Possible hemodynamic basis to urethane anesthesia-induced reductions in renal clearance.
The hemodynamic basis of reported urethane anesthesia-induced reductions in the clearance of some renally eliminated compounds has been investigated in the laboratory rat. The use of urethane as an anesthetic in pharmacokinetic studies still persists, particularly in experiments of long duration. Using a microsphere technique, the per cent distribution of cardiac output to the kidneys, in both ip urethane- and ip Hypnorm/Hypnovel-anesthetized animals was significantly (p less than 0.01) lower than that observed in ip pentobarbital-anesthetized animals. However, the cardiac index in the Hypnorm/Hypnovel-anesthetized animals was 42% greater (p less than 0.01) than in the pentobarbital-treated animals and 86% greater (p less than 0.01) than in the urethane-treated group. Additionally, the cardiac index in the pentobarbital-anesthetized animals was significantly greater (p less than 0.01) than in the urethane-anesthetized animals. The lower cardiac index and reduced cardiac distribution to the kidneys in the urethane-treated group resulted in significant (p less than 0.01) reductions of approximately 40% in renal blood flow and glomerular filtration rate compared with the animals anesthetized with pentobarbital or Hypnorm/Hypnovel. The transport capacity of the basolateral organic anion secretory mechanism was not compromised by an ip injection of urethane, as demonstrated by p-aminohippuric acid transport studies conducted in isolated renal tubule fragments prepared from anesthetized animals. In conclusion, urethane anesthesia results in significant alterations of renal hemodynamics compared with pentobarbital and Hypnorm/Hypnovel anesthesia in the rat. For primarily renally eliminated compounds, such alterations are likely to influence pharmacokinetic data generated using this anesthetic agent.


Prospective evaluation of alcohol consumption and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
Given the adverse effect of alcohol in the development of breast cancer among women in the general population, we evaluated whether a similar association exists among women with a BRCA1 or BRCA2 mutation. Information regarding baseline daily alcohol consumption was abstracted from a research questionnaire for 3067 BRCA mutation carriers enrolled in a prospective cohort study. Women were followed biennially until the date of the last follow-up questionnaire, date of breast cancer diagnosis, date of prophylactic bilateral mastectomy, or date of death. Cox proportional hazards models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for invasive breast cancer associated with alcohol consumed at or prior to completion of the baseline questionnaire. After a mean of 5.4 years of follow-up, we observed 259 incident cases of primary invasive breast cancer. Compared with non-users, the adjusted RRs were 1.06 (95 % CI 0.78-1.44) for ever use and 1.08 (0.79-1.47) for current alcohol use. For women in the highest versus lowest quintile of cumulative alcohol consumption, the RR was 0.94 (95 % CI 0.63-1.40; P trend = 0.65). Our findings suggest that alcohol consumption is not a risk factor for breast cancer among women with a BRCA1 or BRCA2 mutation.


[Differential neuronal loss in the hippocampus in normal aging and in patients with Alzheimer disease].
The causal relationship between the neurodegenerative changes that accompany normal ageing and those that characterize Alzheimer's disease is unclear. The high incidence of Alzheimer's disease associated with old age and the presence of its neuropathological signs in non-demented older individuals suggest that these two phenomena involve the same neurodegenerative processes and mechanisms and that Alzheimer's disease is an extension of normal ageing. On the other hand, the identification of environmental and genetic risk factors associated with Alzheimer's disease suggests the involvement of a specific disease process that is not related to normal ageing. The resolution of this fundamental issue is of importance in the design of investigative and therapeutic strategies. In this report, we describe differences in the regional patterns of neuronal loss, in the hippocampal region of the brains of Alzheimer's patients and normal ageing subjects, that indicate that Alzheimer's disease is not the manifestation of accelerated ageing, but the expression of a distinct pathological process.


Obstetric accidents: the patient's perspective.
Cases from the files of Action for Victims of Medical Accidents which had resulted in stillbirth, perinatal or neonatal death and long term mental or physical handicap were reviewed. In 41 cases there was both a detailed letter from the parents and an independent review by a senior obstetrician. The reviewer's main criticisms were of inadequate fetal heart monitoring, lack of involvement of senior staff and inadequate records. The fetal heart trace was missing in 7 cases and over half of the remaining 34 traces available were misinterpreted or not acted on. In 17 cases junior doctors failed to recognize fetal distress and managed a delivery that they did not have the experience to deal with. In a further 6 cases, senior staff were called but did not come. Records were criticized for being incomplete, illegible or missing. In a few cases unjustified alterations appeared to have been made. Women reported that on some occasions staff ignored their worries, were unsympathetic and gave too little information. Some parents also experienced considerable difficulty in obtaining a clear explanation of the nature and cause of their child's condition.


MITO-Tag Mice enable rapid isolation and multimodal profiling of mitochondria from specific cell types in vivo.
Mitochondria are metabolic organelles that are essential for mammalian life, but the dynamics of mitochondrial metabolism within mammalian tissues in vivo remains incompletely understood. While whole-tissue metabolite profiling has been useful for studying metabolism in vivo, such an approach lacks resolution at the cellular and subcellular level. In vivo methods for interrogating organellar metabolites in specific cell types within mammalian tissues have been limited. To address this, we built on prior work in which we exploited a mitochondrially localized 3XHA epitope tag (MITO-Tag) for the fast isolation of mitochondria from cultured cells to generate MITO-Tag Mice. Affording spatiotemporal control over MITO-Tag expression, these transgenic animals enable the rapid, cell-type-specific immunoisolation of mitochondria from tissues, which we verified using a combination of proteomic and metabolomic approaches. Using MITO-Tag Mice and targeted and untargeted metabolite profiling, we identified changes during fasted and refed conditions in a diverse array of mitochondrial metabolites in hepatocytes and found metabolites that behaved differently at the mitochondrial versus whole-tissue level. MITO-Tag Mice should have utility for studying mitochondrial physiology, and our strategy should be generally applicable for studying other mammalian organelles in specific cell types in vivo.


Regulation of Lipid Specific and Vitamin Specific Non-MHC Restricted T Cells by Antigen Presenting Cells and Their Therapeutic Potentials.
Since initial reports, more than 25 years ago, that T cells recognize lipids in the context on non-polymorphic CD1 molecules, our understanding of antigen presentation to non-peptide-specific T cell populations has deepened. It is now clear that αβ T cells bearing semi-invariant T cell receptor, as well as subsets of γδ T cells, recognize a variety of self and non-self lipids and contribute to shaping immune responses via cross talk with dendritic cells and B cells. Furthermore, it has been demonstrated that small molecules derived from the microbial riboflavin biosynthetic pathway (vitamin B2) bind monomorphic MR1 molecules and activate mucosal-associated invariant T cells, another population of semi-invariant T cells. Novel insights in the biological relevance of non-peptide-specific T cells have emerged with the development of tetrameric CD1 and MR1 molecules, which has allowed accurate enumeration and functional analysis of CD1- and MR1-restricted T cells in humans and discovery of novel populations of semi-invariant T cells. The phenotype and function of non-peptide-specific T cells will be discussed in the context of the known distribution of CD1 and MR1 molecules by different subsets of antigen-presenting cells at steady state and following infection. Concurrent modulation of CD1 transcription and lipid biosynthetic pathways upon TLR stimulation, coupled with efficient lipid antigen processing, result in the increased cell surface expression of antigenic CD1-lipid complexes. Similarly, MR1 expression is almost undetectable in resting APC and it is upregulated following bacterial infection, likely due to stabilization of MR1 molecules by microbial antigens. The tight regulation of CD1 and MR1 expression at steady state and during infection may represent an important mechanism to limit autoreactivity, while promoting T cell responses to foreign antigens.


Islet-1 Is essential for pancreatic β-cell function.
Islet-1 (Isl-1) is essential for the survival and ensuing differentiation of pancreatic endocrine progenitors. Isl-1 remains expressed in all adult pancreatic endocrine lineages; however, its specific function in the postnatal pancreas is unclear. Here we determine whether Isl-1 plays a distinct role in the postnatal β-cell by performing physiological and morphometric analyses of a tamoxifen-inducible, β-cell-specific Isl-1 loss-of-function mouse: Isl-1(L/L); Pdx1-CreER(Tm). Ablating Isl-1 in postnatal β-cells reduced glucose tolerance without significantly reducing β-cell mass or increasing β-cell apoptosis. Rather, islets from Isl-1(L/L); Pdx1-CreER(Tm) mice showed impaired insulin secretion. To identify direct targets of Isl-1, we integrated high-throughput gene expression and Isl-1 chromatin occupancy using islets from Isl-1(L/L); Pdx1-CreER(Tm) mice and βTC3 insulinoma cells, respectively. Ablating Isl-1 significantly affected the β-cell transcriptome, including known targets Insulin and MafA as well as novel targets Pdx1 and Slc2a2. Using chromatin immunoprecipitation sequencing and luciferase reporter assays, we found that Isl-1 directly occupies functional regulatory elements of Pdx1 and Slc2a2. Thus Isl-1 is essential for postnatal β-cell function, directly regulates Pdx1 and Slc2a2, and has a mature β-cell cistrome distinct from that of pancreatic endocrine progenitors.


The Amsterdam Growth and Health Longitudinal Study: how important is physical activity in youth for later health? (ELS 33).
Three important results came from the Amsterdam Growth and Health Longitudinal Study (AGAHLS). This study followed three birth cohorts (1962, 1963 and 1964) of boys and girls in the Amsterdam region in the Netherlands. The follow-up period was 25 years, with 10 measurements from age 12 to 42 years. The main purpose of the AGAHLS was to detect changes in health and lifestyle over time during the teenage and young adult period. In total, 617 subjects were recruited from two secondary schools in Amsterdam and Purmerend. We measured aerobic fitness (VO2 peak), bone mineral density (BMD), obesity from body mass index (BMI) and body fatness from the sum of four skinfolds (S4S). Daily physical activity (DPA) was measured from heart rate, pedometers and an interview. Daily food intake (DFI) was measured by a cross-check dietary history interview. Longitudinal data analyses revealed that: (1) aerobic fitness, as measured by direct measurement of maximal oxygen uptake (VO2 max), increased more significantly in the physically active percentile (P > 75) of males and females than in the physically inactive percentile (P < 25), (2) BMD, as measured with dual X-ray absorptiometry (DEXA) in the wrist, hip and lumbar region, showed that physical activity in youth with a high mechanical load on the bones (mostly weight bearing) increased bone formation in the hip and lumbar region of males and females in adulthood, (3) the longitudinal relationship between DPA and DFI with the development of overweight and obesity (measured from BMI and S4S) showed that more DPA resulted in significantly lower fat mass, but no relationship could be demonstrated with DFI . The main conclusion from this 25-year longitudinal research is that the promotion of physical activity (including physical education and sport) in adolescence can potentially be a strong tool to prevent chronic diseases and reduce healthcare costs later in life.


Stochastic blockmodels with a growing number of classes.
We present asymptotic and finite-sample results on the use of stochastic blockmodels for the analysis of network data. We show that the fraction of misclassified network nodes converges in probability to zero under maximum likelihood fitting when the number of classes is allowed to grow as the root of the network size and the average network degree grows at least poly-logarithmically in this size. We also establish finite-sample confidence bounds on maximum-likelihood blockmodel parameter estimates from data comprising independent Bernoulli random variates; these results hold uniformly over class assignment. We provide simulations verifying the conditions sufficient for our results, and conclude by fitting a logit parameterization of a stochastic blockmodel with covariates to a network data example comprising self-reported school friendships, resulting in block estimates that reveal residual structure.


Review of litter turning during a grow-out as a litter management practice to achieve dry and friable litter in poultry production.
Maintaining dry litter that chickens can "work" is a key objective for successful meat chicken production as it reduces the likelihood of health and welfare issues by breaking down and working excreta and contributing to the water evaporation process. Litter turning is a practice that may help reduce moisture content within the litter by accelerating the drying process when it is combined with effective ventilation. However, information and research about the practice and the effects it could have on the health and well-being of meat chickens (broilers) are minimal. A recent survey of Australian meat chicken growers reiterated the concerns they have about its impact on chicken well-being, but it also demonstrated how growers thought it could enhance the effectiveness of their operation. The aim of this review paper is to identity information relevant to litter turning and the potential effects of this practice on litter quality, ammonia emissions, litter moisture, and animal welfare. This review demonstrates the need for additional research to validate perceptions and address potential concerns and impacts that this practice may have on broiler production. Closing this knowledge gap will improve litter turning practices leading to safer and more consistent outcomes.


Importance of generational status in examining access to and utilization of health care services by Mexican American children.
To describe the sociodemographic differences among Mexican American children (first, second, and third generation), non-Hispanic black children, and non-Hispanic white children; to compare the health status and health care needs of Mexican American children (first, second, and third generation) with those of non-Hispanic black children and non-Hispanic white children; and to determine whether first-generation Mexican American children have poorer health care access and utilization than do non-Hispanic white children, after controlling for health insurance status and socioeconomic status. The Third National Health and Nutrition Examination Survey was used to create a sample of 4372 Mexican American children (divided into 3 generational groups), 4138 non-Hispanic black children, and 4594 non-Hispanic white children, 2 months to 16 years of age. We compared parent/caregiver reports of health status and needs (perceived health of the child and reported illnesses), health care access (usual source of health care and specific provider), and health care utilization (contact with a physician within the past year, use of prescription medications, physician visit because of earache/infection, and hearing and vision screenings) for different subgroups within the sample. More than two thirds of first-generation Mexican American children were poor and uninsured and had parents with low educational attainment. More than one fourth of first-generation children were perceived as having poor or fair health, despite experiencing similar or better rates of illnesses, compared with other children. Almost one half of first-generation Mexican American children had not seen a doctor in the past year, compared with one fourth or less for other groups. Health care needs among first-generation Mexican American children were lower, on the basis of reported illnesses, but perceived health status was worse than for all other groups. After controlling for health insurance coverage and socioeconomic status, first-generation Mexican American children and non-Hispanic black children were less likely than non-Hispanic white children to have a usual source of care, to have a specific provider, or to have seen or talked with a physician in the past year. Of the 3 groups of children, Mexican American children had the least health care access and utilization, even after controlling for socioeconomic status and health insurance status. Our findings showed that Mexican American children had much lower levels of access and utilization than previously reported for Hispanic children on the whole. As a subgroup, first-generation Mexican American children fared substantially worse than second- or third-generation children. The discrepancy between poor perceived health status and lower rates of reported illnesses in the first-generation group leads to questions regarding generalized application of the "epidemiologic paradox." Given the overall growth of the Hispanic population in the United States and the relative growth of individual immigrant subgroups, the identification of subgroups in need is essential for the development of effective research and policy. Furthermore, taking generational status into account is likely to be revealing with respect to disparities in access to and utilization of pediatric services.


Considerations when investigating lncRNA function in vivo.
Although a small number of the vast array of animal long non-coding RNAs (lncRNAs) have known effects on cellular processes examined in vitro, the extent of their contributions to normal cell processes throughout development, differentiation and disease for the most part remains less clear. Phenotypes arising from deletion of an entire genomic locus cannot be unequivocally attributed either to the loss of the lncRNA per se or to the associated loss of other overlapping DNA regulatory elements. The distinction between cis- or trans-effects is also often problematic. We discuss the advantages and challenges associated with the current techniques for studying the in vivo function of lncRNAs in the light of different models of lncRNA molecular mechanism, and reflect on the design of experiments to mutate lncRNA loci. These considerations should assist in the further investigation of these transcriptional products of the genome.


A selective impairment of motion perception following lesions of the middle temporal visual area (MT).
Physiological experiments indicate that the middle temporal visual area (MT) of primates plays a prominent role in the cortical analysis of visual motion. We investigated the role of MT in visual perception by examining the effect of chemical lesions of MT on psychophysical thresholds. We trained rhesus monkeys on psychophysical tasks that enabled us to assess their sensitivity to motion and to contrast. For motion psychophysics, we employed a dynamic random dot display that permitted us to vary the intensity of a motion signal in the midst of masking motion noise. We measured the threshold intensity for which the monkey could successfully complete a direction discrimination. In the contrast task, we measured the threshold contrast for which the monkeys could successfully discriminate the orientation of stationary gratings. Injections of ibotenic acid into MT caused striking elevations in motion thresholds, but had little or no effect on contrast thresholds. The results indicate that neural activity in MT contributes selectively to the perception of motion.


Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation.
The cytokine interleukin-22 (IL-22) is primarily expressed by T helper 17 (Th17) CD4(+) T cells and is highly upregulated during chronic inflammatory diseases. IL-22 receptor expression is absent on immune cells, but is instead restricted to the tissues, providing signaling directionality from the immune system to the tissues. However, the role of IL-22 in inflammatory responses has been confounded by data suggesting both pro- and anti-inflammatory functions. Herein, we provide evidence that during inflammation, IL-22 played a protective role in preventing tissue injury. Hepatocytes from mice deficient in IL-22 were highly sensitive to the detrimental immune response associated with hepatitis. Additionally, IL-22-expressing Th17 cells provided protection during hepatitis in IL-22-deficient mice. On the other hand, interleukin-17 (IL-17), which is coexpressed with IL-22 and can induce similar cellular responses, had no observable role in liver inflammation. Our data suggest that IL-22 serves as a protective molecule to counteract the destructive nature of the immune response to limit tissue damage.


Hospitalization of children for asthma in the Brazilian Amazon: trend and spatial distribution.
To analyze the distribution of hospitalizations of children for asthma in the states comprising the Brazilian Amazon, as well as the variations of hospitalization according to climatic seasonality. A descriptive study of the distribution of hospitalizations for asthma of individuals aged 0 to 14 years living in the Brazilian Amazon, according to trend, spatial distribution, and climatic seasonality over the period from 2001 to 2007. We used the database of authorizations for hospitalizations (AIH) of the Hospital Information System (SIH/SUS) of the Brazilian Ministry of Health. The spatial distribution of hospitalizations for asthma resembles the configuration of the "arc of deforestation," mainly in the states of Rondônia and Maranhão. The distribution of annual hospitalizations for asthma decreased from 8.1 to 2.6 hospitalizations/1,000 inhabitants during the period. There was a peak of hospitalizations in March and May in all states. The seasonal differences were on average 10%, with the highest rates during the rainy season. We concluded that hospitalizations for asthma are more frequent in the months of more intense rainfall, with greater magnitude in the states comprising the "arc of deforestation" in the Brazilian Amazon, especially Rondônia and Maranhão.


Pericentric inversion of chromosome 9: prevalence in 300 Down syndrome families and molecular studies of nondisjunction.
The incidence of Down syndrome (DS) families where one of the parents is an heterozygous carrier of pericentric inversion of the heterochromatic region of chromosome 9-inv(9) (qh) - was determined in 3 independent groups of 100 families each. The total number of 17 such families found in the sample is significantly greater than the expected number of 5.73 for a sample of non-DS families of equal size. Consequently, the statistical association of the presence of inv (9) (qh) in one parent with the birth of a DS offspring, and the correlative 3-fold increased risk of a DS child for such families, seem to be demonstrated. A study of the origin of nondisjunction, using restriction fragment length polymorphism (RFLP) segregation analysis with a sufficient number of chromosome 21 specific probes, has provided complete information in 7 of 8 available families. Although the statistical interpretation of the results is not straightforward, due to the small size of the sample, the observed data do not contradict the assumption that the presence of inv (9) (qh) in a parent increases, by a factor of about 3, the chance that the offspring will inherit an extra chromosome 21 from that parent. Nevertheless, gathering further data appears desirable because stronger evidence would have relevance both for clinical implications and for the understanding of the function of heterochromatin, particularly with respect to meiotic and mitotic processes.


Mechanical Trapping of DNA in a Double-Nanopore System.
Nanopores have become ubiquitous components of systems for single-molecule manipulation and detection, in particular DNA sequencing where electric field driven translocation of DNA through a nanopore is used to read out the DNA molecule. Here, we present a double-pore system where two nanopores are drilled in parallel through the same solid-state membrane, which offers new opportunities for DNA manipulation. Our experiments and molecular dynamics simulations show that simultaneous electrophoretic capture of a DNA molecule by the two nanopores mechanically traps the molecule, increasing its residence time within the nanopores by orders of magnitude. Remarkably, by using two unequal-sized nanopores, the pore of DNA entry and exit can be discerned from the ionic current blockades, and the translocation direction can be precisely controlled by small differences in the effective force applied to DNA. The mechanical arrest of DNA translocation using a double-pore system can be straightforwardly integrated into any solid-state nanopore platform, including those using optical or transverse-current readouts.


Contralateral Approach to Internal Carotid Artery Ophthalmic Segment Aneurysms: Angiographic Analysis and Surgical Results for 30 Patients.
Contralateral aneurysm clipping can be applied to bilateral intracranial aneurysms of the anterior circulation and to selected aneurysms on the medial wall of the internal carotid artery (ICA). To identify anatomic and radiological parameters that would favor a contralateral microsurgical approach to ICA-ophthalmic segment (ICA-opht) aneurysms. For the period January 1957 to December 2012, we retrospectively analyzed 268 patients with ICA-opht aneurysms treated in our institution. Of these patients, 30 underwent a contralateral approach; 15 patients (50%) had multiple intracranial aneurysms, and 15 patients had a single aneurysm on the contralateral side of the craniotomy. Thirty saccular aneurysms located on the contralateral ICA were treated. Six aneurysms (20%) were present in patients with a subarachnoid hemorrhage due to associated aneurysms, whereas 24 aneurysms (80%) had no history of bleeding. Contralateral aneurysms were smaller than 14 mm and showed no wall irregularities, calcifications, or secondary pouches. Projections of the aneurysms were superomedial (n = 23, 77%), medial (n = 4, 13%), and superior (n = 3, 10%). The median prechiasmatic distance was 5.7 mm (range, 3.4-8.7 mm), the median interoptic distance was 10.5 mm (range, 7.6-15.9 mm), and the median distance between both ICAs was 14.7 mm (range, 10.4-21.4 mm). The contralateral approach for ICA-opht aneurysms remains a treatment option for intracranial aneurysms. Its feasibility depends on specific anatomic parameters related to the aneurysm itself and to the prechiasmatic distance, interoptic distance, and relationship of the ICA with the anterior clinoid process.


Interobserver variation of ASPECTS in real time.
The Alberta Stroke Program Early CT Score (ASPECTS) has been used to quantify early ischemic changes on computed tomography (CT) brain scans of acute stroke patients. We sought to assess the reliability of the score when performed in real time as compared with an expert rating performed at a later time point. Two hundred fourteen patients presenting with acute ischemic stroke or transient ischemic attack were prospectively recruited if they had a brain CT scan performed within 12 hours of symptom onset. Each scan was read for ASPECTS prospectively by the treating physician and later by 1 expert reader. A weighted kappa statistic was used to determine the interobserver agreement. The median baseline National Institutes of Health Stroke Scale score was 5 (range: 0 to 32) and the median time to CT scan was 152 minutes (range: 22 to 769). The interobserver agreement between ASPECTS performed in real time and expert ASPECTS was substantial (kappa(w)=0.69). The mean difference between real-time ASPECTS and expert ASPECTS was 0 (SD: 1.1). ASPECTS is a reliable clinical scale for rating early ischemic changes on CT when performed in real time.


Mild cognitive impairment in clinical care: a survey of American Academy of Neurology members.
To assess how neurologists view mild cognitive impairment (MCI) as a clinical diagnosis and how they treat patients with mild cognitive symptoms. Members of the American Academy of Neurology with an aging, dementia, or behavioral neurology practice focus were surveyed by self-administered questionnaire. Survey respondents were 420 providers (response rate 48%), and 88% reported at least monthly encounters with patients experiencing mild cognitive symptoms. Most respondents recognize MCI as a clinical diagnosis (90%) and use its diagnostic code for billing purposes (70%). When seeing these patients, most respondents routinely provide counseling on physical (78%) and mental exercise (75%) and communicate about dementia risk (63%); fewer provide information on support services (27%) or a written summary of findings (15%). Most (70%) prescribe cholinesterase inhibitors at least sometimes for this population, with memantine (39%) and other agents (e.g., vitamin E) prescribed less frequently. Respondents endorsed several benefits of a diagnosis of MCI: 1) involving the patient in planning for the future (87%); 2) motivating risk reduction activities (85%); 3) helping with financial planning (72%); and 4) prescribing medications (65%). Some respondents noted drawbacks, including 1) too difficult to diagnose (23%); 2) better described as early Alzheimer disease (21%); and 3) diagnosis can cause unnecessary worry (20%). Patients with mild cognitive symptoms are commonly seen by neurologists, who view MCI as a useful diagnostic category. Information and treatments provided to patients with MCI vary significantly, suggesting a need for practice guidelines and further research on clinical decision-making with this population.


The therapeutics of lifestyle management on obesity.
The global incidence and prevalence of obesity continue to increase, with the fastest rate of increase in the developing world. Obesity is associated with many chronic diseases including type 2 diabetes, cardiovascular disease and some cancers. Weight loss can reduce the risk of developing these diseases and can be achieved by means of surgery, pharmacotherapy and lifestyle interventions. Lifestyle interventions for prevention and treatment of obesity include diet, exercise and psychological interventions. All lifestyle interventions have a modest but significant effect on weight loss, but there is little evidence to indicate that any one intervention is more effective. There is evidence of an additive effect for adjunct therapy, and the combination of diet, exercise and behavioural interventions appears to be most effective for both the prevention and treatment of obesity.


High reflectance ta-C coatings in the extreme ultraviolet.
The extreme ultraviolet (EUV) reflectance of amorphous tetrahedrally coordinated carbon films (ta-C) prepared by filtered cathodic vacuum arc was measured in the 30-188-nm range at near normal incidence. The measured reflectance of films grown with average ion energies in the ~70-140-eV range was significantly larger than the reflectance of a C film grown with average ion energy of ~20 eV and of C films deposited by sputtering or evaporation. The difference is attributed to a large proportion of sp3 atom bonding in the ta-C film. This high reflectance is obtained for films deposited onto room-temperature substrates. The reflectance of ta-C films is higher than the standard single-layer coating materials in the EUV spectral range below 130 nm. A self-consistent set of optical constants of ta-C films was obtained with the Kramers-Krönig analysis using ellipsometry measurements in the 190-950 nm range and the EUV reflectance measurements. These optical constants allowed calculating the EUV reflectance of ta-C films at grazing incidence for applications such as free electron laser mirrors.


Effect of carrot (Daucus carota) microstructure on carotene bioaccessibility in the upper gastrointestinal tract. 2. In vivo digestions.
Nutrient bioaccessibility and subsequent absorption will be directly influenced by changes in food structure during gastrointestinal processing. The accompanying paper (Tydeman et al. J. Agric. Food Chem. 2010, 58, doi: 10.1021/jf101034a) reported results on the effect of carrot processing on the release of carotene into lipid phases during in vitro gastric and small intestinal digestions. This paper describes results from in vivo digestion of two of the types of processed carrot used previously, raw grated carrot and cooked carrot mashed to a puree. Ileostomy effluents from human volunteers fed meals containing the carrot material were used to study tissue microstructure and carotene release. Raw carrot shreds and intact cells that had survived the pureeing process were identifiable in ileal effluent. The gross tissue structure in the shreds had not changed following digestion. Carotene-containing particles remained encapsulated in intact cells, but were absent from ruptured cells. Microscopy revealed marked changes to the cell walls including swelling and pectin solubilization, which increased in severity with increasing residence time in the upper gut. These observations were entirely consistent with the in vitro observations. It was concluded that a single intact cell wall is sufficient to reduce carotene bioaccessibility from a cell by acting as a physical barrier, which is not broken down during upper gut digestion.


Long-Term Risk of Stroke After Transient Global Amnesia in Two Prospective Cohorts.
Background and Purpose- Transient global amnesia (TGA) is known as a benign syndrome, but recent data from neuroradiological studies support an ischemic cause in some cases, which might suggest an increased susceptibility to cerebrovascular events. We determined the long-term risk of stroke after a first TGA in 2 independent prospective cohorts. Methods- In 2 independent prospective cohorts of patients with TGA (OXVASC [Oxford Vascular Study], population-based; NU (Northern Umbria) cohort, TGA registry), cardiovascular risk factors and long-term outcomes, including stroke and major cardiovascular events, were identified on follow-up. Cardiovascular risk factors were treated according to primary prevention guidelines. In OXVASC, the age-/sex-adjusted risk of stroke during follow-up was compared with that expected from the rate in the underlying study population. Results- Among 525 patients with TGA (425 NU and 100 OXVASC), mean (SD) age was 65.1 (9.5) years and 42.5% male. Hypertension (58.1%), dyslipidemia (40.4%), and smoking (36.4%) were the most frequent cardiovascular risk factors. The risk of stroke was similar in the 2 cohorts, with a pooled annual risk of 0.6% (95% CI, 0.4-0.9) and a 5-year cumulative risk of 2.7% (1.1-4.3). Moreover, the stroke risk in OXVASC cases was no greater than that expected in the underlying study population (adjusted relative risk=0.73; 0.12-4.54; P=0.74). Conclusions- TGA does not carry an increased risk of stroke, at least when cardiovascular risk factors are treated according to primary prevention guidelines.


The patient's view on quality of life and eating disorders.
This study investigated the personal views of eating disorder (ED) patients on their quality of life (QOL). The views of 146 current ED patients and 146 former ED patients on their QOL were studied using a self-report questionnaire. Patients were requested to name the most important aspects of their life and they subsequently rated themselves on these aspects. Qualitative analysis clustered items into meaningful categories. A sense of belonging was mentioned most often (93.0%) by the participants. Work or education, health and well-being were also mentioned frequently. Furthermore, participants stated a sense of self, disease-specific psychopathology, life skills, leisure activities, a sense of purpose, financial situation, living condition, and pets. Current ED patients more frequently mentioned disease-specific psychopathology than former ED patients. Current ED patients reported poor QOL on most domains, particularly on self-image and well-being. Former ED patients reported better QOL than current ED patients, but ratings were just above average. The views on QOL of ED patients broadens the scope of relevant domains of QOL. The assessment of these views may be a useful adjunct to the use of standardized QOL measures.


Optimisation of quantitative lung SPECT applied to mild COPD: a software phantom simulation study.
The amount of inhomogeneities in a (99m)Tc Technegas single-photon emission computed tomography (SPECT) lung image, caused by reduced ventilation in lung regions affected by chronic obstructive pulmonary disease (COPD), is correlated to disease advancement. A quantitative analysis method, the CVT method, measuring these inhomogeneities was proposed in earlier work. To detect mild COPD, which is a difficult task, optimised parameter values are needed. In this work, the CVT method was optimised with respect to the parameter values of acquisition, reconstruction and analysis. The ordered subset expectation maximisation (OSEM) algorithm was used for reconstructing the lung SPECT images. As a first step towards clinical application of the CVT method in detecting mild COPD, this study was based on simulated SPECT images of an advanced anthropomorphic lung software phantom including respiratory and cardiac motion, where the mild COPD lung had an overall ventilation reduction of 5%. The best separation between healthy and mild COPD lung images as determined using the CVT measure of ventilation inhomogeneity and 125 MBq (99m)Tc was obtained using a low-energy high-resolution collimator (LEHR) and a power 6 Butterworth post-filter with a cutoff frequency of 0.6 to 0.7 cm(-1). Sixty-four reconstruction updates and a small kernel size should be used when the whole lung is analysed, and for the reduced lung a greater number of updates and a larger kernel size are needed. A LEHR collimator and 125 (99m)Tc MBq together with an optimal combination of cutoff frequency, number of updates and kernel size, gave the best result. Suboptimal selections of either cutoff frequency, number of updates and kernel size will reduce the imaging system's ability to detect mild COPD in the lung phantom.


Nanostructure domains, voids, and low-frequency spectra in binary mixtures of N,N-dimethylacetamide and ionic liquids with varying cationic size.
Classical molecular dynamics (MD) simulations were carried out on binary mixtures of N,N-dimethylacetamide (DMA) with hydroxide based ammonium ionic liquids (ILs), tetraethylammonium hydroxide (TEAH), tetrapropylammonium hydroxide (TPAH), tetrabutylammonium hydroxide (TBAH), at three different mole fractions of IL (X IL). The solvation of DMA molecules by ions of ILs was studied by the combined distribution function (CDF). CDFs show that anions have strong correlations with the DMA due to the hydrogen bonding. Increasing the DMA disrupts the nanosegregated domains and causes changes in correlations of cation-DMA and anion-DMA. Also, increased translational motion of ions, as well as the fluidity of IL and a significant improvement in self-diffusion coefficients, are observed with the presence of more DMA. The structural microheterogeneity was investigated using the Voronoi tessellation method. Domain analysis confirms the formation of discreet domains by anions at all the mole fractions. The results also complement the experimental observations, which suggest that two types of aggregations are possible in given mixtures: below and above 0.5 X IL. When the alkyl chain length on the cation increases, a notable decrease in ion translational motion was observed in the IL rich region. In the concentrated IL mixture, the self-diffusion coefficient of the cation is higher than that of the corresponding anion; further addition of IL (X IL < 0.5) results in weaker interactions between DMA and anion when compared to DMA-cation. The mean collision time of each species is found to have an inverse relation with X IL. The analysis of the vibrational density of states provides the low-frequency spectral feature of the mixtures.


Response to antiretroviral therapy: improved survival associated with CD4 above 500 cells/μl.
We investigated the association between immune response and mortality in four HIV African programs supported by Médecins Sans Frontières. Multicentric retrospective cohort study. All antiretroviral therapy (ART) naive adults (>15 years) who initiated therapy between March 2001 and November 2010 and receiving therapy for 9 months or more were included. We described the evolution of mortality over time. Mixed Poisson models were used to assess the effect of updated CD4 cell counts and other potential risk factors on mortality. A total of 24 037 patients, of which 68% were women, contributed 69 516.2 person-years of follow-up. At ART initiation, 5718 patients (23.7%) were classified as WHO clinical stage 4, 1587 (6.6%) had a BMI below 16 kg/m and 2568 (10.7%) had CD4 cell count below 50 cells/μl. A total of 568 (2.4%) deaths were recorded during the study period. In the CD4 response categories 500 cells/μl or more, 350-499, 200-349, 50-199 cells/μl and less than 50 cells/μl, unadjusted mortality rates were 0.36; 0.58; 0.88; 1.91 and 7.43 per 100 person-years, respectively. In multivariate analysis, higher mortality was observed in patients with CD4 response levels 350-499 cells/μl [adjusted hazard ratio (aHR) 1.70, 95% confidence interval (CI) 1.26-2.30] and for those between 200-349 (aHR 2.56; 95% CI 1.93-3.38), compared to those with 500 cells/μl or more. The observed higher survival of patients with a CD4 response to ART higher than 500 cells/μl supports the need of further research to evaluate the individual benefit of initiating ART at higher CD4 levels in sub-Saharan Africa.


Growth and development of the ovary and small follicle pool from mid fetal life to pre-puberty in the African elephant (Loxodonta africana).
Follicle numbers and developing ovarian morphology, particularly with reference to the presence of interstitial tissue, are intimately linked within the ovary of the African elephant during the period spanning mid-gestation to puberty. These have not been previously quantified in any studies. The collection of 7 sets of elephant fetal ovaries between 11.2 and 20.2 months of gestation, and 29 pairs of prepubertal calf ovaries between 2 months and 9 years of age during routine management off-takes of complete family groups in private conservancies in Zimbabwe provided an opportunity for a detailed study of this period. The changing morphology of the ovary is described as the presumptive cortex and medulla components of the fetal ovary settled into their adult form. Interstitial tissue dominated the ovary in late fetal life and these cells stained strongly for 3β-hydroxysteroid dehydrogenase. This staining continued postnatally through to 4.5 years of age suggesting continued secretion of progestagens by the ovary during this period. The considerable growth of antral follicles peaked at 28% of ovarian volume at around 16.7 months of fetal age. The numbers of small follicles (primordial, early primary and true primary), counted in the cortex using stereological protocols, revealed fewer small follicles in the ovaries of animals aged 0 to 4.5 years of age than during either late fetal life or prepubertal life. The small follicle populations of the late-fetal and prepubertal ovaries of the African elephant were described along with the changing morphology of these organs. The changes noted represent a series of events that have been recorded only in the elephant and the giraffe species to date. The expansion of the interstitial tissue of the fetal ovary and its continued presence in early post natal life may well contribute to the control of follicle development in these early years. Further research is required to determine the reasons behind the variation of numbers of small follicles in the ovaries of prepubertal calves.


The 1973 Flood and Man's Constriction of the Mississippi River.
The progressive constriction of the Mississippi for navigation since 1837 has caused bottom erosion in some stretches. In others the bottom oscillates up and down with time. The high stages rise much more rapidly. Constriction of the river channel causes flooding and makes floods higher; thus navigation works degrade the protection afforded by levees. The combination of navigation works and levees causes significant rises in the stages of floods. Additional channel constriction and levee building will cause further problems. The 1973 flood's record was man-made.


Theory and data for area summation of contrast with and without uncertainty: evidence for a noisy energy model.
Contrast sensitivity improves with the area of a sine-wave grating, but why? Here we assess this phenomenon against contemporary models involving spatial summation, probability summation, uncertainty, and stochastic noise. Using a two-interval forced-choice procedure we measured contrast sensitivity for circular patches of sine-wave gratings with various diameters that were blocked or interleaved across trials to produce low and high extrinsic uncertainty, respectively. Summation curves were steep initially, becoming shallower thereafter. For the smaller stimuli, sensitivity was slightly worse for the interleaved design than for the blocked design. Neither area nor blocking affected the slope of the psychometric function. We derived model predictions for noisy mechanisms and extrinsic uncertainty that was either low or high. The contrast transducer was either linear (c(1.0)) or nonlinear (c(2.0)), and pooling was either linear or a MAX operation. There was either no intrinsic uncertainty, or it was fixed or proportional to stimulus size. Of these 10 canonical models, only the nonlinear transducer with linear pooling (the noisy energy model) described the main forms of the data for both experimental designs. We also show how a cross-correlator can be modified to fit our results and provide a contemporary presentation of the relation between summation and the slope of the psychometric function.


Killing of targets by CD8 T cells in the mouse spleen follows the law of mass action.
It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response.


Personal, social, and game-related correlates of active and non-active gaming among dutch gaming adolescents: survey-based multivariable, multilevel logistic regression analyses.
Playing video games contributes substantially to sedentary behavior in youth. A new generation of video games-active games-seems to be a promising alternative to sedentary games to promote physical activity and reduce sedentary behavior. At this time, little is known about correlates of active and non-active gaming among adolescents. The objective of this study was to examine potential personal, social, and game-related correlates of both active and non-active gaming in adolescents. A survey assessing game behavior and potential personal, social, and game-related correlates was conducted among adolescents (12-16 years, N=353) recruited via schools. Multivariable, multilevel logistic regression analyses, adjusted for demographics (age, sex and educational level of adolescents), were conducted to examine personal, social, and game-related correlates of active gaming ≥1 hour per week (h/wk) and non-active gaming >7 h/wk. Active gaming ≥1 h/wk was significantly associated with a more positive attitude toward active gaming (OR 5.3, CI 2.4-11.8; P<.001), a less positive attitude toward non-active games (OR 0.30, CI 0.1-0.6; P=.002), a higher score on habit strength regarding gaming (OR 1.9, CI 1.2-3.2; P=.008) and having brothers/sisters (OR 6.7, CI 2.6-17.1; P<.001) and friends (OR 3.4, CI 1.4-8.4; P=.009) who spend more time on active gaming and a little bit lower score on game engagement (OR 0.95, CI 0.91-0.997; P=.04). Non-active gaming >7 h/wk was significantly associated with a more positive attitude toward non-active gaming (OR 2.6, CI 1.1-6.3; P=.035), a stronger habit regarding gaming (OR 3.0, CI 1.7-5.3; P<.001), having friends who spend more time on non-active gaming (OR 3.3, CI 1.46-7.53; P=.004), and a more positive image of a non-active gamer (OR 2, CI 1.07-3.75; P=.03). Various factors were significantly associated with active gaming ≥1 h/wk and non-active gaming >7 h/wk. Active gaming is most strongly (negatively) associated with attitude with respect to non-active games, followed by observed active game behavior of brothers and sisters and attitude with respect to active gaming (positive associations). On the other hand, non-active gaming is most strongly associated with observed non-active game behavior of friends, habit strength regarding gaming and attitude toward non-active gaming (positive associations). Habit strength was a correlate of both active and non-active gaming, indicating that both types of gaming are habitual behaviors. Although these results should be interpreted with caution because of the limitations of the study, they do provide preliminary insights into potential correlates of active and non-active gaming that can be used for further research as well as preliminary direction for the development of effective intervention strategies for replacing non-active gaming by active gaming among adolescents.


Globally distributed Xyleborus species reveal recurrent intercontinental dispersal in a landscape of ancient worldwide distributions.
Invasive species can have devastating effects on native ecosystems and therefore impose a significant threat to human welfare. The introduction rate of invasive species has accelerated dramatically in recent times due to human activity (anthropogenic effects), with a steadily growing pool of widespread tramp species. We present an in-depth analysis of four pantropical species of Xyleborus ambrosia beetles (Xyleborus volvulus, Xyleborus perforans, Xyleborus ferrugineus, and Xyleborus affinis) with similar ecology (fungus cultivation in dead wood), reproductive biology (permanent inbreeding) and genetic system (haplodiploidy). The unique combination of reproductive traits and broad host plant usage pre-adapts these beetles for colonizing of new areas. We found that all four species were broadly distributed long before human-assisted dispersal became common, and that the impact of anthropogenic effects varied among the species. For X. volvulus, X. perforans, and X. affinis there was evidence of ancient establishment in numerous regions, but also of abundant recent introductions into previously colonized areas. For X. ferrugineus, we found clear biogeographical structuring of old clades, but little evidence for recent successful introductions. Our results indicate that current human-aided transoceanic dispersal has strongly affected the genetic makeup of three of the species in this study. However, current biogeographical patterns of all four species are equally, if not more strongly, influenced by ancient establishment on different continents.


Evaluation of a Cannabis Harm Reduction Intervention for People With First-Episode Psychosis: Protocol for a Pilot Multicentric Randomized Trial.
Cannabis use is highly prevalent in young people with first-episode psychosis (FEP). Most report cannabis use and are often diagnosed with a cannabis use disorder upon admission to specialized services for psychosis. Cannabis use in this population is associated with worse clinical and psychosocial outcomes, rendering it an important clinical target. Despite this, few cannabis-specific interventions have been developed for FEP and empirically evaluated through randomized controlled trials. Most evaluated interventions have targeted cannabis abstinence, with limited efficacy, but none have centered on harm reduction outcomes for people with FEP who use cannabis. Early intervention services (EIS), the standard of care for FEP, have not successfully addressed problematic cannabis use in people with FEP either. Clinical trials are needed to explore the potential of harm reduction strategies, although these should be preceded by robust pilot studies to establish optimal design and approaches. Recognizing the need for harm reduction strategies for individuals with FEP who use cannabis and based on research on patients' preferences supporting harm reduction interventions, we developed a mobile app-based cannabis harm reduction intervention for this population. This intervention is called Cannabis Harm-reducing Application to Manage Practices Safely (CHAMPS). Here, we describe the protocol for a multicenter, 2-arm, parallel group, randomized pilot trial evaluating the acceptability of CHAMPS for people with FEP who use cannabis and the feasibility of conducting a full-scale trial in this population using CHAMPS. The impact on key clinical outcomes will also be explored. This pilot trial aims to recruit 100 young people with FEP using cannabis from 6 Canadian EIS clinics. Participants will be randomized in a 1:1 ratio to CHAMPS+EIS or EIS-only. CHAMPS acceptability will be assessed using completion rates for the intervention arm. Trial feasibility will be assessed using a retention rate for randomized participants. Secondary outcomes will explore tendencies of change in the use of protective behavioral strategies and in motivation to change strategies. Exploratory outcomes include cannabis use-related problems, other substance use, the severity of dependence, psychotic symptoms, and health care service use. Recruitment began in December 2021. Data collection and analysis are expected to be completed in early 2024. Study results describing CHAMPS acceptability and trial feasibility will then be submitted for publication in a peer-reviewed journal. CHAMPS uniquely combines evidence-based approaches, patient perspectives, and mobile health technology to support harm reduction in people with FEP who use cannabis. Attaining adequate acceptability and feasibility through this trial may justify further exploration of harm reduction tools, particularly within the context of conducting a larger-scale randomized controlled trial. This pilot trial has the potential to advance knowledge for researchers and clinicians regarding a feasible and user-acceptable research design in the cannabis and early psychosis fields. ClinicalTrials.gov NCT04968275, https://clinicaltrials.gov/ct2/show/NCT04968275. DERR1-10.2196/53094.


Combination of siRNA-directed Gene Silencing With Cisplatin Reverses Drug Resistance in Human Non-small Cell Lung Cancer.
One of the most challenging aspects of lung cancer therapy is the rapid acquisition of multidrug-resistant (MDR) phenotype. One effective approach would be to identify and downregulate resistance-causing genes in tumors using small interfering RNAs (siRNAs) to increase the sensitivity of tumor cells to chemotherapeutic challenge. After identifying the overexpressed resistance-related antiapoptotic genes (survivin and bcl-2) in cisplatin-resistant cells, the siRNA sequences were designed and screened to select the most efficacious candidates. Modifications were introduced in them to minimize off-target effects. Subsequently, the combination of siRNA and cisplatin that gave the maximum synergy was identified in resistant cells. We then demonstrated that the combination treatment of the selected siRNAs and cisplatin encapsulated in CD44-targeting hyaluronic acid (HA)-based self-assembling nanosystems reversed the resistance to cisplatin and delayed the tumor growth significantly (growth inhibition increased from 30 to 60%) in cisplatin-resistant tumors. In addition, no abnormalities in body weights, liver enzyme levels or histopathology of liver/spleen tissues were observed in any of the treatment groups during the study period. Overall, we demonstrate that the combination of siRNA-mediated gene-silencing strategy with chemotherapeutic agents constitutes a valuable and safe approach for the treatment of MDR tumors.Molecular Therapy-Nucleic Acids (2013) 2, e110; doi:10.1038/mtna.2013.29; published online 30 July 2013.


SVM-Based System for Prediction of Epileptic Seizures From iEEG Signal.
This paper describes a data-analytic modeling approach for the prediction of epileptic seizures from intracranial electroencephalogram (iEEG) recording of brain activity. Even though it is widely accepted that statistical characteristics of iEEG signal change prior to seizures, robust seizure prediction remains a challenging problem due to subject-specific nature of data-analytic modeling. Our work emphasizes the understanding of clinical considerations important for iEEG-based seizure prediction, and proper translation of these clinical considerations into data-analytic modeling assumptions. Several design choices during preprocessing and postprocessing are considered and investigated for their effect on seizure prediction accuracy. Our empirical results show that the proposed support vector machine-based seizure prediction system can achieve robust prediction of preictal and interictal iEEG segments from dogs with epilepsy. The sensitivity is about 90-100%, and the false-positive rate is about 0-0.3 times per day. The results also suggest that good prediction is subject specific (dog or human), in agreement with earlier studies. Good prediction performance is possible only if the training data contain sufficiently many seizure episodes, i.e., at least 5-7 seizures. The proposed system uses subject-specific modeling and unbalanced training data. This system also utilizes three different time scales during training and testing stages.


Colorectal cancer test use among Hispanic and non-Hispanic U.S. populations.
Although colorectal cancer mortality rates in the general U.S. population declined slightly from 1992 to 2000, the rates for Hispanic men and women did not. Disparity in colorectal cancer screening among Hispanics may be an important factor in the unchanged mortality trends. This study examined rates of colorectal cancer test use among Hispanic and non-Hispanic adults in the United States. Using sampling weights and logistic regression, we analyzed colorectal cancer test use among 5680 Hispanic and 104,733 non-Hispanic adults aged 50 years and older who participated in the 2002 Behavioral Risk Factor Surveillance System. We estimated the percentages and adjusted odds ratios (ORs) of the respondents' reported test use by sociodemographic characteristics, health care access, and state or territory of residence. Hispanic respondents aged 50 and older reported having had either a fecal occult blood test within the past year or a lower endoscopy (sigmoidoscopy or colonoscopy) within 10 years less frequently (41.9%) than non-Hispanic respondents (55.2%). Rates of test use were lower for respondents who reported less education, lower income, no health insurance, and no usual source of health care, regardless of Hispanic ethnicity. After adjusting for differences in education, income, insurance, and having a usual source of health care, Hispanic respondents remained less likely than non-Hispanic respondents to report colorectal cancer testing (OR for fecal occult blood test, 0.66; 95% confidence interval [CI], 0.56-0.81; OR for lower endoscopy, 0.87; 95% CI, 0.77-0.99). Greater disparity in screening rates between Hispanics and non-Hispanics was observed in Colorado, California, and Texas than in other states. A disparity exists between Hispanic and non-Hispanic U.S. adults in colorectal cancer test use. This disparity varies among the states, highlighting the diverse health care experience of Hispanic adults in the United States.


A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors.
Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors. This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg. Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962. The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146-54. ©2015 AACR.


Trends in pharmacologic management of hypertension in Japan one year after the publication of the JSH 2000 guidelines. First Japanese Society of Hypertension.
Hypertension, a major risk factor for cerebrovascular disease and heart disease, often requires drug therapy. The First Japanese Society of Hypertension Guidelines for the Management of Hypertension were published in June 2000. In the present work, we surveyed 447 doctors who attended continuing medical education meetings between March and July 2001 to elucidate national antihypertensive treatment patterns. A minimum level of 150/95 mmHg was selected by 60% and 140/90 mmHg by 19% of respondents as thresholds for initiating drug treatment, while 130/85 mmHg was selected by 26% of respondents as the goal blood pressure in middle-aged uncomplicated male patients. Sixty-nine percent of respondents selected a calcium antagonist as their previous drug of the first choice and 22% selected an ACE inhibitor. For their future first choice, 55% would prescribe an angiotensin II receptor antagonist (AIIA); 19% an ACE inhibitor; and 16% a calcium antagonist. Seventy-two percent selected a calcium antagonist + an ACE inhibitor and 17% selected a calcium antagonist + AIIA as their previous first-choice drug combinations. For their future drug combinations, 56% would select an AIIA + a calcium antagonist and 25% a calcium antagonist + an ACE inhibitor. Four weeks or less was selected by 69% of respondents as the period intended to reach the goal blood pressure. Eight weeks or more was selected by 28%. Overall, our data suggest that doctors in Japan are still cautious and conservative in controlling blood pressure levels but want rapid achievement of the goal blood pressure. Their first choice drug is shifting from calcium antagonists to AIIAs. These findings indicate the need for continued effort to evaluate the diversity of clinical practice and assess the appropriateness of continuing medical education.


Various Effects of Sandblasting of Dental Restorative Materials.
Sandblasting particles which remain on the surfaces of dental restorations are removed prior to cementation. It is probable that adhesive strength between luting material and sandblasting particle remnants might exceed that with restorative material. If that being the case, blasting particles adhere to sandblasted material surface could be instrumental to increasing adhesive strength like underlying bonding mechanism between luting material and silanized particles of tribochemical silica coating-treated surface. We hypothesize that ultrasonic cleaning of bonding surfaces, which were pretreated with sandblasting, may affect adhesive strength of a resin luting material to dental restorative materials. We therefore observed adhesive strength of resin luting material to aluminum oxide was greater than those to zirconia ceramic and cobalt-chromium alloy beforehand. To measure the shear bond strengths of resin luting material to zirconia ceramic and cobalt-chromium alloy, forty specimens of each restorative material were prepared. Bonding surfaces were polished with silicon abrasive paper and then treated with sandblasting. For each restorative material, 40 sandblasted specimens were equally divided into two groups: ultrasonic cleaning (USC) group and non-ultrasonic cleaning (NUSC) group. After resin luting material was polymerized on bonding surface, shear test was performed to evaluate effect of ultrasonic cleaning of bonding surfaces pretreated with sandblasting on bond strength. For both zirconia ceramic and cobalt-chromium alloy, NUSC group showed significantly higher shear bond strength than USC group. Ultrasonic cleaning of dental restorations after sandblasting should be avoided to retain improved bonding between these materials.


Presence and diversity of Streptomyces in Dendroctonus and sympatric bark beetle galleries across North America.
Recent studies have revealed several examples of intimate associations between insects and Actinobacteria, including the Southern Pine Beetle Dendroctonus frontalis and the Spruce Beetle Dendroctonus rufipennis. Here, we surveyed Streptomyces Actinobacteria co-occurring with 10 species of Dendroctonus bark beetles across the United States, using both phylogenetic and community ecology approaches. From these 10 species, and 19 other scolytine beetles that occur in the same trees, we obtained 154 Streptomyces-like isolates and generated 16S sequences from 134 of those. Confirmed 16S sequences of Streptomyces were binned into 36 distinct strains using a threshold of 0.2% sequence divergence. The 16S rDNA phylogeny of all isolates does not correlate with the distribution of strains among beetle species, localities, or parts of the beetles or their galleries. However, we identified three Streptomyces strains occurring repeatedly on Dendroctonus beetles and in their galleries. Identity of these isolates was corroborated using a house-keeping gene sequence (efTu). These strains are not confined to a certain species of beetle, locality, or part of the beetle or their galleries. However, their role as residents in the woodboring insect niche is supported by the repeated association of their 16S and efTu from across the continent, and also having been reported in studies of other subcortical insects.


Wastewater treatment process impact on energy savings and greenhouse gas emissions.
The objective of this research was to assess the energy consumption of wastewater treatment plants (WWTPs), to apply a mathematical model to evaluate their carbon footprint, and to propose energy saving strategies that can be implemented to reduce both energy consumption and greenhouse gas (GHG) emissions in Greece. The survey was focused on 10 WWTPs in Greece with a treatment capacity ranging from 10,000 to 4,000,000 population equivalents (PE). Based on the results, annual specific energy consumption ranged from 15 to 86 kWh/PE. The highest energy consumer in all the WWTPs was aeration, accounting for 40-75% of total energy requirements. The annual GHG emissions varied significantly according to the treatment schemes employed and ranged between 61 and 161 kgCO₂e/PE. The highest values of CO₂emissions were obtained in extended aeration systems and the lowest in conventional activated sludge systems. Key strategies that the wastewater industry could adopt to mitigate GHG emissions are identified and discussed. A case study is presented to demonstrate potential strategies for energy savings and GHG emission reduction. Given the results, it is postulated that the reduction of dissolved oxygen (DO) set points and sludge retention time can provide significant energy savings and decrease GHG emissions.


Differential diagnosis of lung lesion in breast carcinoma: a metachronous neoplasm or metastasis?
A 34-year-old woman-a diagnosed case of pT1N1MO, stage IIa, estrogen and progesterone receptor positive (ER, PR) positive, Her2 negative carcinoma of the left breast-was managed with modified radical mastectomy and adjuvant chemotherapy. While planning for radiotherapy, she was found to have a well-defined enhancing lesion with spiculated margins in the superior segment of the right lower lobe along with a heterogeneously enhancing right hilar lymph node on CT. Histopathological evaluation of the lesion was suggestive of adenocarcinoma. The lesion was negative for ER, PR receptors, mammoglobin and gross cystic disease fluid protein. Thyroid transcription factor 1 (TTF-1) was positive, suggesting a primary lung adenocarcinoma rather than metastatic lesion from the breast. This case clearly signifies the importance of histopathological diagnosis of suspicious metastatic lesions in the setting of early breast cancer. We would also like to highlight the importance of TTF-1 in differentiating primary lung malignancy from metastasis.


Parameter control for enhanced peak-to-valley current ratio in a MoS2/MoTe2 van der Waals heterostructure.
The Ids-Vds properties of a van der Waals cross-junction of few layered MoS2/MoTe2 were investigated, and the physical device parameters were altered in order to transform the conduction mechanism from thermionic emission to interband tunneling. The pristine heterostructure demonstrated rectification behavior of typical p-n junction diodes, because of the p-type and n-type nature of MoTe2 and MoS2, respectively. Lowering the contact resistance between the metal and channel materials, by changing the electrode metals from Au to Pd and Ti, alone did not give rise to carrier conduction through the hetero-interband tunneling between MoTe2 and MoS2. In addition to the reduction in contact resistance, the chemical doping of MoS2 using Benzyl Viologen (BV) achieves hetero-interband tunneling between MoTe2 and MoS2, which probably narrows the depletion layer by degenerating MoS2. The peak-to-valley ratio of the tunneling current of the BV-doped heterostructure of MoS2/MoTe2 is about 4.8, which is comparable to that of the commercially available Si tunneling diode.


ARCII: A phase II trial of the HIV protease inhibitor Nelfinavir in combination with chemoradiation for locally advanced inoperable pancreatic cancer.
Nelfinavir can enhance intrinsic radiosensitivity, reduce hypoxia and improve vascularity. We conducted a phase II trial combining nelfinavir with chemoradiotherapy (CRT) for locally advanced inoperable pancreatic cancer (LAPC). Radiotherapy (50.4Gy/28 fractions; boost to 59.4Gy/33 fractions) was administered with weekly gemcitabine and cisplatin. Nelfinavir started 3-10days before and was continued during CRT. The primary end-point was 1-year overall survival (OS). Secondary end-points included histological downstaging, radiological response, 1-year progression free survival (PFS), overall survival (OS) and treatment toxicity. An imaging sub-study (n=6) evaluated hypoxia ((18)F-Fluoromisonidazole-PET) and perfusion (perfusion CT) during induction nelfinavir. The study closed after recruiting 23 patients, due to non-availability of Nelfinavir in Europe. The 1-year OS was 73.4% (90% CI: 54.5-85.5%) and median OS was 17.4months (90% CI: 12.8-18.8). The 1-year PFS was 21.8% (90% CI: 8.9-38.3%) and median PFS was 5.5months (90% CI: 4.1-8.3). All patients experienced Grade 3/4 toxicity, but many were asymptomatic laboratory abnormalities. Four of 6 patients on the imaging sub-study demonstrated reduced hypoxia and increased perfusion post-nelfinavir. CRT combined with nelfinavir showed acceptable toxicity and promising survival in pancreatic cancer.


The spatio-temporal mechanical environment of healthy and injured human cartilage during sustained activity and its role in cartilage damage.
Recently we presented a computational model of articular cartilage calibrated for normal human tissue explants. This model was able to capture the transient deformation of cartilage experiencing a cyclic load. The model takes into account the tension-compression nonlinearity of the cartilage and incorporates the dependency of the compressive stiffness and fluid permeability of cartilage on the deformation-dependent aggrecan concentration in cartilage tissue. As such it represents a leading constitutive model of articular cartilage. Here we build on the previous study to develop an experimentally validated computational model to simulate mechanical consolidation response of intact and previously injured cartilage under sustained static loading, to develop our understanding of the implications for rates of tissue damage. We see that the type of prior injuries compromise the cartilage function in different ways. Relatively rapid consolidation is predicted for cartilage with a complete meniscectomy and that with a full thickness defect, indicating the inability of cartilage with such injuries to sustain interstitial fluid pressurisation for long periods of time, as does uninjured cartilage. By comparing the consolidation response of articular cartilage predicted by computational model against experimental measurements of the apparent friction coefficient following static loading, we find a strong linear positive correlation exists between cartilage degree of consolidation (DoC) and friction coefficient at the joint. As the DoC of articular cartilages can be estimated in vivo via medical imaging, the DoC can be used as an index to non-invasively evaluate the apparent friction coefficient between opposing cartilage surfaces, and so estimate the likelihood of frictional surface wear and/or cartilage damage.


A scalable architecture for quantum computation with molecular nanomagnets.
A proposal for a magnetic quantum processor that consists of individual molecular spins coupled to superconducting coplanar resonators and transmission lines is carefully examined. We derive a simple magnetic quantum electrodynamics Hamiltonian to describe the underlying physics. It is shown that these hybrid devices can perform arbitrary operations on each spin qubit and induce tunable interactions between any pair of them. The combination of these two operations ensures that the processor can perform universal quantum computations. The feasibility of this proposal is critically discussed using the results of realistic calculations, based on parameters of existing devices and molecular qubits. These results show that the proposal is feasible, provided that molecules with sufficiently long coherence times can be developed and accurately integrated into specific areas of the device. This architecture has an enormous potential for scaling up quantum computation thanks to the microscopic nature of the individual constituents, the molecules, and the possibility of using their internal spin degrees of freedom.


Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. I. Polyaspartic acid binds gentamicin and displaces it from negatively charged phospholipid layers in vitro.
Coadministration of polyaspartic acid protects rats against aminoglycoside-induced nephrotoxicity, with respect to functional and pathological changes as well as to early signs of renal alterations (lysosomal phospholipidosis of proximal tubular cells, increased proliferation of proximal tubular and peritubular cells), without reduction, but actually by increasing the drug cortical content (Williams et al., J. Pharmacol. Exp. Ther. 237: 919, 1986; Gilbert et al., J. Infect. Dis. 159: 945, 1989; Beauchamp et al., 1990). Because aminoglycoside accumulation in kidney cortex involves their segregation in lysosomes, we have examined the possibility of formation of intracellular aminoglycoside-polyaspartic acid complexes that would render the drug less toxic. We found that in vitro polyaspartic acid (MW 9-15,000) 1) binds gentamicin with an optimum at acidic pH (5.4), 2) displaces it from negatively charged liposomes and 3) restores the activity of gentamicin-inhibited lysosomal phospholipase A1 toward phosphatidylcholine included in negatively charged liposomes. In parallel, we also observed that at pH 7.0, polyaspartic acid binds and displaces gentamicin from purified brush-border membrane vesicles, causing an apparent decrease of affinity of gentamicin for these membranes, which was falsely interpreted by Williams et al., J. Pharmacol. Exp. Ther. 237: 919, 1986 as "competition for a common membrane binding site." Assuming that, after its administration in vivo, polyaspartic acid gains access to lysosomes of proximal tubular cells, as many low molecular weight proteins and polypeptides do, our results suggest that protection against gentamicin-induced nephrotoxicity is obtained by the binding of the aminoglycoside to the polyanion in lysosomes, preventing thereby the development of phospholipidosis and therefore interfering with the cascade of events leading from drug accumulation to nephrotoxicity.


Hormonal modulation of ovarian interstitial cells with particular reference to gap junctions.
Thin-section and freeze-fracture studies on the rat ovarian interstitial cells revealed reductions in the size and the number of gap junctions after pituitary ablation. Small gap junctions, however, persist as long as 90 days after hypophysectomy even though regressive cytoplasmic changes are completed 75 d earlier. Administration of exogenous human chorionic gonadotrophin (HCG) results in the restoration of the normal interstitial cell morphology which is accompanied by amplification of junctional membrane. Within 24 h of hormone application, gap junction growth is characterized by the appearance of formation plaques. These studies suggest that the effect of hormone on interstitial cell gap junctions is to modulate the junctional surface area.


Maternal Perceptions of Evidence-Based Early Childhood Sleep Health Promotion Recommendations: An Explanatory Sequential Study.
The purpose of this explanatory sequential design study was to better understand caregivers' perceptions about and interest in evidence-based early childhood sleep health promotion recommendations. A purposeful sample of mothers of 20 1-5-year-old children (10 children exhibiting optimal sleep and 10 children exhibiting insufficient/fragmented sleep) attending a preschool serving a low socio-economic (SES) status metropolitan community were invited to participate in qualitative interviews. Data were coded according to a grounded theory approach and themes were identified within the optimal and suboptimal sleeper groups. Mothers reported different approaches to managing electronics by optimal/suboptimal sleeper group, with mothers of optimal sleepers limiting access to electronics more than mothers in the suboptimal sleep group. Other themes of sleep health practices did not differ meaningfully between groups. Maternal perspectives about early childhood sleep health were similar across optimal and suboptimal sleepers on most elements of child sleep health. Managing child sleep was contextually influenced and these results highlight the complexities of how families living in lower SES environments perceive common sleep recommendations. Thus, sleep health education efforts should be tailored to the needs and values of specific families and communities.


Age determination by magnetic resonance imaging of the wrist in adolescent male football players.
In football there are established age-related tournaments for males and females to guarantee equal chances within the game for all the different age groups. To prevent participation in the incorrect age group, and owing to the fact that in some Asian and African countries registration at birth is not compulsory, other methods of age determination need to be available. Standard radiographs of the left wrist have been used for assessment of skeletal age for many years. This is, however, not ethical in the sporting environment. To study the possible use of magnetic resonance imaging (MRI), which has no radiation risk, in estimating the age of healthy adolescent football players. The examination protocol was applied in four countries using, their respective MRI equipment using a 1-T or 1.5-T magnet and a wrist coil. 496 healthy male adolescent football players between the ages of 14 and 19 years from Switzerland, Malaysia, Algeria and Argentina were selected for the study. The degree of fusion of the left distal radial physis was determined by three independent raters by a newly developed grading system which can be used in future MRI epiphysial fusion grading studies. The inter-rater reliability for grading was high (r = 0.91 and 0.92); all correlations were highly significant (p<0.001). The average age increased with a higher grading of fusion, and the correlation between age and grade of fusion was highly significant (r = 0.69, p<0.001). Only one player (0.8%) in the 16-year-old age group was graded as completely fused. MRI of the wrist offers an alternative as a non-invasive method of age determination in 14-19-year-old male adolescents. The grading system presented here clearly identifies the skeletal maturity by complete fusion in all MRI slices, which eliminates any risk associated with standard radiographic rating as determined by the International Atomic Energy Agency.


Culturally adapted transdiagnostic CBT for SSRI resistant Turkish adolescents: A pilot study.
The most common mental health problems among adolescents are anxiety and mood disorders. While disorder-specific cognitive behavior therapy (CBT) is effective for each of these conditions, the comorbidity between anxiety and mood disorders indicates a need for the development of evidence-based transdiagnostic treatments. To examine the efficacy of culturally adapted transdiagnostic CBT (CA-CBT) in reducing symptoms of anxiety and depression in treatment-resistant Turkish adolescents, 13 adolescent participants with anxiety or mood disorders who were treatment resistant received 10 sessions of CA-CBT in group format. The main outcome measures were the Screen for Childhood Child Anxiety Related Disorders (SCARED), Beck Depression Inventory (BDI), and the Turkish Symptom and Syndrome Addendum (TSSA), which were assessed at baseline, posttreatment, and at 2-month follow-up. At posttreatment, there were large effect sizes for all measures: depression scores (BDI, d = .9), anxiety scores (SCARED, d = 1.1), and the Turkish Symptom and Syndrome Addendum (TSSA, d = 1.6). Moreover, at 2-month follow-up, depression and anxiety symptoms were either maintained or continued to improve such that from pretreatment to follow-up the effect sizes were as follows: depression scores (BDI, d = 1.4), anxiety scores (SCARED, d = 1.7), and the Turkish Symptom and Syndrome Addendum (TSSA, d = 2.4). In addition, there were no dropouts across treatment. This open trial suggests that CA-CBT is effective in reducing anxiety and depression symptoms and that the treatment is well accepted. A full randomized controlled trial to verify the effectiveness of transdiagnostic CA-CBT in similar populations is needed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Intensive short course chemotherapy in the management of tuberculous meningitis.
Short course chemotherapy for tuberculous meningitis (TBM) is advocated by several groups, but relatively few children have been so treated and followed up. A prospective, observational study of isoniazid (INH), rifampicin (RMP) and ethionamide (ETH) in a dosage of 20 mg/kg, and pyrazinamide (PZA) 40 mg/kg, all given once daily in hospital for 6 months. Surviving children were followed up for a year after discharge. Ninety five children, 39 (41%) at stage III, 52 (55%) at stage II and 4 (4%) at stage I TBM were studied. Ten (26%) at stage III and 3 (6%) at stage II died before completion of therapy. Five surviving children (6%) moved on discharge and were untraceable; seven children (9%) were lost during follow up and three were inadvertently restarted on antituberculosis therapy. Two children with severe stage III disease died after discharge. One child experienced a probable disease recrudescence 1 month after discharge. Eighteen children (20%) developed a mildly elevated serum bilirubin concentration during the first month of treatment. In five of these children INH, RMP, ETH and PZA were stopped and streptomycin (SM) and ethambutol substituted. In all cases the original treatment was restarted without incident. One child developed overt jaundice after 5 months of treatment due to hepatitis A infection. Our experience suggests that young children with TBM can be safely treated for 6 months with high doses of antituberculosis agents without overt hepatotoxicity and with a low risk of relapse.


Inferring Population Structure and Admixture Proportions in Low-Depth NGS Data.
We here present two methods for inferring population structure and admixture proportions in low-depth next-generation sequencing (NGS) data. Inference of population structure is essential in both population genetics and association studies, and is often performed using principal component analysis (PCA) or clustering-based approaches. NGS methods provide large amounts of genetic data but are associated with statistical uncertainty, especially for low-depth sequencing data. Models can account for this uncertainty by working directly on genotype likelihoods of the unobserved genotypes. We propose a method for inferring population structure through PCA in an iterative heuristic approach of estimating individual allele frequencies, where we demonstrate improved accuracy in samples with low and variable sequencing depth for both simulated and real datasets. We also use the estimated individual allele frequencies in a fast non-negative matrix factorization method to estimate admixture proportions. Both methods have been implemented in the PCAngsd framework available at http://www.popgen.dk/software/.


IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity.
Programmed cell death-1 (PD-1) is an inhibitory coreceptor for T lymphocytes that provides feedback inhibition of T cell activation. Although PD-1's expression on T cells is known to be activation dependent, the factors that determine the timing, intensity, and duration of PD-1 expression in immune reactions are not fully understood. To address this question, we performed a fine mapping analysis of a conserved 5'-flanking region of the PD-1 gene and identified a putative IFN stimulation response element, which was responsible for PD-1 transcription in the 2B4.11 T cell line. Consistent with this finding, activation by IFN-α enhanced both the induction and maintenance of PD-1 expression on TCR-engaged primary mouse T cells through an association IFN-responsive factor 9 (IRF9) to the IFN stimulation response element. Furthermore, PD-1 expression on Ag-specific CD8(+) T cells was augmented by IFN-α in vivo. We propose that strong innate inflammatory responses promote primary T cell activation and their differentiation into effector cells, but also cause an attenuated T cell response in sustained immune reactions, at least partially through type I IFN-mediated PD-1 transcription. Based on this idea, we demonstrate that IFN-α administration in combination with PD-1 blockade in tumor-bearing mice effectively augments the antitumor immunity, and we propose this as a novel and rational approach for cancer immunotherapy.


Physician as teacher: promoting health and wellness among elementary school students.
Every day, physicians engage in teaching during their patient encounters. It may be that medical students who are introduced to the principles of teaching and learning are more likely to become good communicators and learners. Service-learning may be an effective way for medical students to practice skills in teaching and communication in a real-world setting, while also filling a need within the community. The purpose of this study was to identify common themes within medical students' reflections on what they learned through participating in a teaching exercise with local elementary school children. As a required component of a longitudinal prevention and public health course that spans the first and second years of undergraduate medical education, second year students at the Oakland University William Beaumont School of Medicine, in Detroit, Michigan, in the USA completed a service-learning activity, which included teaching a standardized curricular module to local elementary school children. Students were required to complete a reflection assignment based on their teaching experience. Medical students' responses to assignment's three guided questions were qualitatively coded to identify common themes among the responses related to the teaching activity. Qualitative analysis of students' reflections revealed several themes regarding what the students learned and viewed as the benefits of the activity: The importance of early education and parental involvement; the importance of understanding your audience when teaching; the importance of simplifying complex concepts to the audience's level; and the importance of preparation for teaching. Medical students identified the difficulties of communicating at an audience appropriate level and providing patient education outside the confines of a controlled classroom setting. This activity provided medical students with hands-on experience presenting to an audience age-appropriate, health-related topics. Presenting in an elementary school environment helped students better understand what health information various age groups knew about and the importance of clarifying information when communicating with a younger audience.


Global Cicada Sound Collection I: Recordings from South Africa and Malawi by B. W. Price & M. H. Villet and harvesting of BioAcoustica data by GBIF.
Sound collections for singing insects provide important repositories that underpin existing research (e.g. Price et al. 2007 at http://bio.acousti.ca/node/11801; Price et al. 2010) and make bioacoustic collections available for future work, including insect communication (Ordish 1992), systematics (e.g. David et al. 2003), and automated identification (Bennett et al. 2015). The BioAcoustica platform (Baker et al. 2015) is both a repository and analysis platform for bioacoustic collections: allowing collections to be available in perpetuity, and also facilitating complex analyses using the BioVeL cloud infrastructure (Vicario et al. 2011). The Global Cicada Sound Collection is a project to make recordings of the world's cicadas (Hemiptera: Cicadidae) available using open licences to maximise their potential for study and reuse. This first component of the Global Cicada Sound Collection comprises recordings made between 2006 and 2008 of Cicadidae in South Africa and Malawi. This collection of sounds includes 219 recordings of 133 voucher specimens, comprising 42 taxa (25 identified to species, all identified to genus) from South Africa and Malawi. The recordings have been used to underpin work on the species limits of cicadas in southern Africa, including Price et al. (2007) and Price et al. (2010). The specimens are deposited in the Albany Museum, Grahamstown, South Africa (AMGS). The harvesting of acoustic data as occurrence records by GBIF has been implemented by the Scratchpads Team at the Natural History Museum, London. This link increases the value of individual recordings and the BioAcoustica platform within the global infrastructure of biodiversity informatics by making specimen/occurence records from BioAcoustica available to a wider audience, and allowing their integration with other occurence datasets that also contribute to GBIF.


Pol V-Mediated Translesion Synthesis Elicits Localized Untargeted Mutagenesis during Post-replicative Gap Repair.
In vivo, replication forks proceed beyond replication-blocking lesions by way of downstream repriming, generating daughter strand gaps that are subsequently processed by post-replicative repair pathways such as homologous recombination and translesion synthesis (TLS). The way these gaps are filled during TLS is presently unknown. The structure of gap repair synthesis was assessed by sequencing large collections of single DNA molecules that underwent specific TLS events in vivo. The higher error frequency of specialized relative to replicative polymerases allowed us to visualize gap-filling events at high resolution. Unexpectedly, the data reveal that a specialized polymerase, Pol V, synthesizes stretches of DNA both upstream and downstream of a site-specific DNA lesion. Pol V-mediated untargeted mutations are thus spread over several hundred nucleotides, strongly eliciting genetic instability on either side of a given lesion. Consequently, post-replicative gap repair may be a source of untargeted mutations critical for gene diversification in adaptation and evolution.


A review of peripheral biomarkers in major depression: the potential of inflammatory and oxidative stress biomarkers.
Biomarkers are regularly used in medicine to provide objective indicators of normal biological processes, pathogenic processes or pharmacological responses to therapeutic interventions, and have proved invaluable in expanding our understanding and treatment of medical diseases. In the field of psychiatry, assessment and treatment has, however, primarily relied on patient interviews and questionnaires for diagnostic and treatment purposes. Biomarkers in psychiatry present a promising addition to advance the diagnosis, treatment and prevention of psychiatric diseases. This review provides a summary on the potential of peripheral biomarkers in major depression with a specific emphasis on those related to inflammatory/immune and oxidative stress/antioxidant defences. The complexities associated with biomarker assessment are reviewed specifically around their collection, analysis and interpretation. Focus is placed on the potential of peripheral biomarkers to aid diagnosis, predict treatment response, enhance treatment-matching, and prevent the onset or relapse of major depression.


Rapid enzymatic hydrolysis using a novel recombinant β-glucuronidase in benzodiazepine urinalysis.
Only trace amounts of parent benzodiazepines are present in urine following extensive metabolism and conjugation. Thus, hydrolysis of glucuronides is necessary for improved detection. Enzyme hydrolysis is preferred to retain identification specificity, but can be costly and time-consuming. The assessment of a novel recombinant β-glucuronidase for rapid hydrolysis in benzodiazepine urinalysis is presented. Glucuronide controls for oxazepam, lorazepam and temazepam were treated with IMCSzyme™ recombinant β-glucuronidase. Hydrolysis efficiency was assessed at 55°C and at room temperature (RT) using the recommended optimum pH. Hydrolysis efficiency for four other benzodiazepines was evaluated solely with positive patient samples. Maximum hydrolysis of glucuronide controls at 5 min at RT (mean analyte recovery ≥ 94% for oxazepam and lorazepam and ≥ 80% for temazepam) was observed. This was considerably faster than the optimized 30 min incubation time for the abalone β-glucuronidase at 65°C. Mean analyte recovery increased at longer incubation times at 55°C for temazepam only. Total analyte in patient samples compared well to targets from abalone hydrolysis after recombinant β-glucuronidase hydrolysis at RT with no incubation. Some matrix effect, differential reactivity, conjugation variability and transformation impacting total analyte recovery were indicated. The unique potential of the IMCSzyme™ recombinant β-glucuronidase was demonstrated with fast benzodiazepine hydrolysis at RT leading to decreased processing time without the need for heat activation.