Health risk assessment of trihalomethanes in water treatment plants in Jiangsu Province, China.
Probabilistic lifetime cancer risks and non-cancer risks of trihalomethanes (THMs) through ingestion, dermal contact, and inhalation exposure in 88 drinking water treatment plants (WTPs) with raw waters from five water systems (WSs) in Jiangsu Province were analyzed and compared. Concentrations of THMs in finished water of study WTPs varied, ranging from 18.81 to 38.96 μg/L, which are lower than the maximum of 80 μg/L recommended by USEPA. The results of health risk assessment indicated that cancer risk as well as non-cancer risks of THMs in WTPs sourced from five water systems decreased in the order of WS3 > WS5 > WS2 > WS1 > WS4. The comparison among multiple exposure routes indicated that when non-boiled drinking water is consumed, ingestion has the highest exposure route, with exposure values greater than dermal contact and inhalation for WTPs with raw water from all five water systems. However, when drinking boiled water, dermal contact is the major risk source for WTPs with raw water from WS1 and WS2, instead of dermal contact, inhalation becomes the major risk source for WTPs with raw water from WS3, WS4, and WS5. In WTPs with raw water from water systems WS1, WS3, WS4, and WS5, dibromochloromethane (DBCM) in THMs has the highest contribution to cancer risk, while chloroform in THMs has the highest contribution to non-cancer risk. However, in WTPs with raw water from water system WS2, bromodichloromethane (BDCM) has the highest contribution to both cancer risk and non-cancer risk. The results also indicated that females are prone to cancer risk induced by THMs since Chinese people are accustomed to drinking boiled water. The results supply valuable information for health departments to put forward more specific and efficient policies to control water borne diseases.


Ginseng as a Treatment for Fatigue: A Systematic Review.
Millions of people with chronic illness suffer from fatigue. Fatigue is a complex, multidimensional symptom with poorly understood causes, wide variations in severity among individuals, and negative effects on multiple domains of daily life. Many patients with fatigue report the use of herbal remedies. Ginseng is one of the most widely used because it is believed to improve energy, physical and emotional health, and well-being. To systematically review the published evidence to evaluate the safety and effectiveness of the two types of Panax ginseng (Asian [Panax ginseng] and American [Panax quinquefolius]) as treatments for fatigue. PubMed, CINAHL (Cumulative Index to Nursing and Allied Health), Ovid MEDLINE, and EMBASE databases were searched using Medical Subject Heading and keyword terms, including ginseng, Panax, ginsenosides, ginsenoside* (wild card), fatigue, fatigue syndrome, cancer-related fatigue, and chronic fatigue. Studies were included if participants had fatigue, had used one of the two Panax ginsengs as an intervention, and had scores from a self-report fatigue measure. Two reviewers independently assessed each article at each review phase and met to develop consensus on included studies. Risk of bias was assessed using version 5.3 of the Cochrane Collaboration Review Manager (RevMan), and results were synthesized in a narrative summary. The search strategy resulted in 149 articles, with 1 additional article located through review of references. After titles, abstracts, and full text were reviewed, 139 articles did not meet inclusion criteria. For the 10 studies reviewed, there was a low risk of adverse events associated with the use of ginseng and modest evidence for its efficacy. Ginseng is a promising treatment for fatigue. Both American and Asian ginseng may be viable treatments for fatigue in people with chronic illness. Because of ginseng's widespread use, a critical need exists for continued research that is methodologically stronger and that includes more diverse samples before ginseng is adopted as a standard treatment option for fatigue.


Effect of Combination l-Citrulline and Metformin Treatment on Motor Function in Patients With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.
Nitric oxide precursors, such as the amino acid l-arginine and the biguanide antidiabetic drug metformin, have been associated with metabolism and muscle function in patients with Duchenne muscular dystrophy (DMD). The treatment of DMD remains an unmet medical need. To evaluate the benefits and harms of a combination of l-citrulline and metformin treatment among patients with DMD. A single-center randomized double-blind placebo-controlled parallel-group clinical trial was conducted between December 12, 2013, and March 30, 2016, at the University Children's Hospital Basel in Switzerland. A total of 47 ambulant male patients aged 6.5 to 10 years with genetically confirmed DMD were recruited locally and from the patient registries of Switzerland, Germany, Austria, and France. Data were analyzed from April 6, 2016, to September 5, 2019. Patients in the treatment group received 2500 mg of l-citrulline and 250 mg of metformin (combination therapy) 3 times a day for 26 weeks compared with patients in the control group, who received placebo. The primary end point was the change in transfer and standing posture, as assessed by the first dimension of the Motor Function Measure, version 32, from baseline to week 26. Secondary end points included assessments of timed function, quantitative muscle force, biomarkers for muscle necrosis, and adverse events. The 2 prespecified subgroups comprised patients who were able to walk 350 m or more in 6 minutes (stable subgroup) and patients who were not able to walk 350 m in 6 minutes (unstable subgroup) at baseline. Among 49 ambulant male children with DMD who were screened for eligibility, 47 patients with a mean (SD) age of 8.2 (1.1) years were randomized to a treatment group receiving combination therapy (n = 23) or a control group receiving placebo (n = 24), and 45 patients completed the study. No significant differences between groups were found in the results of timed function and muscle force tests for overall, proximal and axial, and distal motor function. Among patients receiving combination therapy, the Motor Function Measure first dimension subscore decrease was 5.5% greater than that of patients receiving placebo (95% CI, -1.0% to 12.1%; P = .09). The administration of combination therapy had significantly favorable effects on the first dimension subscore decrease among the 29 patients in the stable subgroup (6.7%; 95% CI, 0.9%-12.6%; P = .03) but not among the 15 patients in the unstable subgroup (3.9%; 95% CI, -13.2% to 20.9%; P = .63). Overall, the treatment was well tolerated with only mild adverse effects. Treatment with combination therapy was not associated with an overall reduction in motor function decline among ambulant patients with DMD; however, a reduction in motor function decline was observed among the stable subgroup of patients treated with combination therapy. The statistically nonsignificant difference of distal motor function in favor of combination therapy and the reduced degeneration of muscle tissue appear to support the treatment concept, but the study may have lacked sufficient statistical power. Further research exploring this treatment option with a greater number of patients is warranted. ClinicalTrials.gov identifier: NCT01995032.


The top eight issues Queensland Australia's aged-care nurses and assistants-in-nursing worried about outside their workplace: a qualitative snapshot.
The attainment of a work-life balance is an important issue for recruitment, retention and workforce planning. This paper aims to report on the free text data provided by the aged-care sector nurses around perceptions of important work-life issues. Data were written responses of aged-care nurses to the open-ended request at the end of a survey, which asked them to list up to five political/social/environmental issues concerning them outside of their work. For aged-care nurses, when asked to list political/social/environmental issues they were concerned about outside of work in late 2007, there emerged considered issues around work and life. Among the top eight themes there is an intriguing balance between the themes work, industrial relations, aged care/elder care and health-care services compared with the themes environment, water, societal values and housing. Qualitative insights into the political/social/environmental issues aged-care nurses are concerned about outside of your work suggest their desire for a labour/life or work/life harmony. Aged-care nurses place an equal importance on the nature of labour and the basics of life. The findings provide information for aged-care sector managers and workforce planners on areas in need of consideration to recruit and retain a workforce within aged care.


Molecular characterization of the follicle defects in the growth differentiation factor 9-deficient ovary.
Growth differentiation factor-9 (GDF-9), a secreted member of the transforming growth factor-beta superfamily, is expressed at high levels in the mammalian oocyte beginning at the type 3a primary follicle stage. We have previously demonstrated that GDF-9-deficient female mice are infertile because of an early block in folliculogenesis at the type 3b primary follicle stage. To address the molecular defects that result from the absence of GDF-9, we have analyzed the expression of several important ovarian marker genes. The major findings of our studies are as follows: 1) There are no detectable signals around GDF-9-deficient follicles for several theca cell layer markers [i.e. 17alpha-hydroxylase, LH receptor (LHR), and c-kit, the receptor for kit ligand]. This demonstrates that in the absence of GDF-9, the follicles are incompetent to emit a signal that recruits theca cell precursors to surround the follicle; 2) The primary follicles of GDF-9-deficient mice demonstrate an up-regulation of kit ligand and inhibin-alpha. This suggests that these two important secreted growth factors, expressed in the granulosa cells, may be directly regulated in a paracrine fashion by GDF-9. Up-regulation of kit ligand, via signaling through c-kit on the oocyte, may be directly involved in the increased size of GDF-9-deficient oocytes and the eventual demise of the oocyte; 3) After loss of the oocyte, the cells of the GDF-9-deficient follicles remain in a steroidogenic cluster that histologically resembles small corpora lutea. However, at the molecular level, these cells are positive for both luteal markers (e.g. LHR and P-450 side chain cleavage) and nonluteal markers (e.g. inhibin alpha and P-450 aromatase). This demonstrates that initially the presence of the oocyte prevents the expression of luteinized markers, but that the absence of GDF-9 at an early timepoint alters the differentiation program of the granulosa cells; and 4) As demonstrated by staining with either proliferating cell nuclear antigen (PCNA) or Ki-67 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) labeling, the granulosa cells of GDF-9-deficient type 3b primary follicles fail to proliferate but also fail to undergo cell death. This suggests that granulosa cells of type 3b follicles require GDF-9 for continued growth and also to become competent to undergo apoptosis, possibly through a differentiation event Thus, these studies have enlightened us as to the paracrine roles of GDF-9 as well as the normal steps of granulosa cell and theca cell growth and differentiation within ovarian follicles.


Dissecting the autocrine and paracrine roles of the CCR2-CCL2 axis in tumor survival and angiogenesis.
The CCL2 CCR2 axis is likely to contributes to the development and progression of cancer diseases by two major mechanisms; autocrine effect of CCL2 as a survival/growth factor for CCR2+ cancer cells and, the attraction of CCR2+ CX₃CR1+tumor associated macrophages that in the absence of CCR2 hardly migrate. Thus far no in vivo system has been set up to differentiate the selective contribution of each of these features to cancer development. Here we employed a chimera animal model in which all non-malignant cells are CCR2-/-, but all cancer cells are CCR2+, combined with an adoptive transfer system of bone marrow (BM) CX₃CR1+ cells from CCR2+ mice harboring a targeted replacement of the CX₃CR1gene by an enhanced green fluorescent protein (EGFP) reporter gene (cx₃cr1(gfp)), together with the CD45.1 congene. Using this system we dissected the selective contribution of CX₃CR1+CCR2+ cells, which comprise only about 7% of CD11b+ BM cells, to tumor development and angiogenesis. Showing that aside for their direct pro-angiogenic effect they are essential for the recruitment of other CD11b+ cells to the tumor site. We further show that the administration of CCR2-Ig, that selectively and specifically neutralize CCL2, to mice in which CCR2 is expressed only on tumor cells, further suppressed tumor development, implicating for the key role of this chemokine supporting tumor survival in an autocrine manner. This further emphasizes the important role of CCL2 as a target for therapy of cancer diseases.


Use of multi-criteria decision analysis in regulatory alternatives analysis: a case study of lead free solder.
Regulators are implementing new programs that require manufacturers of products containing certain chemicals of concern to identify, evaluate, and adopt viable, safer alternatives. Such programs raise the difficult question for policymakers and regulated businesses of which alternatives are "viable" and "safer." To address that question, these programs use "alternatives analysis," an emerging methodology that integrates issues of human health and environmental effects with technical feasibility and economic impact. Despite the central role that alternatives analysis plays in these programs, the methodology itself is neither well-developed nor tailored to application in regulatory settings. This study uses the case of Pb-based bar solder and its non-Pb-based alternatives to examine the application of 2 multi-criteria decision analysis (MCDA) methods to alternatives analysis: multi-attribute utility analysis and outranking. The article develops and evaluates an alternatives analysis methodology and supporting decision-analysis software for use in a regulatory context, using weighting of the relevant decision criteria generated from a stakeholder elicitation process. The analysis produced complete rankings of the alternatives, including identification of the relative contribution to the ranking of each of the highest level decision criteria such as human health impacts, technical feasibility, and economic feasibility. It also examined the effect of variation in data conventions, weighting, and decision frameworks on the outcome. The results indicate that MCDA can play a critical role in emerging prevention-based regulatory programs. Multi-criteria decision analysis methods offer a means for transparent, objective, and rigorous analysis of products and processes, providing regulators and stakeholders with a common baseline understanding of the relative performance of alternatives and the trade-offs they present.


Decoupling the shape parameter to assess gold nanorod uptake by mammalian cells.
The impact of nanoparticles (NPs) upon biological systems can be fundamentally associated with their physicochemical parameters. A further often-stated tenet is the importance of NP shape on rates of endocytosis. However, given the convoluted parameters concerning the NP-cell interaction, it is experimentally challenging to attribute any findings to shape alone. Herein we demonstrate that shape, below a certain limit, which is specific to nanomedicine, is not important for the endocytosis of spherocylinders by either epithelial or macrophage cells in vitro. Through a systematic approach, we reshaped a single batch of gold nanorods into different aspect ratios resulting in near-spheres and studied their cytotoxicity, (pro-)inflammatory status, and endocytosis/exocytosis. It was found that on a length scale of ∼10-90 nm and at aspect ratios less than 5, NP shape has little impact upon their entry into either macrophages or epithelial cells. Conversely, nanorods with an aspect ratio above 5 were preferentially endocytosed by epithelial cells, whereas there was a lack of shape dependent uptake following exposure to macrophages in vitro. These findings have implications both in the understanding of nanoparticle reshaping mechanisms, as well as in the future rational design of nanomaterials for biomedical applications.


Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo.
SATB1 regulates gene expression by acting as a "docking site" for several chromatin remodeling enzymes and also by recruiting corepressors (HDACs) or coactivators (HATs) directly to promoters. However, how these contrasting effectors act at the level of SATB1 is not clear. We show here that phosphorylation by PKC acts as a switch to determine whether SATB1 interacts with HDAC1 or PCAF. Phosphorylation and dephosphorylation of SATB1 exerted opposing effects on MAR-linked reporter activity in vivo. SATB1 interacted with both CBP/p300 and PCAF HATs; however, these interactions resulted in the acetylation of the PDZ-like domain of SATB1 by PCAF but not by CBP/p300 and resulted in loss of its DNA binding activity. Using the T cell activation model, we provide mechanistic insights into how IL-2 transcription is reciprocally governed by the phosphorylation status of SATB1 and propose that a similar mechanism may dictate the ability of SATB1 to function as a global regulator.


Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario.
Vitamin D, from diet and sunlight exposure, may be associated with reduced breast-cancer risk. This study investigated if candidate gene variants in vitamin D pathways are associated with breast cancer risk, or modify the associations between breast cancer and vitamin D exposure. Breast cancer cases aged 25 to 74 years were identified from the Ontario Cancer Registry (histopathologically confirmed and diagnosed 2002-2003) and population-based controls were identified through random digit dialing of Ontario households. Saliva (DNA) was available for 1,777 cases and 1,839 controls. Multivariate logistic regression was used to evaluate associations between 19 single nucleotide polymorphisms (SNP) in vitamin D related genes, including vitamin D binding protein (GC), vitamin D receptor (VDR), and cytochrome P450 type 24A1 (CYP24A1). Statistical interactions were assessed using the likelihood ratio test. Some SNPs were found to be significantly associated with breast cancer risk. For example, breast cancer risk was associated with the GC rs7041 TT genotype (age-adjusted odds ratio (OR) = 1.23; 95% CI: 1.01, 1.51) and inversely with the VDR Fok1 (rs2228570) ff genotype (OR = 0.71; 95% CI: 0.57, 0.88). Few significant gene-environment interactions were observed between dietary vitamin D and genetic variants. Our study suggests certain vitamin D related genetic variants may influence breast-cancer risk and we found limited evidence that genetic variants modify the associations between vitamin D exposure and breast cancer risk. Variation in vitamin D-related genotypes may help to explain inconsistent results from previous epidemiologic studies and may lead to targeted prevention strategies.


Isolation, marine transgression and translocation of the bare-nosed wombat (Vombatus ursinus).
Island populations can represent genetically distinct and evolutionarily important lineages relative to mainland conspecifics. However, phenotypic divergence of island populations does not necessarily reflect genetic divergence, particularly for lineages inhabiting islands periodically connected during Pleistocene low sea stands. Marine barriers may also not be solely responsible for any divergence that is observed. Here, we investigated genetic divergence among and within the three phenotypically distinct subspecies of bare-nosed wombats (Vombatus ursinus) in south-east Australia that are presently-but were not historically-isolated by marine barriers. Using genome-wide single nucleotide polymorphisms, we identified three genetically distinct groups (mainland Australia, Bass Strait island, and Tasmania) corresponding to the recognized subspecies. However, isolation by distance was observed in the Tasmanian population, indicating additional constraints on gene flow can contribute to divergence in the absence of marine barriers, and may also explain genetic structuring among fragmented mainland populations. We additionally confirm origins and quantify the genetic divergence of an island population 46 years after the introduction of 21 individuals from the Vulnerable Bass Strait subspecies. In the light of our findings, we make recommendations for the maintenance of genetic variation and fitness across the species range.


Using syndromic measures of mortality to capture the dynamics of COVID-19 in Java, Indonesia, in the context of vaccination rollout.
As in many countries, quantifying COVID-19 spread in Indonesia remains challenging due to testing limitations. In Java, non-pharmaceutical interventions (NPIs) were implemented throughout 2020. However, as a vaccination campaign launches, cases and deaths are rising across the island. We used modelling to explore the extent to which data on burials in Jakarta using strict COVID-19 protocols (C19P) provide additional insight into the transmissibility of the disease, epidemic trajectory, and the impact of NPIs. We assess how implementation of NPIs in early 2021 will shape the epidemic during the period of likely vaccine rollout. C19P burial data in Jakarta suggest a death toll approximately 3.3 times higher than reported. Transmission estimates using these data suggest earlier, larger, and more sustained impact of NPIs. Measures to reduce sub-national spread, particularly during Ramadan, substantially mitigated spread to more vulnerable rural areas. Given current trajectory, daily cases and deaths are likely to increase in most regions as the vaccine is rolled out. Transmission may peak in early 2021 in Jakarta if current levels of control are maintained. However, relaxation of control measures is likely to lead to a subsequent resurgence in the absence of an effective vaccination campaign. Syndromic measures of mortality provide a more complete picture of COVID-19 severity upon which to base decision-making. The high potential impact of the vaccine in Java is attributable to reductions in transmission to date and dependent on these being maintained. Increases in control in the relatively short-term will likely yield large, synergistic increases in vaccine impact.


Psychotic Experiences in the Context of Police Victimization: Data From the Survey of Police-Public Encounters.
Social defeat has been proposed as the common mechanism underlying several well-replicated risk factors for sub-threshold psychotic experiences (PEs) identified in epidemiological research. Victimization by the police may likewise be socially defeating among vulnerable individuals and, therefore, may be associated with elevated risk for PEs. However, no prior studies have examined the relation between police victimization and PEs. We tested the hypothesis that exposure to police victimization (ie, physical, sexual, psychological, and neglect) would be associated with increased odds for PEs in the Survey of Police-Public Encounters data (N = 1615), a general population sample of adults from 4 US cities. Respondents who reported each type of police victimization were more likely to report PEs in logistic regression analyses (all P < .01), most of which were significant even when adjusting for demographic variables, psychological distress, and self-reported crime involvement (adjusted OR range: 1.30 to 7.16). Furthermore, the prevalence of PEs increased with greater exposure to police victimization in a linear dose-response relation, OR (95% CI) = 1.44 (1.24-1.66). These findings suggest that police victimization is a clinically important and previously unreported risk factor for PEs in the urban US population. These findings support the need for community-based outreach efforts and greater police training to reduce the prevalence of this exposure, particularly in socially disadvantaged urban communities.


The role of fat and calcium in the production of foci of aberrant crypts in the colon of rats fed 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine.
The modulation by dietary fat levels of intestine carcinogenesis is well documented. New developments suggest that calcium ions may also play a role. A rapid bioassay, the induction of foci of aberrant crypts in the colon, was used to explore the interaction between dietary fat and calcium. Male F344 rats 6 weeks of age were placed on diets containing 5 or 20% corn oil, and 0.04 or 0.32% calcium ion, as calcium lactate. Each dietary group was fed 400 ppm 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP), and negative controls received the diets alone. A positive control group was given 2 mg N-nitrosomethylurea (NMU) intrarectally four times in a 2-week period. All rats were killed after 9 weeks. The intestinal tract was rinsed with Krebs-Ringer buffer. After staining a 6-cm segment of the descending colon and rectum with 0.2% methylene blue, foci of aberrant crypts were evaluated microscopically. With PhlP as a carcinogen, the rats on a high-fat, low-calcium level had more foci of aberrant crypts than animals on a low-fat level. With the higher calcium level, there were fewer foci and aberrant crypts, but the effect of fat was still significant. With NMU and a low-calcium level, the effect of fat level was evident. However, with the higher calcium intake, there were considerably more foci of aberrant crypts than on the low-calcium level, and the effect of the dietary fat level was not obvious.(ABSTRACT TRUNCATED AT 250 WORDS)


SIRT2 is involved in cisplatin-induced acute kidney injury through regulation of mitogen-activated protein kinase phosphatase-1.
Activation of mitogen-activated protein kinase phosphatase-1 (MKP-1), a dual-specificity protein phosphatase, regulates mitogen-activated protein kinase signaling. C-Jun N-terminal kinase (JNK) and p38 are activated in cisplatin-induced renal injury. However, the change of MKP-1 expression in cisplatin-induced renal injury and the regulatory effect of sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide-dependent deacetylase, on MKP-1 remains unknown. To address these issues, we used constitutional Sirt2 knockout (KO) mice, transgenic (TG) mice with increased expression of SIRT2 specifically in proximal tubular epithelial cellsand wild-type (WT) mice. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin. MKP-1 expression in the kidney was decreased after cisplatin treatment. Cisplatin-induced downregulation of MKP-1 was reversed in Sirt2 KO mice kidney and further decreased in Sirt2 TG mice kidney. We observed similar phenomenon with SIRT2-knockdown or SIRT2-overexpressed tubular epithelial cells. Phosphorylation of p38 and JNK, a downstream signal pathway of MKP-1, increased in WT mice kidney following treatment with cisplatin. A decrease in SIRT2 suppressed cisplatin-induced phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Overexpression of SIRT2 further increased phosphorylation of p38 and JNK in kidney and tubular epithelial cells. Acetylation of MKP-1 was significantly increased in SIRT2-knockdown cells and decreased in SIRT2-overexpressed cells after cisplatin stimulation. Sirt2 KO mice and Sirt2 TG mice showed amelioration and aggravation of renal injury, apoptosis, necroptosis and inflammation induced by cisplatin. Our data show that SIRT2 is associated with cisplatin-induced renal injury through regulation of MKP-1 expression.


Faculty and resident evaluations of medical students on a surgery clerkship correlate poorly with standardized exam scores.
The clinical knowledge of medical students on a surgery clerkship is routinely assessed via subjective evaluations from faculty members and residents. Interpretation of these ratings should ideally be valid and reliable. However, prior literature has questioned the correlation between subjective and objective components when assessing students' clinical knowledge. Retrospective cross-sectional data were collected from medical student records at The Johns Hopkins University School of Medicine from July 2009 through June 2011. Surgical faculty members and residents rated students' clinical knowledge on a 5-point, Likert-type scale. Interrater reliability was assessed using intraclass correlation coefficients for students with ≥4 attending surgeon evaluations (n = 216) and ≥4 resident evaluations (n = 207). Convergent validity was assessed by correlating average evaluation ratings with scores on the National Board of Medical Examiners (NBME) clinical subject examination for surgery. Average resident and attending surgeon ratings were also compared by NBME quartile using analysis of variance. There were high degrees of reliability for resident ratings (intraclass correlation coefficient, .81) and attending surgeon ratings (intraclass correlation coefficient, .76). Resident and attending surgeon ratings shared a moderate degree of variance (19%). However, average resident ratings and average attending surgeon ratings shared a small degree of variance with NBME surgery examination scores (ρ(2) ≤ .09). When ratings were compared among NBME quartile groups, the only significant difference was for residents' ratings of students with the lower 25th percentile of scores compared with the top 25th percentile of scores (P = .007). Although high interrater reliability suggests that attending surgeons and residents rate students with consistency, the lack of convergent validity suggests that these ratings may not be reflective of actual clinical knowledge. Both faculty members and residents may benefit from training in knowledge assessment, which will likely increase opportunities to recognize deficiencies and make student evaluation a more valuable tool.


Standardized observation of neighbourhood disorder: does it work in Canada?
There is a growing body of evidence that where you live is important to your health. Despite numerous previous studies investigating the relationship between neighbourhood deprivation (and structure) and residents' health, the precise nature of this relationship remains unclear. Relatively few investigations have relied on direct observation of neighbourhoods, while those that have were developed primarily in US settings. Evaluation of the transferability of such tools to other contexts is an important first step before applying such instruments to the investigation of health and well-being. This study evaluated the performance of a systematic social observational (SSO) tool (adapted from previous studies of American and British neighbourhoods) in a Canadian urban context. This was a mixed-methods study. Quantitative SSO ratings and qualitative descriptions of 176 block faces were obtained in six Toronto neighbourhoods (4 low-income, and 2 middle/high-income) by trained raters. Exploratory factor analysis was conducted with the quantitative SSO ratings. Content analysis consisted of independent coding of qualitative data by three members of the research team to yield common themes and categories. Factor analysis identified three factors (physical decay/disorder, social accessibility, recreational opportunities), but only 'physical decay/disorder' reflected previous findings in the literature. Qualitative results (based on raters' fieldwork experiences) revealed the tool's shortcomings in capturing important features of the neighbourhoods under study, and informed interpretation of the quantitative findings. This study tested the performance of an SSO tool in a Canadian context, which is an important initial step before applying it to the study of health and disease. The tool demonstrated important shortcomings when applied to six diverse Toronto neighbourhoods. The study's analyses challenge previously held assumptions (e.g. social 'disorder') regarding neighbourhood social and built environments. For example, neighbourhood 'order' has traditionally been assumed to be synonymous with a certain degree of homogeneity, however the neighbourhoods under study were characterized by high degrees of heterogeneity and low levels of disorder. Heterogeneity was seen as an appealing feature of a block face. Employing qualitative techniques with SSO represents a unique contribution, enhancing both our understanding of the quantitative ratings obtained and of neighbourhood characteristics that are not currently captured by such instruments.


Widening Black/White mortality differentials among US children during the 1980s.
With the exception of infants, mortality rate differentials among Black and White children have received very little attention. We address four empirical questions: 1) Did the Black/White childhood mortality disparity grow between 1980 and 1990? 2) What causes of death account for Black/White disparities in childhood mortality and temporal changes in the size of this disparity? 3) Do economic disparities between Black and White families account for Black/White childhood mortality differentials in 1980 or 1990? 4) Do growing economic disparities between Black and White families explain any growth in childhood mortality differentials? Childhood mortality patterns and causes of excess deaths in Black children are examined in the nation overall and in three major metropolitan areas-Chicago, Detroit, and New York-using a dataset combining death certificate and Census data. Logistic regression analyses utilize Census socioeconomic information to identify the relationship between mortality risk and local area income in the metro areas. Black children's relative mortality disadvantage grew more severe during the 1980s, with startling growth in Black/White disparities seen in many age- and sex-specific metro populations. While White children generally experienced marked mortality declines, Black children's rates fell more slowly or actually increased, most dramatically among adolescent boys in Detroit and Chicago. Excess deaths among younger Black children were most often fire-related, while homicide was the predominant cause at older ages. Regression analyses confirmed that areal income was significantly and strongly related to child mortality at both time points in all study areas. However, the deterioration in areal income for Black children relative to Whites from 1980 to 1990 did not explain their worsening mortality rates over the time period. Black children are increasingly suffering excess deaths relative to White children. We find that Black children's mortality disadvantage is largely accounted for by areal economic disadvantage; however, expanding death rate disparities over time represented more than simply growth in income differentials. Our results suggest that other adverse exposures also have increasingly served to compromise Black children's life chances during the 1980s.


Out-of-hospital airway management in the United States.
Prior studies describe airway management by single EMS agencies, regions or states. We sought to characterize out-of-hospital airway management interventions, outcomes and complications across the United States. Using the 2008 National Emergency Medical Services Information System (NEMSIS) Public-Release Data Set containing data from 16 states, we identified patients receiving advanced airway management, including endotracheal intubation (ETI), alternate airways (Combitube, Laryngeal Mask Airway (LMA), King LT, Esophageal-Obturator Airway (EOA)), and cricothyroidotomy (needle and open). We examined airway management success and complications in the full cohort and in key subsets (cardiac arrest, non-arrest medical, non-arrest injury, children <10 and 10-19 years, rapid-sequence intubation (RSI), population setting and US census region). We analyzed the data using descriptive statistics. Among 4,383,768 EMS activations, there were 10,356 ETI, 2246 alternate airways, and 88 cricothyroidotomies. ETI success rates were: overall 6482/8418 (77.0%; 95% CI: 76.1-77.9%), cardiac arrest 3494/4482 (78.0%), non-arrest medical 616/846 (72.8%), non-arrest injury 417/505 (82.6%), children <10 years 295/397 (74.3%), children 10-19 years 228/289 (78.9%), adult 5829/7552 (77.2%), and rapid-sequence intubation 289/355 (81.4%). ETI success was success was lowest in the South US census region. Alternate airway success was 1564/1794 (87.2%). Major complications included: bleeding 84 (7.0 per 1000 interventions), vomiting 80 (6.7 per 1000) and esophageal intubation 12 (1.0 per 1000). In this study characterizing out-of-hospital airway management across the United States, we observed low out-of-hospital ETI success rates. These data may guide national efforts to improve the quality of out-of-hospital airway management.


The vascular epigenome in patients with obesity and type 2 diabetes: opportunities for personalized therapies.
Our genetic background provides limited information on individual risk of developing vascular complications overtime. New biological layers, namely epigenetic modifications, are now emerging as potent regulators of gene expression thus leading to altered transcriptional programs and vascular disease phenotypes. Such epigenetic modifications, defined as changes to the genome that do not involve changes in DNA sequence, are generally induced by environmental factors and poor lifestyle habits. Of note, adverse epigenetic signals acquired during life can be transmitted to the offspring thus leading to premature alterations of the epigenetic and transcriptional landscape eventually leading to early endothelial dysfunction and vascular senescence. Modifications of the epigenome play a pivotal role in the pathophysiology of cardiometabolic disturbances such as obesity and type 2 diabetes. In these patients, changes of DNA methylation and chromatin structure contribute to alter pathways regulating insulin sensitivity, glucose homeostasis, adipogenesis and vascular function. In this perspective, unveiling the 'epigenetic landscape' in cardiometabolic patients may help to identify new players implicated in obesity and diabetes-related vascular dysfunction and may pave the way for personalized therapies in this setting. In the present review, we discuss current knowledge of the epigenetic routes implicated in vascular damage and cardiovascular disease in patients with metabolic alterations.


Structure and Reactivity of Indolylmethylium Ions: Scope and Limitations in Synthetic Applications.
Eight substituted aryl(indol-3-yl)methylium tetrafluoroborates 3(a-h)-BF4 and three bis(indol-3-yl)methylium tetrafluoroborates 3(i-k)-BF4 have been synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their reactions with π-nucleophiles 8(a-j) (silylated enol ethers and ketene acetals) were studied kinetically using photometric monitoring at 20 °C. The resulting second-order rate constants were found to follow the correlation log k(20 °C) = sN(N + E), in which nucleophiles are characterized by the two solvent-dependent parameters N and sN, and electrophiles are characterized by one parameter, E. From the previously reported N and sN parameters of the employed nucleophiles and the measured rate constants, the electrophilicities of the indol-3-ylmethylium ions 3(a-k) were derived and used to predict potential nucleophilic reaction partners. A discrepancy between published rate constants for the reactions of morpholine and piperidine with the (2-methylindol-3-yl)phenylmethylium ion 3h and those calculated from E, N, and sN was analyzed and demonstrated to be due to a mistake of the value reported in the literature.


Intraspecific Autochthonous and Allochthonous Resource Use by Zooplankton in a Humic Lake during the Transitions between Winter, Summer and Fall.
Seasonal patterns in assimilation of externally produced, allochthonous, organic matter into aquatic food webs are poorly understood, especially in brown-water lakes. We studied the allochthony (share biomass of terrestrial origin) in cladoceran, calanoid and cyclopoid micro-crustacean zooplankton from late winter to fall during two years in a small humic lake (Sweden). The use of allochthonous resources was important for sustaining a small population of calanoids in the water column during late winter. However, in summer the calanoids shifted to 100% herbivory, increasing their biomass several-fold by making efficient use of the pelagic primary production. In contrast, the cyclopoids and cladocerans remained at high levels of allochthony throughout the seasons, both groups showing the mean allochthony of 0.56 (range in mean 0.17-0.79 and 0.34-0.75, for the respective group, depending on model parameters). Our study shows that terrestrial organic matter can be an important resource for cyclopoids and cladocerans on an annual basis, forming a significant link between terrestrial organic matter and the higher trophic levels of the food web, but it can also be important for sustaining otherwise herbivorous calanoids during periods of low primary production in late winter.


Discrete wave mechanics: The hydrogen atom.
The quantum mechanical problem of the hydrogen atom is treated by use of a finite difference equation in place of Schrödinger's differential equation. The exact solution leads to a wave vector energy expression that is readily converted to the Bohr-Rydberg formula. (The calculations here reported are limited to spherically symmetric states.) The wave vectors reduce to the familiar solutions of Schrödinger's equation as c --> infinity. The internal consistency and limiting behavior provide support for the view that the equations employed could well constitute an approach to a relativistic formulation of wave mechanics.


Influence of intrauterine growth status on aortic intima-media thickness and aortic diameter in near-term fetuses: a comparative cross-sectional study.
Intrauterine undernutrition may lead to fetal vascular programming. We compared abdominal aortic intima-media thickness (aIMT) and aortic diameter (aD) between appropriate for gestational age (AGA) and growth-restricted fetuses (GRF). We recruited 136 singleton fetuses at 34-37 weeks of gestation from Fetal Medicine Unit of Aga Khan University Hospital, Karachi (January-November 2017). Subjects were classified as AGA (n = 102) and GRF (n = 34) using INTER-GROWTH 21st growth reference and standard ultrasound protocol. Their far- and near-wall aIMT and aD were compared after adjustment of maternal age, first-trimester body mass index, fetal gender, hypertension and hyperglycemia in pregnancy. As the severity of growth restriction increased in GRF, aIMT and aD showed an increasing and a decreasing trend, respectively. Both far- and near-wall aIMT in GRF [(adj. β = 0.082, 95% confidence interval [CI] 0.042-0.123) and (adj. β = 0.049, 95% CI 0.010-0.089)] were significantly greater with reference to AGA fetuses. GRF subgroup analysis into small for gestational age (SGA) fetuses and intrauterine growth restricted (IUGR) revealed highly significant difference between AGA and IUGR for far (0.142 mm, P-value < 0.001) and near-wall aIMT (0.115 mm, P-value < 0.001) and marginally significant aD difference (0.51 mm, P-value 0.05). These findings suggest that the extent of fetal aortic remodelling is influenced by the severity of growth restriction. Hence, the targeted interventions for the cardiovascular health promotion of IUGR and SGA born neonates are desirable during early childhood, particularly in set ups with high prevalence of low birth weight babies.


Beneficial changes in energy expenditure and lipid profile after eccentric exercise in overweight and lean women.
The aim was to compare lean and overweight females in regard to the effects of eccentric exercise on muscle damage indices, resting energy expenditure (REE) and respiratory quotient (RQ) as well as blood lipid and lipoprotein profile. Lean and overweight females (deviated by their body mass index) performed an eccentric exercise session. Muscle damage, energy cost and lipid profile were assessed pre-exercise and up to 72 h post-exercise. After eccentric exercise (i) muscle damage indices were affected more in the overweight subjects compared with the lean subjects; (ii) the elevation of absolute and relative REE was larger and more prolonged in the overweight group compared with the lean group; (iii) after 24 h, RQ had significantly declined, with the overweight subjects exhibiting a larger reduction compared with the lean group; and (iv) the blood lipid profile was favorably modified, with the overweight group exhibiting more favorable responses compared with the lean group. The differences between the lean and the overweight subjects may be partly due to the fact that overweight individuals experienced greater muscle damage than lean individuals. Eccentric exercise may be a promising lifestyle factor to combat obesity and dyslipidemias.


Below-knee deep vein thrombosis (DVT): diagnostic and treatment patterns.
Guidelines are lacking for isolated below-knee deep vein thrombosis (BKDVT). The American College of Chest Physicians (ACCP) suggests anticoagulation only if symptoms are severe, otherwise surveillance with follow-up ultrasound in 2 weeks is recommended. Yet clinical practice remains highly variable. Little is known about the natural history of BKDVT and how to best manage these patients. A retrospective analysis was conducted of medical records from 2014-2016. Risk factors were assessed such as age, gender, malignancy, recent surgery, and history of DVT. Treatment decisions and outcomes were identified. Radiology reports were graded for clarity. Chi-square and logistic regression were used to correlate risk factors with outcomes and determine odds of treatment. New isolated BKDVT was identified in 102 patients. Patients were symptomatic or had previous pulmonary embolism (PE) or DVT in all cases. Eighteen were positive for PE at diagnosis (17.6% of all patients or 62.1% with chest CT). Malignancy was independently associated with PE (P=0.015); no other risk factors were significant. Treatment was not associated with clinical risk factors. The language used for radiology reports was highly variable and was associated with the decision to treat with anticoagulation. One hundred percent were treated (n=24) when the report stated "positive DVT" and 89.2% (n=58) were treated after an objective description without the word "DVT" (P=0.01). Treatment was much less likely if the report described BKDVT anatomically but was said to be "negative for DVT" (P<0.001). A total of 86.3% (n=88) of all patients were treated, compared to 46.2% (n=6) of patients in this group (n=13). IVC filters were placed in 3 patients. Of the 14 untreated patients, 5 received surveillance, 3 developed new proximal DVT, and none developed PE. About 90% of patients diagnosed with BKDVT received anticoagulation after the initial diagnosis. Surveillance was not commonly recommended and is likely underutilized. Radiology reporting was highly variable and correlated with clinical treatment decisions, whereas other clinical risk factors did not. Describing BKDVT findings only in terms of being "positive" or "negative" for DVT may be inadequate.


Phylogenetic screening of a bacterial, metagenomic library using homing endonuclease restriction and marker insertion.
Metagenomics provides access to the uncultured majority of the microbial world. The approaches employed in this field have, however, had limited success in linking functional genes to the taxonomic or phylogenetic origin of the organism they belong to. Here we present an efficient strategy to recover environmental DNA fragments that contain phylogenetic marker genes from metagenomic libraries. Our method involves the cleavage of 23S ribsosmal RNA (rRNA) genes within pooled library clones by the homing endonuclease I-CeuI followed by the insertion and selection of an antibiotic resistance cassette. This approach was applied to screen a library of 6500 fosmid clones derived from the microbial community associated with the sponge Cymbastela concentrica. Several fosmid clones were recovered after the screen and detailed phylogenetic and taxonomic assignment based on the rRNA gene showed that they belong to previously unknown organisms. In addition, compositional features of these fosmid clones were used to classify and taxonomically assign a dataset of environmental shotgun sequences. Our approach represents a valuable tool for the analysis of rapidly increasing, environmental DNA sequencing information.


A combined heart rate and movement sensor: proof of concept and preliminary testing study.
Heart rate monitoring has previously been used as a technique for measuring energy expenditure (EE) in field studies. However, the combination of heart rate monitoring with movement sensoring could have theoretical advantages compared to either method used alone. Therefore, this study was undertaken to develop and validate a new combined heart rate monitor and movement sensor instrument (HR+M) for measuring EE. The HR+M instrument is a single-piece instrument worn around the chest which records minute-by-minute heart rate and movement. Eight subjects underwent an individual calibration in which EE and heart rate were measured at rest and during a sub-maximal bicycle ergometer test. They then wore the HR+M for 24 hours in a whole-body calorimeter and underwent a standard protocol including periods of physical activity and inactivity. Minute-by-minute heart rate was converted to EE using individual calibration curves with the motion data discriminating between periods of inactivity and activity at low heart rate levels. EE was also calculated using the HRFlex method which relies on heart rate alone. Both estimates of EE were compared to EE measured in the whole-body calorimeter. The mean percentage error of the HR+M method calculating TEE compared with the gold standard of the calorimeter measurement was 0.00% (95% CI of the mean error -0.25, 1. 25). The HRFlex method using the heart rate information alone resulted in a mean percentage error of 16.5% (95% CI of the mean error -0.57, 1.76). This preliminary test of HR+M demonstrates its ability to estimate EE and the pattern of EE and activity throughout the day. Further validation studies in free-living individuals are necessary. NJW is an MRC Clinician Scientist Fellow. KLR holds an MRC PhD scholarship.


Salmonella typhi mutants defective in anaerobic respiration are impaired in their ability to replicate within epithelial cells.
By using MudJ (Kan, lac)-directed operon fusion technology, mutants of Salmonella typhi whose gene expression is induced under anaerobic growth conditions were isolated. Characterization of their phenotypes and regulatory properties revealed that two of the mutants were unable to use nitrate as a terminal electron acceptor in the absence of oxygen, suggesting that they were defective in nitrate reductase activity. Anaerobic induction of these fusions did not further increase in response to nitrate. Strains carrying an additional mutation in oxrA were constructed. They showed a lower level of beta-galactosidase expression both aerobically and anaerobically; however, the ratios of anaerobic induction remained unaltered. These MudJ insertions mapped to the 17-19 min region of the chromosome. Based upon their phenotypes and mapping, one of the mutants probably possessed a modC (chlD)::MudJ insertion and the other a moaA (chlA)::MudJ insertion. A third mutant was unable to use either nitrate or fumarate as a terminal electron acceptor. All three mutants showed a reduced ability to enter into and proliferate within HEp-2 epithelial cells. The oxrA mutation enhanced entry and proliferation of both the wild-type cells and the three mutants. Taken together, these results suggest that anaerobic respiration plays a role in S. typhi invasiveness.


Clinicopathological and molecular characterisation of 'multiple-classifier' endometrial carcinomas.
Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal - p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple-classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd-p53abn), 31 with POLEmut (POLEmut-p53abn), and 12 with all three aberrations (MMRd-POLEmut-p53abn). MMRd-p53abn ECs and POLEmut-p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd-p53abn ECs and 7/15 (46.7%) POLEmut-p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd-p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut-p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd-p53abn and POLEmut-p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd-p53abn EC as MMRd and POLEmut-p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Sociodemographic Variation in Consumption Patterns of Sustainable and Nutritious Seafood in Australia.
National dietary guidelines (DGs) consistently recommend consuming seafood for health benefits, however, the sustainability of increasing seafood consumption is often challenged. Seafood products vary in environmental performance as well as health benefits, yet there is no information integrating the health and ecological impacts of different seafood choices. The first step in optimising improved health and environmental outcomes is to examine more closely the types of seafood being consumed at population and individual levels, to develop the means to increase the intake of seafood that is optimal for human health and the environment. The purpose of this analysis was to better understand the specific types and amounts of seafood consumed by the Australian population, and by socioeconomic subgroups within the population, to determine the relative nutritional content and sustainability of seafood consumed by these groups. Secondary analysis of the Australian Health Survey (AHS) (2011-2013), which reached 32,000 people (25,000 households) was undertaken. The majority of respondents (83%) did not consume any seafood on the day of the survey. Results indicated the proportion of seafood consumers was lowest among adults who were unemployed, had the least education and were the most socio-economically disadvantaged. Crustaceans and farmed fish with low omega 3-content, such as basa and tilapia, were identified as the least nutritious and least sustainable seafood categories. These two categories constituted a substantial amount of total seafood intake for the lowest socio-economic consumers, and over 50% for unemployed consumers. In contrast, consumers in the highest socio-demographic group consumed mainly high trophic level fish (moderate nutrition and sustainability) and farmed fish with high omega-3 content (high nutrition, moderate sustainability). Fewer than 1% of adults or children reported eating seafood identified as both more nutritious and less resource intensive, such as small pelagics or molluscs. Opportunities exist to increase seafood intakes to improve health outcomes by varying current seafood consumption patterns to maximise nutritional outcomes and minimise environmental impacts. Initiatives to promote the health and environmental benefits of seafood should be promoted at the population level, with targeted interventions for specific groups, and should encourage consumption of highly nutritious low resource intensive types of seafood.


Promoting Value for Consumers: Comparing Individual Health Insurance Markets Inside and Outside the ACA's Exchanges.
The new health insurance exchanges are the core of the Affordable Care Act's (ACA) insurance reforms, but insurance markets beyond the exchanges also are affected by the reforms. This issue brief compares the markets for individual coverage on and off of the exchanges, using insurers' most recent projections for ACA-compliant policies. In 2016, insurers expect that less than one-fifth of ACA-compliant coverage will be sold outside of the exchanges. Insurers that sell mostly through exchanges devote a greater portion of their premium dollars to medical care than do insurers selling only off of the exchanges, because exchange insurers project lower administrative costs and lower profit margins. Premium increases on exchange plans are less than those for off-exchange plans, in large part because exchange enrollment is projected to shift to closed-network plans. Finally, initial concerns that insurers might seek to segregate higher-risk subscribers on the exchanges have not been realized.


Tracheal Aspirate Levels of the Matricellular Protein SPARC Predict Development of Bronchopulmonary Dysplasia.
Isolation of tracheal aspirate mesenchymal stromal cells (MSCs) from premature infants has been associated with increased risk of bronchopulmonary dysplasia (BPD). MSCs show high levels of mRNAs encoding matricellular proteins, non-structural extracellular proteins that regulate cell-matrix interactions and participate in tissue remodeling. We hypothesized that lung matricellular protein expression predicts BPD development. We collected tracheal aspirates and MSCs from mechanically-ventilated premature infants during the first week of life. Tracheal aspirate and MSC-conditioned media were analyzed for seven matricellular proteins including SPARC (for Secreted Protein, Acidic, Rich in Cysteine, also called osteonectin) and normalized to secretory component of IgA. A multiple logistic regression model was used to determine whether tracheal aspirate matricellular protein levels were independent predictors of BPD or death, controlling for gestational age (GA) and birth weight (BW). We collected aspirates from 89 babies (38 developed BPD, 16 died before 36 wks post-conceptual age). MSC-conditioned media showed no differences in matricellular protein abundance between cells from patients developing BPD and cells from patients who did not. However, SPARC levels were higher in tracheal aspirates from babies with an outcome of BPD or death (p<0.01). Further, our logistic model showed that tracheal aspirate SPARC (p<0.02) was an independent predictor of BPD/death. SPARC deposition was increased in the lungs of patients with BPD. In mechanically-ventilated premature infants, tracheal aspirate SPARC levels predicted development of BPD or death. Further study is needed to determine the value of SPARC as a biomarker or therapeutic target in BPD.


Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.
Limited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL. This study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4). Of 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. The HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.


Age and ratings of manic psychopathology.
Clinicians have suggested that manic psychopathology in adulthood changes with advanced age. We used rating scale evaluations of manic psychopathology in adult patients with bipolar (BP) disorder to test whether older age is associated with scores on items related to excesses of behaviors: i.e., Sexual Interest, Increased Activity-Energy, Speech--Rate and Amount, and Disruptive-Aggressive Behavior. The association of Young Mania Rating Scale item scores with current age was studied in symptomatic inpatients meeting DSM-IV criteria for BP disorder, manic. The sample consisted of 149 patients ranging in age from 18 to 89 years; 48 of these were male. Age was not associated with differences in overall severity reflected in total score. Age was associated with lower scores on the Sexual Interest item (r = - 0.26, p < 0.001). A trend for higher scores with age on Speech--Rate and Amount (r = 0.19, p < 0.02) did not meet criteria for significance. Increased Activity-Energy, Disruptive-Aggressive Behavior and other item scores were not associated with age. In an exploratory analysis, age and Sexual Interest and Speech item scores were associated in female patients but not in male patients. These findings suggest that age minimally influences manic psychopathology in patients with BP disorder. The modest correlation between age and Sexual Interest item scores warrants further investigation and the trend for an association between age and Speech--Rate and Amount can be examined in future studies. Possible gender differences in the associations between age and these item scores also invite future study.


Identification of the potentiating mutations and synergistic epistasis that enabled the evolution of inter-species cooperation.
Microbes often engage in cooperation through releasing biosynthetic compounds required by other species to grow. Given that production of costly biosynthetic metabolites is generally subjected to multiple layers of negative feedback, single mutations may frequently be insufficient to generate cooperative phenotypes. Synergistic epistatic interactions between multiple coordinated changes may thus often underlie the evolution of cooperation through overproduction of metabolites. To test the importance of synergistic mutations in cooperation we used an engineered bacterial consortium of an Escherichia coli methionine auxotroph and Salmonella enterica. S. enterica relies on carbon by-products from E. coli if lactose is the only carbon source. Directly selecting wild-type S. enterica in an environment that favored cooperation through secretion of methionine only once led to a methionine producer, and this producer both took a long time to emerge and was not very effective at cooperating. On the other hand, when an initial selection for resistance of S. enterica to a toxic methionine analog, ethionine, was used, subsequent selection for cooperation with E. coli was rapid, and the resulting double mutants were much more effective at cooperation. We found that potentiating mutations in metJ increase expression of metA, which encodes the first step of methionine biosynthesis. This increase in expression is required for the previously identified actualizing mutations in metA to generate cooperation. This work highlights that where biosynthesis of metabolites involves multiple layers of regulation, significant secretion of those metabolites may require multiple mutations, thereby constraining the evolution of cooperation.


A case of fetal midgut volvulus and jejunal atresia: nutritional support and maintenance of mucosal function and integrity.
Fetal midgut volvulus is a quite rare disease. Here, we report a case of a preterm newborn with fetal peritonitis, jejunal atresia with volvulus of post-atresic small bowel since about 30 cm from ileo-cecal valve (ICV) followed by a not-used microileus and microcolon. The surgical intervention consisted in the resection of volvulated necrotic small bowel followed by primary anastomosis. After surgery, total parenteral nutrition (TPN) has been started since 16(th) of post-operative days when enteral feeding (EN) was administered with a lactose-free formula containing hydrolyzed protein and medium-chain triglycerides (Pregestimil). Re-establishing intestinal continuity was preferred rather than stoma that would have required TPN. In fact, re-operation could have led to a shorter residual small bowel (RSB), since the anastomosis was at 15 cm from ICV. Our study provides evidence that not only the type of procedure (enteral versus parenteral) of nutritional support, but also the type of milk may modify the outcome. Early EN should be encouraged in newborn abdominal surgical patients because it is associated with reduced complications.


Optofluidic Modulation of Self-Associated Nanostructural Units Forming Planar Bragg Microcavities.
Bragg microcavities (BMs) formed by the successive stacking of nanocolumnar porous SiO2 and TiO2 layers with slanted, zigzag, chiral, and vertical configurations are prepared by physical vapor deposition at oblique angles while azimuthally varying the substrate orientation during the multilayer growth. The slanted and zigzag BMs act as wavelength-selective optical retarders when they are illuminated with linearly polarized light, while no polarization dependence is observed for the chiral and vertical cavities. This distinct optical behavior is attributed to a self-nanostructuration mechanism involving a fence-bundling association of nanocolumns as observed by focused ion beam scanning electron microscopy in the slanted and zigzag microcavities. The outstanding retarder response of the optically active BMs can be effectively modulated by dynamic infiltration of nano- and mesopores with liquids of different refraction indices acting as a switch of the polarization behavior. The unprecedented polarization and tunable optofluidic properties of these nanostructured photonic systems have been successfully simulated with a simple model that assumes a certain birefringence for the individual stacked layers and accounts for the light interference phenomena developed in the BMs. The possibilities of this type of self-arranged nanostructured and optically active BMs for liquid sensing and monitoring applications are discussed.


Musculoskeletal coccidioidomycosis.
Coccidioidomycosis (valley fever) is a systemic fungal infection caused by soil fungi, Coccidioides species, and is associated with significant morbidity and mortality. This infection is endemic in northern Mexico, the southwestern United States, and parts of Central and South America. The risk factors include ethnicity (especially African and Pacific Island ancestry), male gender, and immunosuppression. The primary infection occurs in lungs, but fewer than 40% of patients are symptomatic. Fewer than 1% of infections result in disseminated disease, which may involve any organ. Skeletal infection occurs in 10 to 50% of these patients and is frequently multicentric with axial skeleton involvement. The diagnosis can be confirmed by culture of the organism or visual detection from cytological or histological specimens obtained from sites of disease. A presumptive diagnosis can be made in patients with a compatible illness and a positive serologic test. Imaging plays a significant role in diagnosis and follow-up treatment of musculoskeletal coccidioidomycosis and includes radiography, magnetic resonance imaging, computed tomography, and bone scintigraphy. Skeletal coccidioidomycosis is difficult to treat and frequently requires a combination of medical therapy and surgical debridement. Medical therapy must be continued for a prolonged period of time, potentially for a lifetime in some patients.


Social, economic and legal dimensions of tobacco and its control in South-East Asia region.
This paper examines the social, cultural, economic and legal dimensions of tobacco control in the South-East Asia Region in a holistic view through the review of findings from various studies on prevalence, tobacco economics, poverty alleviation, women and tobacco and tobacco control laws and regulations. Methods were Literature review of peer reviewed publications, country reports, WHO publications, and reports of national and international meetings on tobacco and findings from national level surveys and studies. Tobacco use has been a social and cultural part of the people of South-East Asia Region. Survey findings show that 30% to 60% of men and 1.8% to 15.6% of women in the Region use one or the other forms of tobacco products. The complex nature of tobacco use with both smoking and smokeless forms is a major challenge for implementing tobacco control measures. Prevalence of tobacco use is high among the poor and the illiterate. It is higher among males than females but studies show a rising trend among girls and women due to intensive marketing of tobacco products by the tobacco industry. Tobacco users spend a huge percent of their income on tobacco which deprives them and their families of proper nutrition, good education and health care. Some studies of the Region show that cost of treatment of diseases attributable to tobacco use was more than double the revenue that governments received from tobacco taxation. Another challenge the Region faces is the application of uniform tax to all forms of tobacco, which will reduce not only the availability of tobacco products in the market but also control people switching over to cheaper tobacco products. Ten out of eleven countries are Parties to the WHO Framework Convention on Tobacco Control and nine countries have tobacco control legislation. Enforcement of control measures is weak, particularly in areas such as smoke-free environments, advertisement at the point of sale and sale of tobacco to minors. Socio-cultural acceptance of tobacco use is still a major challenge in tobacco control efforts for the governments and stakeholders in the South-East Asia Region. The myth that chewing tobacco is less harmful than smoking tobacco needs to be addressed with public awareness campaigns. Advocacy on the integration of tobacco control with poverty alleviation campaigns and development programs is urgently required. Law enforcement is a critical area to be strengthened and supported by WHO and the civil society organizations working in the area of tobacco control.


Vital Signs: Trends in Reported Vectorborne Disease Cases - United States and Territories, 2004-2016.
Vectorborne diseases are major causes of death and illness worldwide. In the United States, the most common vectorborne pathogens are transmitted by ticks or mosquitoes, including those causing Lyme disease; Rocky Mountain spotted fever; and West Nile, dengue, and Zika virus diseases. This report examines trends in occurrence of nationally reportable vectorborne diseases during 2004-2016. Data reported to the National Notifiable Diseases Surveillance System for 16 notifiable vectorborne diseases during 2004-2016 were analyzed; findings were tabulated by disease, vector type, location, and year. A total 642,602 cases were reported. The number of annual reports of tickborne bacterial and protozoan diseases more than doubled during this period, from >22,000 in 2004 to >48,000 in 2016. Lyme disease accounted for 82% of all tickborne disease reports during 2004-2016. The occurrence of mosquitoborne diseases was marked by virus epidemics. Transmission in Puerto Rico, the U.S. Virgin Islands, and American Samoa accounted for most reports of dengue, chikungunya, and Zika virus diseases; West Nile virus was endemic, and periodically epidemic, in the continental United States. Vectorborne diseases are a large and growing public health problem in the United States, characterized by geographic specificity and frequent pathogen emergence and introduction. Differences in distribution and transmission dynamics of tickborne and mosquitoborne diseases are often rooted in biologic differences of the vectors. To effectively reduce transmission and respond to outbreaks will require major national improvement of surveillance, diagnostics, reporting, and vector control, as well as new tools, including vaccines.


Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues.
The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes.


Renin-Angiotensin-Aldosterone System Blockers Are Not Associated With Coronavirus Disease 2019 (COVID-19) Hospitalization: Study of 1,439 UK Biobank Cases.
Background: Cardiometabolic morbidity and medications, specifically Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), have been linked with adverse outcomes from coronavirus disease 2019 (COVID-19). This study aims to investigate, factors associated with COVID-19 positivity in hospital for 1,436 UK Biobank participants; compared with individuals who tested negative, and with the untested, presumed negative, rest of the cohort. Methods: We studied 7,099 participants from the UK Biobank who had been tested for COVID-19 in hospital. We considered the following exposures: age, sex, ethnicity, body mass index (BMI), diabetes, hypertension, hypercholesterolaemia, ACEi/ARB use, prior myocardial infarction (MI), and smoking. We undertook comparisons between (1) COVID-19 positive and COVID-19 negative tested participants; and (2) COVID-19 tested positive and the remaining participants (tested negative plus untested, n = 494,838). Logistic regression models were used to investigate univariate and mutually adjusted associations. Results: Among participants tested for COVID-19, Black, Asian, and Minority ethnic (BAME) ethnicity, male sex, and higher BMI were independently associated with a positive result. BAME ethnicity, male sex, greater BMI, diabetes, hypertension, and smoking were independently associated with COVID-19 positivity compared to the remaining cohort (test negatives plus untested). However, similar associations were observed when comparing those who tested negative for COVID-19 with the untested cohort; suggesting that these factors associate with general hospitalization rather than specifically with COVID-19. Conclusions: Among participants tested for COVID-19 with presumed moderate to severe symptoms in a hospital setting, BAME ethnicity, male sex, and higher BMI are associated with a positive result. Other cardiometabolic morbidities confer increased risk of hospitalization, without specificity for COVID-19. ACE/ARB use did not associate with COVID-19 status.


Expanding micelle nanolithography to the self-assembly of multicomponent core-shell nanoparticles.
Size, composition, and pattern formation are crucial elements in the fabrication of functional multicomponent nanoparticles (NPs). Self-assembly techniques provide relevant control over NP size distribution (down to a few nanometers in diameter), but more importantly, such techniques are amenable for practical applications since the resulting NPs (and arrays thereof) are programmed in the molecular structure of the precursors. Here, the diblock copolymer micelle nanolithography concept of achieving monodisperse NPs is extended to direct the synthesis of multicomponent core-shell NPs arranged in a triangular lattice. Special emphasis is set on Co(core)@Fe(shell) and corrosion resistant (FeCo)(core)@Au(shell) NPs. Electron microscopy analyses show a variety of core-shell geometries spanning a wide range of oxide, metal, and alloy combinations.


Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop.
An expression cloning strategy was devised to isolate the keratinocyte growth factor (KGF) receptor complementary DNA. NIH/3T3 fibroblasts, which secrete this epithelial cell-specific mitogen, were transfected with a keratinocyte expression complementary DNA library. Among several transformed foci identified, one demonstrated the acquisition of specific high-affinity KGF binding sites. The pattern of binding competition by related fibroblast growth factors (FGFs) indicated that this receptor had high affinity for acidic FGF as well as KGF. The rescued 4.2-kilobase complementary DNA was shown to encode a predicted membrane-spanning tyrosine kinase related to but distinct from the basic FGF receptor. This expression cloning approach may be generally applicable to the isolation of genes that constitute limiting steps in mitogenic signaling pathways.


Investigation of the steps involved in the difference of susceptibility of Ephestia kuehniella and Spodoptera littoralis to the Bacillus thuringiensis Vip3Aa16 toxin.
BUPM95 is a Bacillus thuringiensis subsp. kurstaki strain producing the Vip3Aa16 toxin with an interesting insecticidal activity against the Lepidopteran larvae Ephestia kuehniella. Study of different steps in the mode of action of this Vegetative Insecticidal Protein on the Mediterranean flour moth (E. kuehniella) was carried out in the aim to investigate the origin of the higher susceptibility of this insect to Vip3Aa16 toxin compared to that of the Egyptian cotton leaf worm Spodoptera littoralis. Using E. kuehniella gut juice, protoxin proteolysis generated a major band corresponding to the active toxin and another band of about 22kDa, whereas the activation of Vip3Aa16 by S. littoralis gut juice proteases generated less amount of the 62kDa active form and three other proteolysis products. As demonstrated by zymogram analysis, the difference in proteolysis products was due to the variability of proteases in the two gut juices larvae. The study of the interaction of E. kuehniella BBMV with biotinylated Vip3Aa16 showed that this toxin bound to a putative receptor of 65kDa compared to the 55 and 100kDa receptors recognized in S. littoralis BBMV. The histopathological observations demonstrated similar damage caused by the toxin in the two larvae midguts. These results demonstrate that the step of activation, mainly, is at the origin of the difference of susceptibility of these two larvae towards B. thuringiensis Vip3Aa16 toxin.


Novel therapies for microvascular permeability in sepsis.
Sepsis is characterized physiologically by an aberrant systemic inflammatory response and microvascular dysfunction. While appropriate antibiotics and supportive care are essential in the management of the septic patient, therapies targeting specific aspects of the pathophysiology could have a significant impact on the morbidity and mortality associated with both sepsis and its sequlea, including acute lung injury (ALI). We have characterized several mediators of endothelial cell (EC) barrier function that may serve as novel therapies for sepsis-induced microvascular dysfunction including simvastatin, adenosine triphosphate (ATP), sphingosine 1-phosphate (S1P), and activated protein C (APC). Notably, APC is already available for the treatment of severe sepsis, however, to date its mechanism of action has been unclear. While distinct in many ways, we have found that these agonists have in common the ability to induce dynamic rearrangement of the EC actin cytoskeleton that corresponds to barrier protection. In addition, we have extended our in vitro findings to relevant animal models of endotoxin-induced acute lung injury and have confirmed beneficial effects of both simvastatin and S1P which are associated with evidence of decreased vascular permeability in this setting. Moreover, our data also indicate that APC effects in sepsis may be largely due to augmentation of EC barrier function affecting decreased microvascular permeability. We speculate that the administration of direct modulators of EC barrier function and microvascular permeability, such as those described here, may ultimately become the standard of care for the septic patient.


The influence of violent and nonviolent computer games on implicit measures of aggressiveness.
We examined the causal relationship between playing violent video games and increases in aggressiveness by using implicit measures of aggressiveness, which have become important for accurately predicting impulsive behavioral tendencies. Ninety-six adults were randomly assigned to play one of three versions of a computer game that differed only with regard to game content (violent, peaceful, or abstract game), or to work on a reading task. In the games the environmental context, mouse gestures, and physiological arousal-as indicated by heart rate and skin conductance-were kept constant. In the violent game soldiers had to be shot, in the peaceful game sunflowers had to be watered, and the abstract game simply required clicking colored triangles. Five minutes of play did not alter trait aggressiveness, yet an Implicit Association Test detected a change in implicit aggressive self-concept. Playing a violent game produced a significant increase in implicit aggressive self-concept relative to playing a peaceful game. The well-controlled study closes a gap in the research on the causality of the link between violence exposure in computer games and aggressiveness with specific regard to implicit measures. We discuss the significance of importing recent social-cognitive theory into aggression research and stress the need for further development of aggression-related implicit measures.


Ceramide synthesis regulates T cell activity and GVHD development.
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for a variety of hematologic malignances, yet its efficacy is impeded by the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells. Hence, strategies to limit GVHD are highly desirable. Ceramides are known to contribute to inflammation and autoimmunity. However, their involvement in T-cell responses to alloantigens is undefined. In the current study, we specifically characterized the role of ceramide synthase 6 (CerS6) after allo-HCT using genetic and pharmacologic approaches. We found that CerS6 was required for optimal T cell activation, proliferation, and cytokine production in response to alloantigen and for subsequent induction of GVHD. However, CerS6 was partially dispensable for the T cell-mediated antileukemia effect. At the molecular level, CerS6 was required for efficient TCR signal transduction, including tyrosine phosphorylation, ZAP-70 activation, and PKCθ/TCR colocalization. Impaired generation of C16-ceramide was responsible for diminished allogeneic T cell responses. Furthermore, targeting CerS6 using a specific inhibitor significantly reduced T cell activation in mouse and human T cells in vitro. Our study provides a rationale for targeting CerS6 to control GVHD, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.


In-plane motions of the stapes in human ears.
The piston-like (translation normal to the footplate) and rocking-like (rotation along the long and short axes of the footplate) are generally accepted as motion components of the human stapes. It has been of issue whether in-plane motions, i.e., transversal movements of the footplate in the oval window, are comparable to these motion components. In order to quantify the in-plane motions the motion at nine points on the medial footplate was measured in five temporal bones with the cochlea drained using a three-dimensional (3D) laser Doppler vibrometer. It was found that the stapes shows in-plane movements up to 19.1 ± 8.7% of the piston-like motion. By considering possible methodological errors, i.e., the effects of the applied reflective glass beads and of alignment of the 3D laser Doppler system, such value was reduced to be about 7.4 ± 3.1%. Further, the in-plane motions became minimal (≈ 4.2 ± 1.4% of the piston-like motion) in another plane, which was anatomically within the footplate. That plane was shifted to the lateral direction by 118 μm, which was near the middle of the footplate, and rotated by 4.7° with respect to the medial footplate plane.


Studies on relationships between metastatic and non-metastatic tumor cell populations using lineages labeled with dominant selectable genetic markers.
The relationships between metastatic and non-metastatic cell populations co-existing in composite neoplasms have been studied using cell lineages marked with a dominant selectable marker (neomycin resistance), by transfection. The experimental circumstances were arranged so that the lineages were known to be genotypically distinct (i.e. not merely phenotypic variants of the same lineage) and so that a single metastatic clone was each time combined with a mixed polyclonal non-metastatic population and both partners were distinctly and recognizably marked. This made it possible to ascertain the fates of clones with different metastatic capabilities during tumor progression and metastasis and evaluate their relative contributions to the clinical extent of disease. It was found that metastatic and non-metastatic cell lineages co-existed in most of the late-stage primary tumors examined and that a cell lineage that is invariably non-metastatic, when growing on its own, can with surprising frequency be found thriving in distant metastatic deposits, when it grows to form a primary tumor in combination with a metastatic partner. In fact, occasional metastases from such tumors contained no detectable cells of the metastatic lineage. The endowment of a tumor cell lineage with a new, clinically significant, capability which it convincingly and reproducibly did not manifest before, by another coexisting cell population raises several new questions about the contribution of such phenomena to the overall debilitating properties of the neoplasm and the geometric progression of its impact on the host.


Effects of extreme temperatures on cardiovascular emergency hospitalizations in a Mediterranean region: a self-controlled case series study.
Cold spells and heatwaves increase mortality. However little is known about the effect of heatwaves or cold spells on cardiovascular morbidity. This study aims to assess the effect of cold spells and heatwaves on cardiovascular diseases in a Mediterranean region (Catalonia, Southern Europe). We conducted a population-based retrospective study. Data were obtained from the System for the Development of Research in Primary Care and from the Catalan Meteorological Service. The outcome was first emergency hospitalizations due to coronary heart disease, stroke, or heart failure. Exposures were: cold spells; cold spells and 3 or 7 subsequent days; and heatwaves. Incidence rate ratios (IRR) and 95% confidence intervals were calculated using the self-controlled case series method. We accounted for age, time trends, and air pollutants; results were shown by age groups, gender or cardiovascular event type. There were 22,611 cardiovascular hospitalizations in winter and 17,017 in summer between 2006 and 2013. The overall incidence of cardiovascular hospitalizations significantly increased during cold spells (IRR = 1.120; CI 95%: 1.10-1.30) and the effect was even stronger in the 7 days subsequent to the cold spell (IRR = 1.29; CI 95%: 1.22-1.36). Conversely, cardiovascular hospitalizations did not increase during heatwaves, neither in the overall nor in the stratified analysis. Cold spells but not heatwaves, increased the incidence of emergency cardiovascular hospitalizations in Catalonia. The effect of cold spells was greater when including the 7 subsequent days. Such knowledge might be useful to develop strategies to reduce the impact of extreme temperature episodes on human health.


The case for the use of evidence-based management research for the control of hospital costs.
This article explores the current state of the creation and use of evidence by managers for cost containment in hospitals. We assert that hospitals do not know enough about what things cost, and until they get evidence on costs, it is not likely that much can be done to narrow the chasm between common practice and best practice. Part of the problem is that managers do not seek out available evidence that exists, and part of the problem is a lack of sufficient research efforts to generate evidence for managers to use. The article strives to help direct future efforts by researchers and managers in the area of evidence-based cost containment research by presenting a framework for priorities that managers and researchers can use to increase the amount of research done to generate evidence and to increase the use of evidence by health care managers.


The Use of Dynamic Assessment for the Diagnosis of Language Disorders in Bilingual Children: A Meta-Analysis.
Purpose Dynamic assessment (DA) has generally been accepted and recommended for use with bilingual children; however, no meta-analysis or systematic review of the diagnostic accuracy for language impairment within this population exists. Therefore, this study aimed to examine the current use of DA and its diagnostic accuracy for language impairment in bilingual children. Method Through a key word search of PsycINFO, ERIC, Academic Search Premier, and MEDLINE via EBSCOhost, 7 studies were identified. Participants ranged from 3 to 8 years old. Areas of language addressed through DA included labeling single words, morpheme rule learning, ability to learn nonwords, and narratives. Study results were analyzed with respect to diagnostic accuracy, participant modifiability, and methodological quality. Results Overall, participants with typically developing language received higher scores on the language assessments used in DA studies compared to participants with a language impairment. Gain scores were generally not useful for differentiating between children who did or did not have language impairments. However, clinician judgments of modifiability during the teaching phase of DA consistently yielded significant group effects favoring the typically developing children. Across the 7 studies, sensitivity and specificity were reasonably high, with all studies meeting or close to meeting the set criteria (≥ 0.8). Conclusion Suggestive evidence supports the use of DA for diagnosing language disorders in bilingual children. However, limitations in the methodological quality of the studies that were reviewed could have resulted in inflated diagnostic accuracy and decreased validity. Supplemental Material https://doi.org/10.23641/asha.8232926.


Combined results of two phase II studies of Taxol (paclitaxel) in patients with relapsed or refractory lymphomas.
This study was performed to determine the clinical activity and safety of paclitaxel in the treatment of patients with refractory or relapsing aggressive Non-Hodgkin's lymphoma (NHL). Between May 3, 1994 and February 16, 1996, 39 patients with refractory or relapsing NHL consented to be enrolled in two, multicenter, open-labelled studies to evaluate the efficacy, safety, time to progression and overall survival of paclitaxel given at a dose of 175 mg/m2 by a 3-hour IV infusion every three weeks without G-CSF use. Data from the two studies is combined. One patient, although registered, did not receive treatment. Of the remaining 38 patients, 17 men and 21 women aged 26-82 years (median 60) were given 104 courses of paclitaxel [median 2 (range 1-6)]. Seventeen patients had stage IV, 7 stage III, 8 stage II, 5 stage 1 and 1 unknown stage of disease. Histologic grades included 1 low, 33 intermediate, and 4 high. Three patients had bone marrow involvement. Median time from diagnosis to study entry was 19 months (1-160). The median number of previous chemotherapy regimens was 2 (range 1-6). Three of the 35 (8.6%) patients evaluable for response had partial remission (PR) of their disease for 1-7 months (median 2) and 11/35 (31.4%) stable disease (SD) for 1 to 19 months (median 3). All three responders and 3 of the 11 SD patients had received paclitaxel after relapsing from a CR. At analysis, nine of the 38 patients were alive. Median duration of follow up at analysis was 6 months (3 days-29 months). The estimated survival rates for all patients at 1 and 2 years are 34% and 27%, respectively (Kaplan-Meier) from the start of paclitaxel treatment. The median survival time was 5.4 months (3 days to 28+ months). Febrile neutropenia occurred in two patients. Seven (18%) patients developed a neutrophil nadir of < 0.5 x 10(9)/L and 2 (5%) patients developed a platelet nadir of < 50 x 10(9)/L. Six patients received blood transfusions. Non-hematologic toxicity was generally mild to moderate with all patients experiencing some toxicity. Twenty-seven patients experienced grade III toxicity including: alopecia (n = 19), pain (n = 9), fatigue (n = 5), nausea/vomiting (n = 3), diarrhoea (n = 2), pulmonary/shortness of breath (n = 2), anorexia (n = 1) and fluctuating levels of consciousness and somnolence (n = 1). Two patients experienced grade IV toxicity (infection, peripheral neuropathy, pain). No patient discontinued paclitaxel for a severe hypersensitivity reaction. In summary, administered as a 3-hour infusion, paclitaxel 175 mg/m2 results in mild myelotoxicity but minimal antitumor activity in patients with refractory NHL.


Vascular K ATP channels: dephosphorylation and deactivation.
Vascular ATP-sensitive potassium (K(ATP)) channels (Kir6.1/SUR2B) are regulated by both cell metabolism and chemical transmitters. They are the target for a number of vasodilators and vasoconstrictors whose mechanisms of action involve activation of protein kinase A (PKA) and protein kinase C (PKC), respectively. The article by Orie et al. in this issue of the BJP sheds new light on the (opposing) role of protein phosphatases in the regulation of this ion channel activity. Their data suggest that calcineurin, a Ca(2+)-dependent protein phosphatase, modulates Kir6.1/SUR2B by inhibiting PKA-dependent phosphorylation of the channel. This novel mechanism may provide a modulation opposing the action of vasodilators on the K(ATP) channel.


Immediate loading of dental implants in the edentulous mandible.
The authors review the literature regarding immediate implant loading in the anterior edentulous mandible, demonstrate the technique they currently use, review preliminary results and present an illustrative case. The authors conducted a literature search using PUBMED and Ovid databases. They considered for review 31 articles in English from 1969 to 2003 that pertained to immediate loading of the anterior mandible. The authors developed a technique to provide a bar-supported prosthesis on the day of surgery. They treated five patients and followed them up for at least six months. The preliminary results are presented. This literature review demonstrated that immediate loading of anterior mandibular implants is an acceptable method, with predictable results. This case series demonstrates the potential for delivering a final bar on the day of surgery, based on the current evidence and clinical application. The method described provides patients with immediate prosthetic restorations and a decreased treatment time compared with that for the traditional two-stage implant approach.