Meta-regression demonstrated a significant negative correlation of pain score with age. For children at 8.5 years, cold-vibration reduced the pain score by 0.13 averagely for every increment in year compared with controls (MD -0.13; 95% CI: -0.25, -0.01). No adverse events were reported in included studies. The cold-vibrating device reduced pain levels significantly among children without adverse effects. Variation of factors might contribute to the heterogeneity of our study, such as age, different needle procedures, psychological strategies…etc. Cool-vibration treatment reduced pain levels in children who underwent needle procedures and the treatment appears more effective in older children. The device is promising in clinical setting due to its non-invasiveness and ease of usage.


Electrolyte disturbances in foals with severe rhabdomyolysis.
Marked electrolyte abnormalities characterized by profound hyperkalemia, hyponatremia, hypocalcemia, and hyperphosphatemia were noted in 4 neonatal foals with acute rhabdomyolysis and pigmenturia. In 2 foals, rhabdomyolysis developed 4-6 days after admission for dysmaturity, and in 2 foals, rhabdomyolysis was evident on presentation. Rhabdomyolysis was a consequence of selenium deficiency with or without vitamin E deficiency, possibly combined with increased oxidant stress due to sepsis or hypoxia and reperfusion injury after parturition. Foals gained from 7 to 15% of their initial body weight within 48 hours of developing rhabdomyolysis. Three of the foals developed cardiac arrhythmias characterized by spiked T waves and decreased-amplitude P waves. Postmortem examination of 2 foals revealed extensive myodegeneration and renal tubular nephrosis; renal cortical necrosis with myocardial necrosis was noted in 1 foal. Destruction of the major intracellular compartment (intracellular fluid [ICF]) through extensive myonecrosis combined, in some cases, with myoglobinuric renal insufficiency produced major fluid shifts and life-threatening electrolyte derangements. With the major ICF compartment disrupted, hyperkalemia was most effectively treated using mineralocorticoids, loop diuretics, and ion exchange resins to enhance elimination. In addition, i.v. calcium, glucose, insulin, and sodium bicarbonate were administered, which helped redistribute potassium to the ICF. Severe rhabdomyolysis should be included in the differential diagnoses of hyperkalemia, hyponatremia, hypocalcemia, and hyperphosphatemia in neonatal foals.


Environmental implications of adopting a dominant factor approach to salinity management.
Additive or multiplicative models of crop response on which salinity management theory have been developed may lead to an erroneous perception regarding compensative interaction among salinity and other growth factors. We present results from studies of biomass production and transpiration of corn (Zea mays L. cv. Jubilee), melon (Cucumis melo L. subsp. melo cv. Galia), tomato (Lycopersicon esculentum Mill. cv. 5656), onion (Allium cepa L. cv. HA 944), and date palms (Phoenix dactylifera L. cv. Medjool) under salinity combined with water or nitrate (growth promoters) or with boron (growth inhibitor). The measured crop responses were to the more severe stress rather than to combinations of the individual effects of the various stresses. Consequences of shifting management of saline water to a dominant factor approach include reduction of environmental contamination and conservation of water resources.


Polyamine- and NADPH-dependent generation of ROS during Helicobacter pylori infection: A blessing in disguise.
Helicobacter pylori is a Gram-negative bacterium that specifically colonizes the gastric ecological niche. During the infectious process, which results in diseases ranging from chronic gastritis to gastric cancer, the host response is characterized by the activation of the innate immunity of gastric epithelial cells and macrophages. These cells thus produce effector molecules such as reactive oxygen species (ROS) to counteract the infection. The generation of ROS in response to H. pylori involves two canonical pathways: 1) the NADPH-dependent reduction of molecular oxygen to generate O2•-, which can dismute to generate ROS; and 2) the back-conversion of the polyamine spermine into spermidine through the enzyme spermine oxidase, leading to H2O2 production. Although these products have the potential to affect the survival of bacteria, H. pylori has acquired numerous strategies to counteract their deleterious effects. Nonetheless, ROS-mediated oxidative DNA damage and mutations may participate in the adaptation of H. pylori to its ecological niche. Lastly, ROS have been shown to play a major role in the development of the inflammation and carcinogenesis. It is the purpose of this review to summarize the literature about the production of ROS during H. pylori infection and their role in this infectious gastric disease.


Supernatant of endothelial cells exposed to laminar flow inhibits mesangial cell proliferation.
We investigated the effects of culture medium conditioned with endothelial cells exposed to hemodynamic shear forces on modulation of mesangial cell (MC) growth. Confluent monolayers of bovine aortic endothelial cells, grown in medium containing 10% fetal calf serum, were exposed to static or to laminar flow conditions for 24 h using a cone-and-plate device. Endothelial cell-conditioned medium was used to study the growth of bovine MC by [3H]thymidine uptake. The proliferative response of MC to fresh medium (containing 10% fetal calf serum) and to culture medium from endothelial cells under static flow [66.7 +/- 34.1 vs. 73.9 +/- 30.0 counts/min (cpm) x 10(-3)] was comparable. In contrast, medium conditioned with endothelial cells exposed to laminar shear stress of 8 dyn/cm2 almost completely abolished MC proliferation (5.8 +/- 6.9 cpm x 10(-3), P < 0.01). To establish whether this effect is due to endothelial cell production of a substance that inhibits MC proliferation or simply to metabolization of serum growth factors in the culture medium, we performed shear stress experiments using serum free medium and we added 10% fetal calf serum after shear exposure just before the proliferation assay. In this condition a significant antiproliferative effect of endothelial cell supernatant under laminar flow was obtained (27.7 +/- 23.4 vs. 68.8 +/- 45.8 cpm x 10(-3), laminar vs. static, P < 0.05), suggesting that endothelial cells under shear stress effectively produce a factor that inhibits MC proliferation. These results would suggest that local glomerular capillary blood flow could play a role in the regulation of MC mitogenesis.


Changes in lens power in Singapore Chinese children during refractive development.
To examine changes in lens power during refractive development in Singapore Chinese children. Children aged six to nine years from three Singapore schools were invited to participate in the Singapore Cohort study Of the Risk factors for Myopia (SCORM) study. Cycloplegic refractions and biometry were measured annually in the schools over a five year period from 1999. Children were classified into five refractive error groups: persistent hyperopia, emmetropizing hyperopia, persistent emmetropia, newly developed myopia, or persistent myopia. Crystalline lens power was calculated using Bennett's formula. The rate of change per year across the refractive groups was adjusted for age and sex using General Linear Models. There were 1747 children with at least three sets of measurements for lens power calculations. The mean age at baseline was 7.94 ± 0.84 years and the mean spherical equivalent refraction was -0.41 ± 1.71 diopters (D). Lower lens power and lower lens thickness were associated with persistent myopia. As expected, the newly developed myopes and the persistent myopes showed the largest changes in axial length (AL). Changes in lens power and thickness at follow-up were similar in all refractive groups, except for the newly developed myopes, who showed significantly greater decreases in lens power (0.36 vs. 0.29 D/year; P < 0.001) and lens thickness (0.015 vs. 0.0003 mm/year; P < 0.001) than the persistently emmetropic group. Newly developed myopes showed a significantly greater decrease in lens power than other refractive groups, which may be linked to rapid changes in AL and refraction that occur around the onset of myopia.


The effect of honey consumption compared with sucrose on lipid profile in young healthy subjects (randomized clinical trial).
Several studies have demonstrated that honey consumption has beneficial effects on cardiovascular disease indicators. The current study aimed to investigate the effect of honey consumption compared with sucrose on lipid profile among young healthy subjects. Sixty healthy subjects, aged 18-30 years, were randomly recruited into this double blind randomized trial and assigned into two groups: honey (received 70 g honey per day) and sucrose (received 70 g sucrose per day) groups. Total cholesterol, TG, LDL and HDL were measured in the control and intervention groups at the beginning and end of study. In this trial, the baseline FBS, SBP and DBP were not different between honey and sucrose groups (P > 0.3). We found evidence indicating consumption of honey can decrease total cholesterol, TG and LDL and increase HDL in healthy young subjects, but intake of sucrose increase total cholesterol, TG and LDL and decreased HDL. In all of these analyses, confounding variable including age, physical activity and some nutrient intake were adjusted. Honey consumption can improve the lipid profile such as; total cholesterol, TG and LDL and increase HDL, but consumption of sucrose increases total cholesterol, TG and LDL and decreases HDL. Further clinical trial studies are required to confirm our findings.


The effect of renal dysfunction on circulating sclerostin level in patients with type 2 diabetes.
Objective. Sclerostin is a Wnt inhibitor produced specifically by osteocytes. However, it is not currently clear whether renal dysfunction has an effect on circulating sclerostin level in patients with type 2 diabetes. The aim of the study was to evaluate this relationship. Design and Patients. We conducted a cross-sectional observational study of 302 type 2 diabetic patients with or without chronic kidney disease. Serum sclerostin level was analyzed by ELISA, and renal function was assessed by estimated glomerular filtration rate (eGFR) using chronic kidney disease epidemiology collaboration (CKD-EPI) equation. Results. There was a strong correlation between sclerostin level with renal function presented as serum creatinine (r = 0.745, P < 0.001) and eGFR (r = -0.590, P < 0.001). Serum sclerostin level was significantly higher in patients with CKD-G3 stage than those with CKD-G1/2 stages after adjusting for age, sex, and BMI (P = 0.011). Patients with CKD-G4/5 stages had dramatically increased level of circulating sclerostin. Multiple regression analyses found that age, sex, and eGFR were independent determining factors for circulating sclerostin level. Conclusion. Our data showed that serum sclerostin levels start to increase in diabetic patients with CKD-G3 stage. Further studies are needed to establish the potential role of elevated sclerostin in diabetic patients with CKD.


Investigation using whole genome sequencing of a prolonged restaurant outbreak of Salmonella Typhimurium linked to the building drainage system, England, February 2015 to March 2016.
Following notification of a Salmonella enterica serovar Typhimurium gastroenteritis outbreak, we identified 82 cases linked to a restaurant with symptom onset from 12 February 2015 to 8 March 2016. Seventy-two cases had an isolate matching the nationally unique whole genome sequencing profile (single nucleotide polymorphism (SNP) address: 18.104.22.168.395.395). Interviews established exposure to the restaurant and subsequent case-control analysis identified an association with eating carvery buffet food (adjusted odds ratios (AOR): 20.9; 95% confidence interval (CI): 2.2 - ∞). Environmental inspections, food/water testing, and a food trace-back investigation were inconclusive. Repeated cycles of cleaning were undertaken, including hydrogen peroxide fogging, however, transmission continued. After 7 months of investigation, environmental swabbing identified 106 isolates from kitchen surfaces and restaurant drains matching the outbreak profile. We found structural faults with the drainage system and hypothesised that a reservoir of bacteria in drain biofilm and underfloor flooded areas may have sustained this outbreak. Ineffective drain water-traps (U-bends) may have also contributed by allowing transmission of contaminated aerosols into the kitchen environment. These findings suggest that routine swabbing of sink drain points and inspection of drainage systems should be considered in future outbreak scenarios.


Are claims data accurate enough to identify patients for performance measures or quality improvement? The case of diabetes, heart disease, and depression.
The objective of this study was to demonstrate a method to accurately identify patients with specific conditions from claims data for care improvement or performance measurement. In an iterative process of trial case definitions followed by review of repeated random samples of 10 to 20 cases for diabetes, heart disease, or newly treated depression, a final identification algorithm was created from claims files of health plan members. A final sample was used to calculate the positive predictive value (PPV). Each condition had unacceptably low PPVs (0.20, 0.60, and 0.65) when cases were identified on the basis of only 1 International Classification of Diseases, ninth revision, code per year. Requiring 2 outpatient codes or 1 inpatient code within 12 months (plus consideration of medication data for diabetes and extra criteria for depression) resulted in PPVs of 0.97, 0.95, and 0.95. This approach is feasible and necessary for those wanting to use administrative data for case identification for performance measurement or quality improvement.


Agent-specific impact of single trades in financial markets.
We present an analysis of the price impact associated with single trades effected by different financial firms. Using data from the Spanish Stock Market, we find a high degree of heterogeneity across different market members, both in the instantaneous impact functions and in the time-dependent market response to trades by individual members. This heterogeneity is statistically incompatible with the existence of market-wide universal impact dynamics that apply uniformly to all trades and suggest that, rather, market dynamics emerge from the complex interaction of different behaviors of market participants. Several possible reasons for this are discussed, along with potential extensions one may consider to increase the range of applicability of existing models of market impact.


4,5-Substituted C^C* cyclometalated thiazol-2-ylidene platinum(ii) complexes - synthesis and photophysical properties.
We report the synthesis of seven novel backbone functionalized N-phenyl-1,3-thiazol-2-ylidene platinum(ii) complexes and their photophysical properties. Electronically diverse N-phenyl-1,3-thiazol-2-thiones were prepared by a reaction of aniline with carbon disulfide and different α-haloketone compounds. Oxidative desulfuration and salt metathesis yielded the desired NHC-precursors with hexafluorophosphate counterions. In addition, a new route for the synthesis of N-phenyl-1,3-benzo[d]thiazole tetrafluoroborate via N-arylation using hypervalent iodine species is presented. All complexes were prepared from the corresponding NHC precursor in a one-pot process using silver(i)oxide, transmetalation to platinum and reaction with the β-diketone acetylacetone under basic conditions. These complexes exhibit strong phosphorescence with quantum yields up to 72% in 2 wt% PMMA films with decay lifetimes of 8.8-12.3 μs. The influence of methyl- and phenyl-groups, and an ester-substituent at the 4- and/or 5-position of the 1,3-thiazole moiety, as well as the N-phenyl-1,3-benzo[d]thiazole-derived motif is discussed. The 4,5-unsubstituted-N-phenyl-1,3-thiazol-2-ylidene platinum(ii) acetylacetonato complex served as a reference in this study to evaluate the electronic effects originating from the backbone substitution. All complexes emit in a narrow range of the bluish-green spectrum of the visible light (510 ± 10 nm).


The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy.
The discrepancy in results regarding neuroprotective agents in animal experiments compared to clinical trials is a major problem. While many neuroprotective agents have been proven effective in a variety of animal ischemic stroke models, none have been shown to work in phase III clinical trials. This review retrospectively summarizes the neuroprotectants selected for human randomized controlled trials (RCT) and explores the reasons behind the clinical translational failure of these agents. Here, we suggest that there are many factors (model selection, anesthetic choice, physiological monitoring, model success criteria, embolus property, reperfusion damage, infarction area, therapeutic time window, drug penetration, blood concentration, gender difference, and outcome evaluation) responsible for this phenomenon. Ultra-early treatment using a "home run" drug and multi-target therapy may be the most promising for future consideration.


Accuracy of the Hospital Anxiety and Depression Scale Depression subscale (HADS-D) to screen for major depression: systematic review and individual participant data meta-analysis.
To evaluate the accuracy of the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) to screen for major depression among people with physical health problems. Systematic review and individual participant data meta-analysis. Medline, Medline In-Process and Other Non-Indexed Citations, PsycInfo, and Web of Science (from inception to 25 October 2018). Eligible datasets included HADS-D scores and major depression status based on a validated diagnostic interview. Primary study data and study level data extracted from primary reports were combined. For HADS-D cut-off thresholds of 5-15, a bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, in studies that used semi-structured diagnostic interviews (eg, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders), fully structured interviews (eg, Composite International Diagnostic Interview), and the Mini International Neuropsychiatric Interview. One stage meta-regression was used to examine whether accuracy was associated with reference standard categories and the characteristics of participants. Sensitivity analyses were done to assess whether including published results from studies that did not provide raw data influenced the results. Individual participant data were obtained from 101 of 168 eligible studies (60%; 25 574 participants (72% of eligible participants), 2549 with major depression). Combined sensitivity and specificity was maximised at a cut-off value of seven or higher for semi-structured interviews, fully structured interviews, and the Mini International Neuropsychiatric Interview. Among studies with a semi-structured interview (57 studies, 10 664 participants, 1048 with major depression), sensitivity and specificity were 0.82 (95% confidence interval 0.76 to 0.87) and 0.78 (0.74 to 0.81) for a cut-off value of seven or higher, 0.74 (0.68 to 0.79) and 0.84 (0.81 to 0.87) for a cut-off value of eight or higher, and 0.44 (0.38 to 0.51) and 0.95 (0.93 to 0.96) for a cut-off value of 11 or higher. Accuracy was similar across reference standards and subgroups and when published results from studies that did not contribute data were included. When screening for major depression, a HADS-D cut-off value of seven or higher maximised combined sensitivity and specificity. A cut-off value of eight or higher generated similar combined sensitivity and specificity but was less sensitive and more specific. To identify medically ill patients with depression with the HADS-D, lower cut-off values could be used to avoid false negatives and higher cut-off values to reduce false positives and identify people with higher symptom levels. PROSPERO CRD42015016761.


Electron spin resonance study of light-induced conformational changes in nitroxide labelled bovine rhodopsin.
Bovine rhodopsin was isolated in the unbleached form as a retinal disc membrane suspension and spin-labelled with 4-maleimido-2,2,6,6-tetramethylpiperidine-N-oxyl. Both conventional and saturation transfer electron spin resonance methods were used to investigate the sensitivity of the spin-label to conformational changes of rhodopsin induced by both transient and long-term exposure to light. The results indicate that the ESR methods do display sensitivity to such changes. An exponential decay curve with a time constant of 10 s was obtained by following the height of a single peak in the saturation transfer electron spin resonance spectrum in response to a single light flash.


Inherited renal cysts in rats.
A strain of rats that form renal cysts has been developed. The number of visible cysts increases with age after animals are 20 days old. Micropuncture studies indicate that the cystic fluid has a variable sodium concentration, but that the ratios of inulin concentration in tubular fluid to that in plasma are high.


A systematic review of the antipsychotic properties of cannabidiol in humans.
Despite extensive study over the past decades, available treatments for schizophrenia are only modestly effective and cause serious metabolic and neurological side effects. Therefore, there is an urgent need for novel therapeutic targets for the treatment of schizophrenia. A highly promising new pharmacological target in the context of schizophrenia is the endocannabinoid system. Modulation of this system by the main psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), induces acute psychotic effects and cognitive impairment. However, the non-psychotropic, plant-derived cannabinoid agent cannabidiol (CBD) may have antipsychotic properties, and thus may be a promising new agent in the treatment of schizophrenia. Here we review studies that investigated the antipsychotic properties of CBD in human subjects. Results show the ability of CBD to counteract psychotic symptoms and cognitive impairment associated with cannabis use as well as with acute THC administration. In addition, CBD may lower the risk for developing psychosis that is related to cannabis use. These effects are possibly mediated by opposite effects of CBD and THC on brain activity patterns in key regions implicated in the pathophysiology of schizophrenia, such as the striatum, hippocampus and prefrontal cortex. The first small-scale clinical studies with CBD treatment of patients with psychotic symptoms further confirm the potential of CBD as an effective, safe and well-tolerated antipsychotic compound, although large randomised clinical trials will be needed before this novel therapy can be introduced into clinical practice.


Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen.
Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, may be the infectious cause of KS. Its prevalence in the general population, on the basis of detection of the virus genome, is controversial. To investigate the seroprevalence, we measured antibodies to a recombinant capsid-related (lytic cycle) KSHV antigen and a latent antigen complex. We selected potentially immunoreactive capsid-related proteins of KSHV by expressing them as recombinant proteins and testing them in western blot assays. We used a truncated recombinant protein encoded by KSHV open reading frame 65 (orf 65) to develop a diagnostic enzyme-linked immunosorbent assay (ELISA) and tested sera from HIV-infected individuals with KS, HIV-uninfected patients with "classic" KS, other HIV risk groups, and blood donors. We also compared the antibody response to this capsid-related protein to the response to latent antigen(s) in an immunofluorescence assay. 77/92 (84%) sera from KS patients reacted with the KSHV orf 65 protein and 84/103 (81.5%) reacted with KSHV latent antigen(s). The dominant immunogenic region of orf 65 is within the carboxyterminal 80 aminoacids, a region with little sequence similarity to the related Epstein-Barr virus, suggesting that orf 65 is a KSHV specific antigen. Only three sera from patients with haemophilia (1/84) or from intravenous drug users (2/63) had KSHV specific antibodies in the orf 65 assay whereas none of these sera reacted with latent antigen. Antibodies to KSHV were also infrequently found in UK and US blood donors by either assay (UK, 3/174 with orf 65 and 4/150 with latent antigen; US, 6/117 with orf 65 and 0/117 with latent antigen). They were more common among HIV-infected gay men without KS (5/16 by orf 65 ELISA, 10/33 by IFA), HIV-uninfected STD clinic attenders (14/166 by IFA), and Ugandan HIV-uninfected controls (6/17 by orf 65 ELISA, 9/17 by IFA). Antibody reactivity to the orf 65 protein (ELISA) and to latent antigen(s) (IFA) was concordant in 89% of 462 sera tested but reactive blood donor sera were discordant in both assays. Four AIDS-KS sera were unreactive in both assays. The distribution of antibodies to both a capsid-related recombinant protein and latent antigen(s) of KSHV strongly supports the view that infection with this virus is largely confined to individuals with, or at increased risk for, KS. However, infection with KSHV does occur, rarely, in the general UK and US population and is more common in Uganda. Antibodies to latent antigen(s) or to orf 65 encoded capsid protein will not detect all cases of KSHV infection, and a combination of several antigens will probably be required for accurate screening and confirmatory assays.


General purpose graphics-processing-unit implementation of cosmological domain wall network evolution.
Topological defects unavoidably form at symmetry breaking phase transitions in the early universe. To probe the parameter space of theoretical models and set tighter experimental constraints (exploiting the recent advances in astrophysical observations), one requires more and more demanding simulations, and therefore more hardware resources and computation time. Improving the speed and efficiency of existing codes is essential. Here we present a general purpose graphics-processing-unit implementation of the canonical Press-Ryden-Spergel algorithm for the evolution of cosmological domain wall networks. This is ported to the Open Computing Language standard, and as a consequence significant speedups are achieved both in two-dimensional (2D) and 3D simulations.


Measurement of left ventricular dimensions with contrast-enhanced three-dimensional cine imaging facilitated by k-t SENSE.
To compare three-dimensional (3D) k-t sensitivity encoded (k-t SENSE) cine cardiovascular magnetic resonance (CMR), before and after contrast administration, against standard 2D imaging for the assessment of left ventricular volumes and mass. Twenty-six subjects (14 volunteers, 12 patients) underwent multiple breathhold 2D balanced turbo-field echo cine CMR in addition to k-t SENSE accelerated 3D imaging (acceleration factor 5; 5x k-t SENSE), performed before and after administration of a high-relaxivity gadolinium-based contrast agent (Gadobutrolum). k-t acceleration factors of 7 and 10 were also assessed in six volunteers. Left ventricular end diastolic volume (EDV), end systolic volume (ESV), mass, and ejection fraction (EF) were calculated for each method. There was at least moderate agreement between the EDV, ESV, mass and EF calculated by 2D and 3D 5x k-t SENSE methods before contrast (concordance coefficients 0.92, 0.95, 0.97, 0.92, respectively). Agreement improved following contrast (concordance coefficients 0.97, 0.99, 0.98, 0.93, respectively). The 3D method underestimated all parameters compared to 2D (mean bias pre-contrast 6.1 ml, 0.6 ml, 3.5 g, 2.0% respectively). 3D image quality scores were significantly poorer than 2D, showing a non-significant trend to improvement following contrast administration. Parameters derived with k-t acceleration factors of 7 and 10 showed poorer agreement with 2D values. Left ventricular volumes and mass are reliably assessed using 3D 5x k-t SENSE accelerated CMR. Contrast administration further improves agreement between 5x k-t SENSE and 2D-derived measurements. k-t acceleration factors greater than 5, though feasible, produce poorer agreement with 2D values.


A reliable method for evaluating upper molar distalization: Superimposition of three-dimensional digital models.
The aim of this study was to evaluate the reliability of measurements obtained after the superimposition of three-dimensional (3D) digital models by comparing them with those obtained from lateral cephalometric radiographs and photocopies of plaster models for the evaluation of upper molar distalization. Data were collected from plaster models and lateral cephalometric radiographs of 20 Class II patients whose maxillary first molars were distalized with an intraoral distalizer. The posterior movements of the maxillary first molars were evaluated using lateral cephalometric radiographs (group CP), photocopies of plaster models (group PH), and digitized 3D models (group TD). Additionally, distalization and expansion of the other teeth and the degrees of molar rotation were measured in group PH and group TD and compared between the two groups. No significant difference was observed regarding the amount of molar distalization among the three groups. A comparison of the aforementioned parameters between group PH and group TD did not reveal any significant difference. 3D digital models are reliable to assess the results of upper molar distalization and can be considered a valid alternative to conventional measurement methods.


Bordetella pertussis diagnosis in children under five years of age in the Regional Hospital of Cajamarca, Northern Peru.
Bordetella pertussis is an important human pathogen that causes whooping cough (pertussis), an endemic illness responsible of significant morbidity and mortality, especially in infants and children. Worldwide, there are an estimated of 16 million cases of pertussis, resulting in about 195,000 child deaths per year. In Peru, pertussis is a major health problem that has been on the increase despite immunization efforts. The objective of this study was to determine the prevalence of B. pertussis among children under five years of age suspected to have whopping cough in Cajamarca, Peru. Children diagnosed with whooping cough admitted to the Hospital Regional de Cajamarca from August 2010 to July 2013 were included. Nasopharyngeal samples were obtained for B. pertussis culture and polymerase chain reaction (PCR) detection. In 133 children, the pertussis toxin and IS481 gene were detected in 38.35% (51/133) of the cases by PCR, while only 9.02% (12/133) of the Bordetella cultures were positive. The most frequent symptoms in patients with positive B. pertussis were paroxysm of coughing 68.63% (35/51), cyanosis 56.86% (29/51), respiratory distress 43.14% (22/51), and fever 39.22% (20/51). Pneumonia and acute bronchial obstructive syndrome were present in 17.65% (9/51) and 13.72% (7/51) of the cases, respectively. B. pertussis is responsible for an important proportion of whooping cough in hospitalized children in Cajamarca. Epidemiologic surveillance programs for B. pertussis are essential in Peru, especially in children who could most benefit from the vaccine.


Alpha-1,2-mannosidase and hence N-glycosylation are required for regulatory T cell migration and allograft tolerance in mice.
Specific immunological unresponsiveness to alloantigens can be induced in vivo by treating mice with a donor alloantigen in combination with a non-depleting anti-CD4 antibody. This tolerance induction protocol enriches for alloantigen reactive regulatory T cells (Treg). We previously demonstrated that alpha-1,2-mannosidase, an enzyme involved in the synthesis and processing of N-linked glycoproteins, is highly expressed in tolerant mice, in both graft infiltrating leukocytes and peripheral blood lymphocytes. In this study we have identified that alpha-1,2-mannosidase expression increases in CD25(+)CD4(+) Treg when they encounter alloantigen in vivo. When alpha-1,2-mannosidase enzyme activity was blocked, Treg retained their capacity to suppress T cell proliferation in vitro but were unable to bind to physiologically relevant ligands in vitro. Further in vivo analysis demonstrated that blocking alpha-1,2-mannosidase in Treg resulted in the migration of significantly lower numbers to the peripheral lymph nodes in skin grafted mice following adoptive transfer, where they were less able to inhibit the proliferation of naïve T cells responding to donor alloantigen and hence unable prevent allograft rejection in vivo. Taken together, our results suggest that activation of alloantigen reactive Treg results in increased alpha-1,2-mannosidase expression and altered N-glycosylation of cell surface proteins. In our experimental system, altered N-glycosylation is not essential for intrinsic Treg suppressive capacity, but is essential in vivo as it facilitates Treg migration to sites where they can regulate immune priming. Migration of Treg is central to their role in regulating in vivo immune responses and may require specific changes in N-glycosylation upon antigen encounter.


The moderating role of different sources of perceived social support on the dispositional optimism-- posttraumatic growth relationship in postoperative breast cancer patients.
The purpose of this study was to investigate the dispositional optimism-posttraumatic growth (PTG) relationship in postoperative breast cancer patients and to examine if perceived social support moderates this relationship. The study was conducted with 104 women undergoing postoperative chemotherapy treatment or coming to the hospital for their routine controls. Hierarchical multiple regression analyses indicated that breast cancer survivors high on dispositional optimism and perceived social support, are more likely to develop PTG. Among the different sources of social support, only social support perceived from a private person moderated the dispositional optimism-PTG relationship. Strengths, limitations and possible implications of the findings are discussed.


Astaxanthin reduces hepatic lipid accumulations in high-fat-fed C57BL/6J mice via activation of peroxisome proliferator-activated receptor (PPAR) alpha and inhibition of PPAR gamma and Akt.
We have previously reported that astaxanthin (AX), a dietary carotenoid, directly interacts with peroxisome proliferator-activated receptors PPARα and PPARγ, activating PPARα while inhibiting PPARγ, and thus reduces lipid accumulation in hepatocytes in vitro. To investigate the effects of AX in vivo, high-fat diet (HFD)-fed C57BL/6J mice were orally administered AX (6 or 30mg/kg body weight) or vehicle for 8weeks. AX significantly reduced the levels of triglyceride both in plasma and in liver compared with the control HFD mice. AX significantly improved liver histology and thus reduced both steatosis and inflammation scores of livers with hematoxylin and eosin staining. The number of inflammatory macrophages and Kupffer cells were reduced in livers by AX administration assessed with F4/80 staining. Hepatic PPARα-responsive genes involved in fatty acid uptake and β-oxidation were upregulated, whereas inflammatory genes were downregulated by AX administration. In vitro radiolabeled assays revealed that hepatic fatty acid oxidation was induced by AX administration, whereas fatty acid synthesis was not changed in hepatocytes. In mechanism studies, AX inhibited Akt activity and thus decreased SREBP1 phosphorylation and induced Insig-2a expression, both of which delayed nuclear translocation of SREBP1 and subsequent hepatic lipogenesis. Additionally, inhibition of the Akt-mTORC1 signaling axis by AX stimulated hepatic autophagy that could promote degradation of lipid droplets. These suggest that AX lowers hepatic lipid accumulation in HFD-fed mice via multiple mechanisms. In addition to the previously reported differential regulation of PPARα and PPARγ, inhibition of Akt activity and activation of hepatic autophagy reduced hepatic steatosis in mouse livers.


Novel use of proton beam therapy for neoadjuvant treatment of radiation-associated squamous cell carcinoma of the esophagus.
Secondary esophageal cancers from prior thoracic radiation therapy are rare but challenging cases to deliver standard combined modality therapy as part of a curative approach. In patients with prior exposure to cardiopulmonary-toxic chemotherapy or radiotherapy, management requires meticulous multidisciplinary evaluation given the morbidity associated with surgery in the previously irradiated thorax and re-irradiation of the spinal cord, heart, and lungs. Oftentimes, suboptimal treatment regimens, either with compromised radiation coverage, attenuated chemotherapy doses, or exclusion of surgery, are required to avoid significant toxicity. The physical properties inherent to protons allow for optimal coverage of tumor while achieving remarkably low dose to surrounding normal tissue compared to standard photon treatment. Proton therapy has been studied across various disease sites and may facilitate treatment intensification for radiation-associated esophageal tumors. While no comparative studies have evaluated the efficacy and safety of protons versus photons for esophageal cancer, three cases of radiation-associated esophageal cancer presented in this series are exemplary to highlight the benefit of protons in this unique clinical circumstance. The technical considerations in planning, including passively scattered versus pencil-beam scanning technique, as well as the clinical course and tolerance to treatment, are discussed, which may guide consideration of this advanced treatment modality in this disease site.


Parallel synthesis and splicing redirection activity of cell-penetrating peptide conjugate libraries of a PNA cargo.
A novel method for the parallel synthesis of peptide-biocargo conjugates was developed that utilizes affinity purification for fast isolation of the conjugates in order to avoid time consuming HPLC purification. The methodology was applied to create two libraries of cell-penetrating peptide (CPP)-PNA705 conjugates from parallel-synthesized peptide libraries. The conjugates were tested for their ability to induce splicing redirection in HeLa pLuc705 cells. The results demonstrate how the novel methodology can be applied for screening purposes in order to find suitable CPP-biocargo combinations and further optimization of CPPs.


Results of the seven-year prospective study of stroke patients.
Using the registry method, 1,538 stroke patients were detected in one district of Moscow between January 1, 1972, and December 31, 1974. Of the 965 patients who survived the acute stage of stroke (the first 3 weeks after onset), 941 (505 women and 436 men) were followed for the next 7 years. We analyzed incidence and types of recurrent strokes. During this 7-year follow-up, we recorded 32.1% of the patients as having recurrent strokes, most of which developed in the first 3 years and especially during the first year after the index stroke. The majority of recurrent strokes were of the same type as the index stroke and were localized in the same area of the brain. The cumulative mortality rates for the initial 1,538 patients were 37.3% dead by 3 weeks, 63.6% dead by 3 years, 72.1% dead by 5 years, and 76.5% dead by 7 years. In the first 3 months (excluding the first 3 weeks), most patients who died died of pulmonary thromboembolism. The mortality rate from recurrent strokes and pneumonia was higher than that from cardiovascular mortality. Transient ischemic attacks occurred in 49.5% of all patients and myocardial infarction in 16.4%. Functional prognosis was determined mainly by age, motor function, and concomitant diseases. After 1 year, 68.2% of the surviving patients were fully independent, while 81% of those surviving 7 years had reached this level. A significant number of patients were capable of returning to their previous work.


Neurogenesis and developmental anesthetic neurotoxicity.
The mechanism by which anesthetics might act on the developing brain in order to cause long term deficits remains incompletely understood. The hippocampus has been identified as a structure that is likely to be involved, as rodent models show numerous deficits in behavioral tasks of learning that are hippocampal-dependent. The hippocampus is an unusual structure in that it is the site of large amounts of neurogenesis postnatally, particularly in the first year of life in humans, and these newly generated neurons are critical to the function of this structure. Intriguingly, neurogenesis is a major developmental event that occurs during postulated windows of vulnerability to developmental anesthetic neurotoxicity across the different species in which it has been studied. In this review, we examine the evidence for anesthetic effects on neurogenesis in the early postnatal period and ask whether neurogenesis should be studied further as a putative mechanism of injury. Multiple anesthetics are considered, and both in vivo and in vitro work is presented. While there is abundant evidence that anesthetics act to suppress neurogenesis at several different phases, evidence of a causal link between these effects and any change in learning behavior remains elusive.


A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial.
A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.


Revision with cementless acetabular components: a concise follow-up, at a minimum of twenty years, of previous reports.
The purpose of the present study was to analyze the longer-term results for a previously reported cohort of patients who were managed with cementless acetabular fixation at the time of revision arthroplasty. Sixty-one consecutive revision total hip arthroplasties were performed in fifty-five patients with use of a cementless acetabular component and screw-augmented fixation. This series was evaluated at minimum of twenty years. Twelve patients (fourteen hips) were living at twenty years. In this group of sixty-one arthroplasties, there were nineteen revisions in fourteen hips (22.9%) during the follow-up period, but no revisions were performed because of loosening of the acetabular component and no additional cups had loosened since the time of the last report at a minimum of ten years. Two components had previously been reported as loose and had migrated, but neither had been revised at the time of the latest follow-up. The minimum twenty-year follow-up of these cementless acetabular components demonstrated durable long-term fixation. The survival rate was 100% with revision of the shell because of aseptic loosening as the end point and 97.7% (95% confidence interval, ± 8.8%) with radiographic evidence of loosening as the end point. The authors continue to use cementless acetabular fixation with screw augmentation for most revision total hip arthroplasty procedures. Therapeutic Level IV.


Ethnic/racial homogeneity and sexually transmitted disease: a study of 77 Chicago community areas.
Sexually transmitted diseases (STDs) remain an intractable public health problem in the United States. Wide ethnic and racial disparities persist in the rates of reported STDs. Blacks and Hispanics have higher rates of chlamydia and gonorrhea than European Americans. With data collected in 2002 from 77 well defined communities in Chicago, we examined the association of ethnic/racial homogeneity of the communities and incidence of chlamydia and gonorrhea. The multivariate regression models controlled for other sociodemographic variables. Communities where at least 60% of the residents were black had significantly higher incidence rates of these 2 STDs compared with communities where at least 60% of the residents were Hispanic. Independent of ethnic/racial homogeneity of the community, the incidence of these STDs was higher in communities that had a larger percentage of persons living in poverty, a larger percentage unemployed, fewer high school graduates, and more residents between the ages of 15 and 44. The challenge for public health authorities is to consider policy options that respond not only to sexual risk behaviors, but also to the contextual attitudes, cultural traditions, and norms, and social circumstances in ethnically homogeneous communities that may affect the spread of STDs in disadvantaged urban populations.


Association Between NCAP Ratings and Real-World Rear Seat Occupant Risk of Injury.
Several studies have evaluated the correlation between U.S. or Euro New Car Assessment Program (NCAP) ratings and injury risk to front seat occupants, in particular driver injuries. Conversely, little is known about whether NCAP 5-star ratings predict real-world risk of injury to restrained rear seat occupants. The NHTSA has identified rear seat occupant protection as a specific area under consideration for improvements to its NCAP. In order to inform NHTSA's efforts, we examined how NCAP's current 5-star rating system predicts risk of moderate or greater injury among restrained rear seat occupants in real-world crashes. We identified crash-involved vehicles, model year 2004-2013, in NASS-CDS (2003-2012) with known make and model and nonmissing occupant information. We manually matched these vehicles to their NCAP star ratings using data on make, model, model year, body type, and other identifying information. The resultant linked NASS-CDS and NCAP database was analyzed to examine associations between vehicle ratings and rear seat occupant injury risk; risk to front seat occupants was also estimated for comparison. Data were limited to restrained occupants and occupant injuries were defined as any injury with a maximum Abbreviated Injury Scale (AIS) score of 2 or greater. We linked 95% of vehicles in NASS-CDS to a specific vehicle in NCAP. The 18,218 vehicles represented an estimated 6 million vehicles with over 9 million occupants. Rear seat passengers accounted for 12.4% of restrained occupants. The risk of injury in all crashes for restrained rear seat occupants was lower in vehicles with a 5-star driver rating in frontal impact tests (1.4%) than with 4 or fewer stars (2.6%, P =.015); results were similar for the frontal impact passenger rating (1.3% vs. 2.4%, P =.024). Conversely, side impact driver and passenger crash tests were not associated with rear seat occupant injury risk (driver test: 1.7% for 5-star vs. 1.8% for 1-4 stars; passenger test: 1.6% for 5 stars vs 1.8% for 1-4 stars). Current frontal impact test procedures provide some degree of discrimination in real-world rear seat injury risk among vehicles with 5 compared to fewer than 5 stars. However, there is no evidence that vehicles with a 5-star side impact passenger rating, which is the only crash test procedure to include an anthropomorphic test dummy (ATD) in the rear, demonstrate lower risks of injury in the rear than vehicles with fewer than 5 stars. These results support prioritizing modifications to the NCAP program that specifically evaluate rear seat injury risk to restrained occupants of all ages.


Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus.
The amyloid beta protein has been identified as an important component of both cerebrovascular amyloid and amyloid plaques of Alzheimer's disease and Down syndrome. A complementary DNA for the beta protein suggests that it derives from a larger protein expressed in a variety of tissues. Overexpression of the gene in brain tissue from fetuses with Down syndrome (trisomy 21) can be explained by dosage since the locus encoding the beta protein maps to chromosome 21. Regional localization of this gene by both physical and genetic mapping places it in the vicinity of the genetic defect causing the inherited form of Alzheimer's disease.


Modal liquid crystal wavefront corrector.
Results are presented of the properties of a liquid crystal wavefront corrector for adaptive optics. The device is controlled using modal addressing in which case the device behaves more like a continuous facesheet deformable mirror than a segmented one. Furthermore, the width and shape of the influence functions are electrically controllable. We describe the construction of the device, the optical properties, and we show experimental results of low order aberration generation.


The social structural production of HIV risk among injecting drug users.
There is increasing appreciation of the need to understand how social and structural factors shape HIV risk. Drawing on a review of recently published literature, we seek to describe the social structural production of HIV risk associated with injecting drug use. We adopt an inclusive definition of the HIV 'risk environment' as the space, whether social or physical, in which a variety of factors exogenous to the individual interact to increase vulnerability to HIV. We identify the following factors as critical in the social structural production of HIV risk associated with drug injecting: cross-border trade and transport links; population movement and mixing; urban or neighbourhood deprivation and disadvantage; specific injecting environments (including shooting galleries and prisons); the role of peer groups and social networks; the relevance of 'social capital' at the level of networks, communities and neighbourhoods; the role of macro-social change and political or economic transition; political, social and economic inequities in relation to ethnicity, gender and sexuality; the role of social stigma and discrimination in reproducing inequity and vulnerability; the role of policies, laws and policing; and the role of complex emergencies such as armed conflict and natural disasters. We argue that the HIV risk environment is a product of interplay in which social and structural factors intermingle but where political-economic factors may play a predominant role. We therefore emphasise that much of the most needed 'structural HIV prevention' is unavoidably political in that it calls for community actions and structural changes within a broad framework concerned to alleviate inequity in health, welfare and human rights.


Mineralocorticoid receptors in pulmonary hypertension and right heart failure: From molecular biology to therapeutic targeting.
Pulmonary hypertension (PH) is a devastating condition characterized by pulmonary vascular remodelling, leading to progressive increase in pulmonary artery pressure and subsequent right ventricular failure. Aldosterone and the mineralocorticoid receptor (MR), a nuclear transcription factor, are key drivers of cardiovascular disease and MR antagonists are well-established in heart failure. Now, a growing body of evidence points at a detrimental role of MR in PH. Pharmacological MR blockade attenuated PH and prevented RV failure in experimental models. Mouse models with cell selective MR deletion suggest that this effect is mediated by MR in endothelial cells. While the evidence from experimental studies appears convincing, the available clinical data on MR antagonist use in patients with PH is more controversial. Integrated analysis of clinical data together with MR-dependent molecular alterations may provide insights why some patients respond to MRA treatment while others do not. Potential ways to identify MRA 'responders' include the analysis of underlying PH causes, stage of disease, or sex, as well as new biomarkers.


Experimental iron deficiency in rats: mechanical and electrophysiological alterations in the cardiac muscle.
1. Our aim was to investigate the effect of experimental iron deficiency on cardiac functional properties. We recorded ventricular isometric twitch, action potentials and the L-type Ca2+ current in isolate ventricular myocytes from iron-deficient rats and control rats. 2. Twitch tension and maximal rates of tension activation and relaxation were reduced in iron-deficient compared with control rats, whereas twitch duration was prolonged. Isoproterenol (10-(6) mol/l) augmented tension in iron-deficient rats (P < 0.05), but only moderately affected control rats. In contrast, maximal rates of tension activation and relaxation were increased equally by isoproterenol in the two groups. 3. To determine the mechanism(s) responsible for the reduced mechanical function in iron-deficient rats, action potentials and the L-type Ca2+ current (with or without isoproterenol) were recorded in both groups. 4. The L-type Ca2+ current was smaller in ventricular myocytes from control rats than in those from iron-deficient rats; at a membrane potential of 0 mV, L-type Ca2+ current amplitudes were -1.44 +/- 0.18 and -0.97 +/- 0.07 nA in myocytes from control and iron-deficient rats respectively (P < 0.05). 5. Action potential duration was markedly shortened in myocytes from iron-deficient compared with control rats; action potential duration at 50% repolarization was 12.0 +/- 1.6 and 7.2 +/- 1.4 ms in myocytes from control and iron-deficient rats respectively (P < 0.01). These iron deficiency-induced electrophysiological alterations most probably contribute to the depressed mechanical function in iron-deficient rats. 6. The L-type Ca2+ current was augmented equally by isoproterenol in the two groups, suggesting that the enhanced inotropic responsiveness in iron-deficient rats was not due to an increased response of the L-type Ca2+ current. 7. These results may have an important implication for anaemic (iron-deficient) patients; the attenuation of their cardiac mechanical performance may be compensated by an increased reactivity to beta-adrenergic stimulation.


Influence of lifestyle patterns on perceptions of obesity and overweight among expatriates in Abha city of Kingdom of Saudi Arabia.
We evaluated the influence of lifestyle patterns such as watching TV, working with computer and idle sitting time on perceptions of obesity and beliefs about overweight are associated with obesity and overweight amongst Expatriates in Abha. The method used in this study was a cross-sectional survey with a self-administered paper-based questionnaire. The survey collected information on lifestyle choices and the risk factors that contribute to obesity. In addition, height and weight were measured. Greater number of our study subjects spent over 2 h/day without any physical activity, specifically accounting for over 2 h/day each in viewing TV, computer, and spending idle time. This increased lack of physical activities was significantly associated with overweight. While the overweight subjects were aware of very wide options for treating their condition, a significant number believed in self-effort in managing their diet and exercise regimen as the best efforts to reduce their overweight. Interestingly very few overweight subjects considered medication or surgery as a potential therapeutic option and 75% of the overweight subjects considered overweight to be of no or only slight concern on wellbeing. Overweight and obesity among expatriates within Saudi Arabia poses an important public health problem. The lack of awareness about the potential impact of obesity on health and optimal treatment options is a serious concern, which needs to be addressed by appropriate public health programs at national level.


Molecular Characterization of Monocyte Subsets Reveals Specific and Distinctive Molecular Signatures Associated With Cardiovascular Disease in Rheumatoid Arthritis.
Objectives: This study, developed within the Innovative Medicines Initiative Joint Undertaking project PRECISESADS framework, aimed at functionally characterize the monocyte subsets in RA patients, and analyze their involvement in the increased CV risk associated with RA. Methods: The frequencies of monocyte subpopulations in the peripheral blood of 140 RA patients and 145 healthy donors (HDs) included in the PRECISESADS study were determined by flow cytometry. A second cohort of 50 RA patients and 30 HDs was included, of which CD14+ and CD16+ monocyte subpopulations were isolated using immuno-magnetic selection. Their transcriptomic profiles (mRNA and microRNA), proinflammatory patterns and activated pathways were evaluated and related to clinical features and CV risk. Mechanistic in vitro analyses were further performed. Results: CD14++CD16+ intermediate monocytes were extended in both cohorts of RA patients. Their increased frequency was associated with the positivity for autoantibodies, disease duration, inflammation, endothelial dysfunction and the presence of atheroma plaques, as well as with the CV risk score. CD14+ and CD16+ monocyte subsets showed distinctive and specific mRNA and microRNA profiles, along with specific intracellular signaling activation, indicating different functionalities. Moreover, that specific molecular profiles were interrelated and associated to atherosclerosis development and increased CV risk in RA patients. In vitro, RA serum promoted differentiation of CD14+CD16- to CD14++CD16+ monocytes. Co-culture with RA-isolated monocyte subsets induced differential activation of endothelial cells. Conclusions: Our overall data suggest that the generation of inflammatory monocytes is associated to the autoimmune/inflammatory response that mediates RA. These monocyte subsets, -which display specific and distinctive molecular signatures- might promote endothelial dysfunction and in turn, the progression of atherosclerosis through a finely regulated process driving CVD development in RA.


Establishing health insurance exchanges: three states' progress.
California, Colorado, and Maryland were among the first states to enact legislation establishing health insurance exchanges called for in the Affordable Care Act. This brief outlines differences that stand out in the states' initial approaches: the numbers and types of people initially appointed to the boards governing the exchanges; the role of the board relative to the state legislature; how the exchanges interact with existing insurance markets; and the involvement of stakeholders in each state. The decisions made by these states provide information that will be useful for other states implementing their exchanges. Going forward, these states will face a more challenging set of decisions, including how to finance the exchanges, how to make risk-adjusted payments to insurers for people likely to have high medical expenses, and how to avoid gaps in coverage and care for people who may have changes in income.


Alternatives to Animal Use in Risk Assessment of Mixtures.
Risk assessment of chemical mixtures has emerged as a focus of research efforts, but traditional toxicology testing in mammals is costly, time-consuming, and subject to ethical scrutiny in the context of recent trends to reduce reliance on animal testing. In this review, which is a summary of presentations given at a workshop in Havana, Cuba, in April 2019, we survey the utility of zebra fish as an alternative laboratory model in whole-mixture and component-based testing, as well as in vitro modeling in 3-dimensional organotypic cultures from primary human cells cultured at the air-liquid interface and organ-on-a-chip platforms. Finally, we discuss the complexities of assessing the dynamics and delivery of multispecies liquid aerosol mixtures along the human respiratory tract, with examples of alternative and computational approaches to aerosol dosimetry. The workshop contributed to the professional development of Cuban toxicologists, an underserved segment of the global scientific community, delivering a set of tools and recommendations that could potentially provide cost-effective solutions for scientists with limited research resources.


HEPATOCELLULAR CARCINOMA: DIAGNOSIS AND OPERATIVE MANAGEMENT.
Hepatocellular carcinoma is an aggressive malignant tumor with high lethality. To review diagnosis and management of hepatocellular carcinoma. Literature review using web databases Medline/PubMed. Hepatocellular carcinoma is a common complication of hepatic cirrhosis. Chronic viral hepatitis B and C also constitute as risk factors for its development. In patients with cirrhosis, hepatocelular carcinoma usually rises upon malignant transformation of a dysplastic regenerative nodule. Differential diagnosis with other liver tumors is obtained through computed tomography scan with intravenous contrast. Magnetic resonance may be helpful in some instances. The only potentially curative treatment for hepatocellular carcinoma is tumor resection, which may be performed through partial liver resection or liver transplantation. Only 15% of all hepatocellular carcinomas are amenable to operative treatment. Patients with Child C liver cirrhosis are not amenable to partial liver resections. The only curative treatment for hepatocellular carcinomas in patients with Child C cirrhosis is liver transplantation. In most countries, only patients with hepatocellular carcinoma under Milan Criteria are considered candidates to a liver transplant. Hepatocellular carcinoma is potentially curable if discovered in its initial stages. Medical staff should be familiar with strategies for early diagnosis and treatment of hepatocellular carcinoma as a way to decrease mortality associated with this malignant neoplasm.


Radiomic Features Are Superior to Conventional Quantitative Computed Tomographic Metrics to Identify Coronary Plaques With Napkin-Ring Sign.
Napkin-ring sign (NRS) is an independent prognostic imaging marker of major adverse cardiac events. However, identification of NRS is challenging because of its qualitative nature. Radiomics is the process of extracting thousands of quantitative parameters from medical images to create big-data data sets that can identify distinct patterns in radiological images. Therefore, we sought to determine whether radiomic analysis improves the identification of NRS plaques. From 2674 patients referred to coronary computed tomographic angiography caused by stable chest pain, expert readers identified 30 patients with NRS plaques and matched these with 30 non-NRS plaques with similar degree of calcification, luminal obstruction, localization, and imaging parameters. All plaques were segmented manually, and image data information was analyzed using Radiomics Image Analysis package for the presence of 8 conventional and 4440 radiomic parameters. We used the permutation test of symmetry to assess differences between NRS and non-NRS plaques, whereas we calculated receiver-operating characteristics' area under the curve values to evaluate diagnostic accuracy. Bonferroni-corrected P<0.0012 was considered significant. None of the conventional quantitative parameters but 20.6% (916/4440) of radiomic features were significantly different between NRS and non-NRS plaques. Almost half of these (418/916) reached an area under the curve value >0.80. Short- and long-run low gray-level emphasis and surface ratio of high attenuation voxels to total surface had the highest area under the curve values (0.918; 0.894 and 0.890, respectively). A large number of radiomic features are different between NRS and non-NRS plaques and exhibit excellent discriminatory value.


Use of intracellular cytokine staining and bacterial superantigen to document suppression of the adaptive immune system in injured patients.
To determine the percentages of major T lymphocyte subsets in the circulating peripheral blood mononuclear cell population in patients with major traumatic injury at early and late time points and to determine the expression of coreceptors and cytokine production by these T cell subsets. Prior studies suggest that serious injury in humans suppresses the adaptive immune system as revealed by diminished proliferation and altered cytokine production in response to polyclonal T cell activation. However, the contribution of individual cell types to this immune dysfunction has not been well characterized. The percentage of circulating CD4+ and CD8+ T cells and the relative density of CD4 and CD8 coreceptor expression was determined by flow cytometry in 17 consecutive trauma patients (injury severity score > 20) within 24 hours of injury and at day 7. Intracellular expression of the cytokines interleukin 2 (IL-2), interferon gamma (IFNgamma), IL-4, and IL-10 were also studied after stimulation with bacterial superantigen (SEB). Patients were compared with age- and sex-matched controls and to themselves for differences between early and late cytokine expression. The percentage of circulating CD4+ and CD8+ T cells was decreased versus controls at day 1 and further decreased by day 7 following injury. CD4 and CD8 cell surface expression was also decreased at days 1 and 7. CD4+ T cells in injured patients responded to SEB activation with decreased expression of IFNgamma and IL-2 on day 1 versus controls (P < 0.05) and of all 4 cytokines by day 7 (P < 0.05), while CD8+ T cells showed diminished expression of IFNgamma and IL-2 only at both time points. When day 1 and day 7 cytokine expression results were compared in the same patients, CD4+ T cells showed diminished expression of IFNgamma, IL-2, and IL-4 by day 7 (P < 0.05), but maintained expression of IL-10. CD8 T cells showed diminished expression of IFNgamma only. Severe injury induces a loss of circulating CD4+ and CD8+ T lymphocytes and diminished coreceptor expression by these cells. Both T cell subsets show progressive loss of immunostimulatory cytokine production with maintenance of potentially suppressive IL-10 production. These events may have negative consequences for host defense.


Firearm Prevalence and Homicides of Law Enforcement Officers in the United States.
In the United States, state firearm ownership has been correlated with homicide rates. More than 90% of homicides of law enforcement officers (LEOs) are committed with firearms. We examined the relationship between state firearm ownership rates and LEO occupational homicide rates. We obtained the number LEOs killed from 1996 to 2010 from a Federal Bureau of Investigation (FBI) database. We calculated homicide rates per state as the number of officers killed per number of LEOs per state, obtained from another FBI database. We obtained the mean household firearm ownership for each state from the Behavioral Risk Factor Surveillance System. Using Poisson regression and controlling for factors known to affect homicide rates, we associated firearm ownership with the homicide rates for LEOs (incidence rate ratio = 1.044; P = .005); our results were supported by cross-sectional and longitudinal sensitivity analyses. LEO homicide rates were 3 times higher in states with high firearm ownership compared with states with low firearm ownership. High public gun ownership is a risk for occupational mortality for LEOs in the United States. States could consider methods for reducing firearm ownership as a way to reduce occupational deaths of LEOs.


Cardio-cerebrovascular protective effects of valsartan in high-risk hypertensive patients with coronary artery disease (from the Kyoto Heart Study).
The objective was to examine whether previous coronary artery disease (CAD) influences the add-on effects of the angiotensin II receptor blocker (ARB) valsartan on cardio-cerebrovascular morbidity and mortality in high-risk hypertensive patients who participated in the Kyoto Heart Study. The primary end point was the same as in the main study: a composite of new-onset and/or worsening of cardiovascular and cerebrovascular events. Median follow-up was 3.27 years. According to the presence of previous CAD at baseline, the study population was divided into 2 groups (with CAD, n = 707; without CAD, n = 2,324) in which primary end-point events occurred more frequently in patients with CAD than in patients without CAD (15.1% vs 5.6%, hazard ratio [HR] 2.68, 95% confidence interval [CI] 2.11 to 3.42). Add-on valsartan significantly decreased the occurrence of the primary end-point events in patients with CAD (11.3% vs 19.0%, HR 0.59, 95% CI 0.41 to 0.85) and without CAD (3.7% vs 7.6%, HR 0.49, 95% CI 0.34 to 0.70) compared to non-ARB treatment. In the presence of previous CAD, patients with valsartan add-on treatment had a significantly lower prevalence of angina pectoris and stroke than those with non-ARB treatment, whereas the valsartan add-on effects on angina and stroke were not significant in the absence of CAD. Changes in blood pressure during the follow-up period did not differ significantly between study subgroups. In conclusion, in the presence or absence of previous CAD, valsartan add-on treatment prevented more cardio-cerebrovascular events than conventional non-ARB treatment in high-risk hypertensive patients. In addition, valsartan add-on treatment conferred not only an antianginal effect but also stroke prevention exclusively in hypertensive patients with CAD compared to those without CAD.


Clinical Significance of Tumour-Infiltrating B Lymphocytes (TIL-Bs) in Breast Cancer: A Systematic Literature Review.
Although T lymphocytes have been considered the major players in the tumour microenvironment to induce tumour regression and contribute to anti-tumour immunity, much less is known about the role of tumour-infiltrating B lymphocytes (TIL-Bs) in solid malignancies, particularly in breast cancer, which has been regarded as heterogeneous and much less immunogenic compared to other common tumours like melanoma, colorectal cancer and non-small cell lung cancer. Such paucity of research could translate to limited opportunities for this most common type of cancer in the UK to join the immunotherapy efforts in this era of precision medicine. Here, we provide a systematic literature review assessing the clinical significance of TIL-Bs in breast cancer. Articles published between January 2000 and April 2022 were retrieved via an electronic search of two databases (PubMed and Embase) and screened against pre-specified eligibility criteria. The majority of studies reported favourable prognostic and predictive roles of TIL-Bs, indicating that they could have a profound impact on the clinical outcome of breast cancer. Further studies are, however, needed to better define the functional role of B cell subpopulations and to discover ways to harness this intrinsic mechanism in the fight against breast cancer.


On handling ephemeral resource constraints in evolutionary search.
We consider optimization problems where the set of solutions available for evaluation at any given time t during optimization is some subset of the feasible space. This model is appropriate to describe many closed-loop optimization settings (i.e., where physical processes or experiments are used to evaluate solutions) where, due to resource limitations, it may be impossible to evaluate particular solutions at particular times (despite the solutions being part of the feasible space). We call the constraints determining which solutions are non-evaluable ephemeral resource constraints (ERCs). In this paper, we investigate two specific types of ERC: one encodes periodic resource availabilities, the other models commitment constraints that make the evaluable part of the space a function of earlier evaluations conducted. In an experimental study, both types of constraint are seen to impact the performance of an evolutionary algorithm significantly. To deal with the effects of the ERCs, we propose and test five different constraint-handling policies (adapted from those used to handle standard constraints), using a number of different test functions including a fitness landscape from a real closed-loop problem. We show that knowing information about the type of resource constraint in advance may be sufficient to select an effective policy for dealing with it, even when advance knowledge of the fitness landscape is limited.


Telecommunicator Cardiopulmonary Resuscitation: A Policy Statement From the American Heart Association.
Every year in the United States, >350 000 people have sudden cardiac arrest outside of a hospital environment. Sudden cardiac arrest is the unexpected loss of heart function, breathing, and consciousness and is commonly the result of an electric disturbance in the heart. Unfortunately, only ≈1 in 10 victims survives this dramatic event. Early access to 9-1-1 and early cardiopulmonary resuscitation (CPR) are the first 2 links in the chain of survival for out-of-hospital cardiac arrest. Although 9-1-1 is frequently accessed, in the majority of cases, individuals with out-of-hospital cardiac arrest do not receive lay rescuer CPR and wait for the arrival of professional emergency rescuers. Telecommunicators are the true first responders and a critical link in the cardiac arrest chain of survival. In partnership with the 9-1-1 caller, telecommunicators have the first opportunity to identify a patient in cardiac arrest and provide initial care by delivering CPR instructions while quickly dispatching emergency medical services. The telecommunicator and the caller form a unique team in which the expertise of the telecommunicator is provided just in time to a willing caller, transforming the caller into a lay rescuer delivering CPR. The telecommunicator CPR (T-CPR) process, also previously described as dispatch CPR, dispatch-assisted CPR, or telephone CPR, represents an important opportunity to improve survival from sudden cardiac arrest. Conversely, failure to provide T-CPR in this manner results in preventable harm. This statement describes the public health impact of out-of-hospital cardiac arrest, provides guidance and resources to construct and maintain a T-CPR program, outlines the minimal acceptable standards for timely and high-quality delivery of T-CPR instructions, and identifies strategies to overcome common implementation barriers to T-CPR.


Biliary complications of cystic fibrosis.
One hundred and four adult patients with cystic fibrosis were evaluated for the presence of liver disease as defined by abnormal liver function tests of six months' duration, histological evidence of fibrosis or cirrhosis, or the presence of portal hypertension, or both. Twenty patients fulfilled these criteria and were evaluated further for the presence of biliary tract abnormalities with biliary scintigraphy using 99Tc diisopropylphenyl-carboxymethyl iminodiacetic acid (DISIDA) and endoscopic retrograde cholangiography. Clearance of 99Tc DISIDA from the liver and biliary tree was diminished at 45 (E45) and 60 (E60) minutes in the patients with liver disease compared with those without liver disease; E45 = 37.8% and 65.8%, p less than 0.01; E60 = 48.2% and 77.5%, p less than 0.01 respectively. Serial analogue images of the extrahepatic biliary tree were consistent with common bile duct obstruction with retention of DISIDA and tapering of the common bile duct in seven of 18 patients with and two of 10 patients without liver disease. Endoscopic retrograde cholangiography showed changes consistent with sclerosing cholangitis, with beading and stricturing of the intrahepatic ducts in 12 of the 14 patients. In all 14 patients, including those in whom biliary scintigraphy had suggested obstruction, no abnormality of the common bile duct was identified. These results indicate that abnormalities of the bile ducts in patients with cystic fibrosis related liver disease are confined to the intrahepatic biliary tree and that common bile duct strictures do not contribute to either the progression or development of liver disease in these patients.


Soy intake is associated with increased 2-hydroxylation and decreased 16alpha-hydroxylation of estrogens in Asian-American women.
In Asian and Asian-American women, soy consumption is associated with reduced breast cancer risk, perhaps due to its effects on estrogen production or metabolism. In a sample of Asian-American women, we investigated the associations of usual adult soy intake with the urinary concentrations of 15 estrogens and estrogen metabolites (EM) measured using liquid chromatography-tandem mass spectrometry. Participants included 430 Chinese-American, Japanese-American, and Filipino-American women, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California), or Oahu (Hawaii). They were postmenopausal (n = 167) or premenopausal in luteal phase (n = 263) when 12-hour urine samples were collected. Robust linear regression was used to assess soy tertiles as predictors of log-transformed EM measures. Individual and grouped EM were considered as concentrations (pmol/mg creatinine) and as percentages of total EM (%EM). Factor analysis confirmed that EM groups defined by metabolic pathways appropriately captured covariation in EM profiles. Total EM concentrations were not significantly associated with soy in premenopausal or postmenopausal women. Among all women, %2-hydroxylated EM and %4-hydroxylation pathway EM were 16% higher (P(trend) = 0.02) and 19% higher (P(trend) = 0.03) in the highest versus lowest soy tertiles, respectively. In contrast, 16% hydroxylated EM were 11% lower (P(trend) < 0.01). Results were consistent across ethnic and menopausal groups and after adjustment for westernization measured by birthplace (Asia or United States). Findings suggest that regular soy intake is associated with increased ratios of 2:16-pathway EM and with higher relative levels of 4-hydroxylated EM. The observed variations in estrogen metabolism might modify breast cancer risk.


Beliefs and behavior of Malaysia undergraduate female students in a public university toward breast self-examination practice.
Breast cancer is the most common cancer and the second principal cause of cancer deaths among women worldwide, including Malaysia. A cross-sectional study was carried out among 262 female undergraduate students in University Putra Malaysia using a validated questionnaire which was developed for this study. The mean age of respondents was 22∓2.3 years. Most of them were single (83.1%), Malay (42.3%) and 20.7% reported having a family history of breast cancer. Eighty-seven (36.7%) claimed they had practiced BSE. Motivation and self-efficacy of the respondents who performed BSE were significantly higher compared with women who did not (p<0.05).There was no association between BSE practice and demographic details (p<0.05). Logistic regression analysis indicated that women who perceived greater motivation (OR=1.089, 95%CI: 1.016-1.168) and had higher confidence of BSE (OR=1.076, 95%CI: 1.028-1.126) were more likely to perform the screening. The findings show that Malaysian young female's perception regarding breast cancer and the practice of BSE is low. Targeted education should be implemented to improve early detection of breast cancer.