Toxicological and immunological aspects of occupational latex allergy.
Latex allergy continues to be an important occupational health problem as latex products are used increasingly worldwide, particularly in healthcare. Although there are few epidemiological studies on the incidence of latex allergy, there has been an increase in the number of case reports over the last 10 years and, based on skin-prick tests, estimates of prevalence of latex allergy in healthcare workers range from 2% to 17%. The allergic health effects arise either from the latex proteins, generally causing a type I immediate hypersensitivity reaction, or from the chemicals added to latex during processing, causing a type IV delayed hypersensitivity reaction. Clinical manifestations of latex allergy depend on the route of exposure and occur by direct contact either with skin or mucosa, or by inhalation. The diagnosis of latex allergy is based on the history, skin tests, serological tests and challenge tests. Thirteen latex allergens have been identified and isolated so far from natural rubber latex. They differ in their potential to elicit immunological responses in individuals allergic to latex and thus have been designated as major or minor allergens. In latex gloves, cornstarch powder used as a donning agent carries latex proteins, thereby increasing inhalational and mucosal exposure to latex proteins. There also appears to be a positive correlation between protein content and allergenicity of gloves. The use of powder-free, low-protein gloves is effective in reducing symptoms and markers of sensitisation. Alternatives to latex gloves, such as nitrile or vinyl gloves are available but may be inferior in respect to manual dexterity and biological impermeability.


Fractal markets hypothesis and the global financial crisis: wavelet power evidence.
We analyze whether the prediction of the fractal markets hypothesis about a dominance of specific investment horizons during turbulent times holds. To do so, we utilize the continuous wavelet transform analysis and obtained wavelet power spectra which give the crucial information about the variance distribution across scales and its evolution in time. We show that the most turbulent times of the Global Financial Crisis can be very well characterized by the dominance of short investment horizons which is in hand with the assertions of the fractal markets hypothesis.


Antigenic cross reactivity between p195 and a distinct protein of 100 kDa in Plasmodium falciparum.
A monoclonal antibody raised against merozoites of Plasmodium falciparum clone T9/96 was shown to react with an extremely strain specific epitope on a 195 kDa protein synthesized only by late trophozoites and schizonts. This protein was shown to exhibit all of the characteristics attributed to the molecule known variously as merozoite surface protein precursor, polymorphic schizont antigen and p195. The monoclonal antibody also identified a cross-reactive epitope on a distinct protein of 100 kDa in ring stage parasites which was shown to be synthesized throughout the asexual cycle and was not a processing product of p195. One-dimensional peptide mapping studies suggested that these two proteins share a degree of common sequence or structure.


Mindfulness-based cognitive therapy for inflammatory bowel disease patients: findings from an exploratory pilot randomised controlled trial.
Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition with a relapsing disease course. Managing the relapsing nature of the disease causes daily stress for IBD patients; thus, IBD patients report higher rates of depression and anxiety than the general population. Mindfulness-based Cognitive Therapy (MBCT) is an evidence-based psychological program designed to help manage depressive and stress symptoms. There has been no randomized controlled trial (RCT) testing the use of MBCT in IBD patients. The purpose of this pilot study is to test the trial methodology and assess the feasibility of conducting a large RCT testing the effectiveness of MBCT in IBD. The IBD patients, who were recruited from gastroenterology outpatient clinics at two Scottish NHS Boards, were randomly allocated to an MBCT intervention group (n = 22) or a wait-list control group (n = 22). The MBCT intervention consisted of 16 hours of structured group training over 8 consecutive weeks plus guided home practice and follow-up sessions. The wait-list group received a leaflet entitled 'Staying well with IBD'. All participants completed a baseline, post-intervention and 6-month follow up assessment. The key objectives were to assess patient eligibility and recruitment/dropout rate, to calculate initial estimates of parameters to the proposed outcome measures (depression, anxiety, disease activity, dispositional mindfulness and quality of life) and to estimate sample size for a future large RCT. In total, 350 patients were assessed for eligibility. Of these, 44 eligible patients consented to participate. The recruitment rate was 15%, with main reasons for ineligibility indicated as follows: non-response to invitation, active disease symptoms, planned surgery or incompatibility with group schedule. There was a higher than expected dropout rate of 44%. Initial estimates of parameters to the proposed outcomes at post-intervention and follow-up showed a significant improvement of scores in the MBCT group when compared to the control for depression, trait anxiety and dispositional mindfulness. The sample-size calculation was guided by estimates of clinically important effects in depression scores. This pilot study suggests that a multicentre randomized clinical trial testing the effectiveness of MBCT for IBD patients is feasible with some changes to the protocol. Improvement in depression, trait anxiety and dispositional mindfulness scores are promising when coupled with patients reporting a perceived improvement of their quality of life. ISRCTN27934462. 2 August 2013.


The lymphatics revisited: new perspectives from the hyaluronan receptor LYVE-1.
The lymphatic vasculature forms a second circulatory system that drains extracellular fluid from the tissues and provides an exclusive environment in which immune cells can encounter and respond to foreign antigen. Although equally important for the functioning of both the cardiovascular and immune systems, there is only a rudimentary knowledge of the molecular biology of lymphatics, owing to longstanding difficulties in identifying and isolating lymphatic endothelial cells. Recently, however, a number of interesting molecules have been identified that may be exploited as markers for lymphatic endothelium, including the hyaluronan receptor LYVE-1, the subject of this review. This article considers the biology of LYVE-1 and outlines how recent research into this molecule is providing new insights into the nature of lymphatics and their role in tumor metastasis.


The Role of Colloidal Stability and Charge in Functionalization of Aqueous Quantum Dots.
Semiconductor quantum dots (QDs), also known as nanocrystals, have unique photophysical properties that have allowed them to find utility in many applications, including television and display technologies. They also have significant potential as imaging agents in the biomedical field. To gain the most value from the use of QDs as health-related fluorescent probes, they must be biologically targetable and sensitive to metabolic analytes such as pH and O2, and the resulting signal must be quantifiable. To achieve these goals, QDs need to be conjugated to vectors such as antibodies or environmentally sensitive chromophores. Until recently, the functionalization of these nanomaterials required a complex fully "bottom-up" approach beginning with the synthesis of the QDs and subsequent manipulations. To simplify this process, our group set out to develop straightforward methods to prepare functionalized nanomaterials for biological imaging and sensing using low-cost, commercially available aqueous QD dispersions. In this Account, we review the common problems and likely solutions related to functionalization of QDs in water with chemical and biological vectors. Early in our investigations, we found that established protocols using a commercially available activating reagent resulted in either low reaction yields or QD precipitation. This was a consequence of the perturbation of the QDs' surface charges by the activating reagent and the conjugation substrate. These surface charges are derived from the anionic surfactants that are commonly employed for encapsulating water-soluble nanomaterials. Thus, cancellation of the surface charges by reagents or substrates results in colloidal instability. To address this problem, we devised conjugation methods that do not alter the overall charge balance of the system. Incorporating reactive moieties directly into the QD's water-solubilizing polymer encapsulants negates the need for destabilizing activators, allowing for functionalization of aqueous samples without precipitation. The most successful approach was realized using neutral activating reagents, such as poly(ethylene glycol) carbodiimide (PEG-CD). PEG-CD binds to the carboxylic acid coating of water-soluble QDs, which primes them for amide bond formation with amine-functionalized substrates. Most importantly, this method can be applied to commercially available aqueous QDs. Using this method, we achieved reaction yields as high as 95%, allowing us to demonstrate a wide-range of QD functionalities and applications for chemical and biological sensing. Conjugation of environmentally sensitive dyes to water-soluble QDs results in reversible and ratiometrically reporting fluorescent probes for metabolic analytes such as pH, bisulfide, and O2. QDs can also be functionalized with proteins for passive cell delivery or coated with poly(ethylene glycol) to enhance biocompatibility for in vivo studies. In the future, these capabilities may be combined to realize the full potential of quantum dot nanotechnology for biological discovery.


Identification of novel linear megaplasmids carrying a ß-lactamase gene in neurotoxigenic Clostridium butyricum type E strains.
Since the first isolation of type E botulinum toxin-producing Clostridium butyricum from two infant botulism cases in Italy in 1984, this peculiar microorganism has been implicated in different forms of botulism worldwide. By applying particular pulsed-field gel electrophoresis run conditions, we were able to show for the first time that ten neurotoxigenic C. butyricum type E strains originated from Italy and China have linear megaplasmids in their genomes. At least four different megaplasmid sizes were identified among the ten neurotoxigenic C. butyricum type E strains. Each isolate displayed a single sized megaplasmid that was shown to possess a linear structure by ATP-dependent exonuclease digestion. Some of the neurotoxigenic C. butyricum type E strains possessed additional smaller circular plasmids. In order to investigate the genetic content of the newly identified megaplasmids, selected gene probes were designed and used in Southern hybridization experiments. Our results revealed that the type E botulinum neurotoxin gene was chromosome-located in all neurotoxigenic C. butyricum type E strains. Similar results were obtained with the 16S rRNA, the tetracycline tet(P) and the lincomycin resistance protein lmrB gene probes. A specific mobA gene probe only hybridized to the smaller plasmids of the Italian C. butyricum type E strains. Of note, a ß-lactamase gene probe hybridized to the megaplasmids of eight neurotoxigenic C. butyricum type E strains, of which seven from clinical sources and the remaining one from a food implicated in foodborne botulism, whereas this ß-lactam antibiotic resistance gene was absent form the megaplasmids of the two soil strains examined. The widespread occurrence among C. butyricum type E strains associated to human disease of linear megaplasmids harboring an antibiotic resistance gene strongly suggests that the megaplasmids could have played an important role in the emergence of C. butyricum type E as a human pathogen.


Germ plasm anchoring is a dynamic state that requires persistent trafficking.
Localized cytoplasmic determinants packaged as ribonucleoprotein (RNP) particles direct embryonic patterning and cell fate specification in a wide range of organisms. Once established, the asymmetric distributions of such RNP particles must be maintained, often over considerable developmental time. A striking example is the Drosophila germ plasm, which contains RNP particles whose localization to the posterior of the egg during oogenesis results in their asymmetric inheritance and segregation of germline from somatic fates in the embryo. Although actin-based anchoring mechanisms have been implicated, high-resolution live imaging revealed persistent trafficking of germ plasm RNP particles at the posterior cortex of the Drosophila oocyte. This motility relies on cortical microtubules, is mediated by kinesin and dynein motors, and requires coordination between the microtubule and actin cytoskeletons. Finally, we show that RNP particle motility is required for long-term germ plasm retention. We propose that anchoring is a dynamic state that renders asymmetries robust to developmental time and environmental perturbations.


Prioritizing perioperative quality improvement in orthopaedic surgery.
Surgical quality improvement has received increasing attention in recent years, but it is not clear where orthopaedic surgeons should focus their efforts for the greatest impact on perioperative safety and quality. We sought to guide these efforts by prioritizing orthopaedic procedures according to those that generate the greatest number of adverse events. We used data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) to identify all patients who had undergone an orthopaedic surgical procedure between 2005 and 2007 (n = 7970). Patients were assigned to forty-four unique procedure groups on the basis of the Current Procedural Terminology (CPT) codes. We first assessed the relative contribution of each procedure group to the overall number of adverse events in the first thirty postoperative days, and we followed that with a description of their relative contribution to an excess length of stay in the hospital. Ten procedures accounted for 70% of the adverse events and 65% of the excess hospital days. Hip fracture repair accounted for the greatest share of adverse events, followed by total knee arthroplasty, total hip arthroplasty, revision total hip arthroplasty, knee arthroscopy, laminectomy, lumbar/thoracic arthrodesis, and femoral fracture repair. No other procedure group accounted for >2% of the adverse events. Only a few procedures account for the vast majority of adverse events in the first thirty days following orthopaedic surgery. Concentrating quality-improvement efforts on these procedures may be an effective way for surgeons and other stakeholders to improve perioperative care and reduce costs in orthopaedic surgery. Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.


Magnetization transfer imaging provides a quantitative measure of chondrogenic differentiation and tissue development.
The goal of the present investigation was to test whether quantitative magnetization transfer imaging can be used as a noninvasive evaluation method for engineered cartilage. In this work, we used magnetic resonance imaging (MRI) to monitor the chondrogenesis of stem-cell-based engineered tissue over a 3-week period by measuring on a pixel-by-pixel basis the relaxation times (T₁ and T₂), the apparent diffusion coefficient, and the magnetization transfer parameters: bound proton fraction and cross-relaxation rate (k). Tissue-engineered constructs for generating cartilage were created by seeding mesenchymal stem cells in a gelatin sponge. Every 7 days, tissue samples were analyzed using MRI, histological, and biochemical methods. The MRI measurements were verified by histological analysis, and the imaging data were correlated with biochemical analysis of the developing cartilage matrix for glycosaminoglycan content. The MRI analysis for bound proton fraction and k showed a statistically significant increase that was correlated with the increase of glycosaminoglycan (R = 0.96 and 0.87, respectively, p < 0.05), whereas T₁, T₂, and apparent diffusion coefficient results did not show any significant changes over the 3-week measurement period.


Mixed infection by Clostridium difficile in an in vitro model of the human gut.
Clostridium difficile infection (CDI) is still a major clinical challenge. Previous studies have demonstrated multiple distinct C. difficile strains in the faeces of patients with CDI; yet whether true mixed CDI occurs in vivo is unclear. In this study we evaluated whether two distinct C. difficile strains could co-germinate and co-proliferate in an in vitro human gut model. An in vitro triple-stage chemostat was used to study the responses of two PCR ribotype 001 C. difficile strains following exposure to ceftriaxone at concentrations observed in vivo (7 days). C. difficile viable counts (vegetative and spore forms), cytotoxin titres and indigenous microflora viable counts were monitored throughout the experiment. Both C. difficile strains germinated and proliferated following exposure to ceftriaxone. Cytotoxin production was detected in the gut model following C. difficile spore germination and proliferation. Ceftriaxone elicited reduced viable counts of Bifidobacterium spp. and elevated viable counts of Enterococcus spp. These data suggest that multiple C. difficile strains are able to proliferate concurrently in an in vitro model reflective of the human colon. Previous studies in the gut model have reflected clinical observations so clinicians should be mindful of the possibility that multiple C. difficile strains may infect patients. These observations augment recent human epidemiological studies in this area.


Expectations and changing attitudes of bar workers before and after the implementation of smoke-free legislation in Scotland.
In Scotland on March 26, 2006 a comprehensive prohibition on smoking in all enclosed public places was introduced. This study examines bar workers' attitudes towards a smoke-free working environment. An intervention study comparing bar workers' opinions before and after the implementation of the smoke-free legislation. Bars were randomly selected in three Scottish cities (Glasgow, Edinburgh & Aberdeen) and towns (Aberdeenshire & Borders). Bar workers were recruited from 72 bars that agreed to participate from 159 approached. Pre- and post-implementation attitudes towards legislation, second-hand smoke and smoke-free working environments were compared. Initially the majority of bar workers agreed with the proposed legislation on smoking (69%) and the need for it to protect the health of workers (80%), although almost half (49%) thought the legislation would damage business. In 266 bar workers seen at both surveys, a significant positive attitudinal change towards the legislation was seen. Post-implementation, support for the legislation rose to 79%, bar workers continued to believe it was needed to protect health (81%) and concerns about the impact on business were expressed by fewer than 20%. Only the statement that the legislation would encourage smokers to quit showed reduced support, from 70% pre-implementation to fewer than 60% post-implementation. Initial acceptance was greater among younger bar workers; older workers, initially more sceptical, became less so with experience of the legislation's effects. This study shows that bar workers had generally positive attitudes towards the legislation prior to implementation, which became stronger after implementation. The affirmative attitudes of these key stakeholders are likely to contribute towards the creation of 'smoke-free' as the new social norm.


Decoding complexity in biomolecular recognition of DNA i-motifs with microarrays.
DNA i-motifs (iMs) are non-canonical C-rich secondary structures implicated in numerous cellular processes. Though iMs exist throughout the genome, our understanding of iM recognition by proteins or small molecules is limited to a few examples. We designed a DNA microarray containing 10976 genomic iM sequences to examine the binding profiles of four iM-binding proteins, mitoxantrone and the iMab antibody. iMab microarray screens demonstrated that pH 6.5, 5% BSA buffer was optimal, and fluorescence was correlated with iM C-tract length. hnRNP K broadly recognizes diverse iM sequences, favoring 3-5 cytosine repeats flanked by thymine-rich loops of 1-3 nucleotides. Array binding mirrored public ChIP-Seq datasets, in which 35% of well-bound array iMs are enriched in hnRNP K peaks. In contrast, other reported iM-binding proteins had weaker binding or preferred G-quadruplex (G4) sequences instead. Mitoxantrone broadly binds both shorter iMs and G4s, consistent with an intercalation mechanism. These results suggest that hnRNP K may play a role in iM-mediated regulation of gene expression in vivo, whereas hnRNP A1 and ASF/SF2 are possibly more selective in their binding preferences. This powerful approach represents the most comprehensive investigation of how biomolecules selectively recognize genomic iMs to date.


A tale of two public dental benefit programs: Iowa dentist participation in traditional Medicaid versus a Medicaid expansion program.
In Iowa from 2014 to 2017, there were 2 separate public dental benefit programs for Medicaid-enrolled adults: one for the Medicaid expansion population called the Dental Wellness Plan (DWP), and one for the traditional, non-expansion adult Medicaid population. The programs differed with respect to reimbursement, administration, and benefit structure. This study explored differences in patterns and predictors of dentist participation in the two programs. Authors sent a survey to all private practice dentists in Iowa (n = 1301) 2 years after DWP implementation. Descriptive, bivariate, and logistic regression analyses were used to examine patterns and predictors of dentist participation in Medicaid and DWP. Overall rates of dentists' acceptance of new Medicaid and DWP patients were 45 and 43%, respectively. However, Medicaid participants were much more likely than DWP participants to place limits on patient acceptance. Adjusting for other factors, practice busyness was the only significant predictor of DWP participation, and practice location was the only significant predictor of Medicaid participation. Dentists who were not busy enough were more than twice as likely to participate in DWP compared to others, and dentists in rural areas were almost twice as likely to participate in Medicaid compared to dentists in urban areas. Dentist participation in Medicaid is an ongoing concern for states aiming to ensure access to dental care for low-income populations. We found distinct participation patterns and predictors between a traditional Medicaid dental program and the DWP, suggesting different motivations for participation between the two programs.


Neurocognition in help-seeking individuals at risk for psychosis: Prediction of outcome after 24 months.
An important aim in schizophrenia research is to optimize the prediction of psychosis and to improve strategies for early intervention. The objectives of this study were to explore neurocognitive performance in individuals at risk for psychosis and to optimize predictions through a combination of neurocognitive and psychopathological variables. Information on clinical outcomes after 24 months was available from 118 subjects who had completed an extensive assessment at baseline. Subjects who had converted to psychosis were compared with subjects who had not. Multivariate Cox regression analyses were used to determine which baseline measure best predicted a conversion to psychosis. The premorbid IQ and the neurocognitive domains of processing speed, learning/memory, working memory and verbal fluency significantly discriminated between converters and non-converters. When entered into multivariate regression analyses, the combination of PANSS positive/negative symptom severity and IQ best predicted the clinical outcomes. Our results confirm previous evidence suggesting moderate premorbid cognitive deficits in individuals developing full-blown psychosis. Overall, clinical symptoms appeared to be a more sensitive predictor than cognitive performance. Nevertheless, the two might serve as complementary predictors when assessing the risk for psychosis.


The Effect of MSM and CD4+ Count on the Development of Cancer AIDS (AIDS-defining Cancer) and Non-cancer AIDS in the HAART Era.
The HIV epidemic is increasing among Men who have Sex with Men (MSM) and the risk for AIDS defining cancer (ADC) is higher among them. To examine the effect of MSM and CD4+ count on time to cancer AIDS (ADC) and noncancer AIDS in competing risks setting in the HAART era. Using Ontario HIV Treatment Network Cohort Study data, HIV-positive adults diagnosed between January 1997 and October 2012 having baseline CD4+ counts ≤ 500 cells/mm3 were evaluated. Two survival outcomes, cancer AIDS and non-cancer AIDS, were treated as competing risks. Kaplan-Meier analysis, Cox cause-specific hazards (CSH) model and joint modeling of longitudinal and survival outcomes were used. Among the 822 participants, 657 (79.9%) were males; 686 (83.5%) received anti-retroviral (ARV) ever. Regarding risk category, the majority (58.5%) were men who have Sex with men (MSM). Mean age was 37.4 years (SD = 10.3). In the multivariate Cox CSH models, MSM were not associated with cancer AIDS but with non-cancer AIDS [HR = 2.92; P = 0.055, HR = 0.54; P = 0.0009, respectively]. However, in joint models of longitudinal and survival outcomes, MSM were associated with cancer AIDS but not with non-cancer AIDS [HR = 3.86; P = 0.013, HR = 0.73; P = 0.10]. CD4+ count, age, ARV ever were associated with both events in the joint models. This study demonstrates the importance of considering competing risks, and timedependent biomarker in the survival model. MSM have higher hazard for cancer AIDS. CD4+ count is associated with both survival outcomes.


Proficiency testing of academic and nonacademic preparation in five therapeutic activities.
Occupational therapy pre-majors at Cleveland State University (CSU) were required to demonstrate proficiency in five craft areas before admission into the program. Proficiency examinations were constructed to determine the students' level of knowledge in each craft area. Reliability and validity of the examinations were determined. Using these examinations, a study was conducted to compare the knowledge level of the pre-majors at CSU with that of occupational therapy students throughout the United States on the associate, baccalaureate, and entry-level master's levels of education. The results of the study demonstrated that CSU students scored significantly higher on the examinations than both the associate and baccalaureate students, and at least as well as the entry-level master's students.


JAK inhibition and progressive kidney disease.
To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases. The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy and their inhibition appears to reduce the disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. On the basis of data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases. Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases.


Repression of mammary stem/progenitor cells by p53 is mediated by Notch and separable from apoptotic activity.
Breast cancer is the most common tumor among women with inherited mutations in the p53 gene (Li-Fraumeni syndrome). The tumors represent the basal-like subtype, which has been suggested to originate from mammary stem/progenitor cells. In mouse mammary epithelium, mammosphere-forming potential was increased with decreased dosage of the gene encoding the p53 tumor suppressor protein (Trp53). Limiting dilution transplantation also showed a 3.3-fold increase in the frequency of long-term regenerative mammary stem cells in Trp53-/- mice. The repression of mammospheres by p53 was apparent despite the absence of apoptotic responses to radiation indicating a dissociation of these two activities of p53. The effects of p53 on progenitor cells were also observed in TM40A cells using both mammosphere-forming assays and the DsRed-let7c-sensor. The frequency of long-term label-retaining epithelial cells was decreased in Trp53-/- mammary glands indicating that asymmetric segregation of DNA is diminished and contributes to the expansion of the mammary stem cells. Treatment with an inhibitor of γ-secretase (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) reduced the number of Trp53-/- mammospheres to the level found in Trp53+/+ cells. These results demonstrate that basal levels of p53 restrict mammary stem/progenitor cells through Notch and that the Notch pathway is a therapeutic target to prevent expansion of this vulnerable pool of cells.


Racial and ethnic disparities in severe maternal morbidity and anesthetic techniques for obstetric deliveries: A multi-state analysis, 2007-2014.
To evaluate racial and ethnic disparities in severe maternal morbidity (SMM) and administered anesthesia techniques. Retrospective cohort study. Administrative database study using 2007-2014 data from California, Florida, New York, Maryland, and Kentucky from the State Inpatient Databases (SID), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality (AHRQ). 6,879,332 parturients aged ≥18 years old who underwent deliveries were identified by International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) codes: V27.0 and V27.1 for singleton deliveries, and V27.2 through V27.8 for multiple births. Patients who had a singleton or multiple delivery. Patients were cohorted by race/ethnicity: white (reference category), black, Hispanic, other, or missing. Demographic characteristics and comorbidities were compared. Adjusted odds ratios with generalized linear mixed modeling were calculated for SMM. We also conducted additional exploratory analyses of racial/ethnic disparities in the anesthesia technique used for cesarean deliveries, as well as the use of analgesia in vaginal deliveries. When controlling for patient demographics, comorbidities, and hospital characteristics, black women were more likely than white women to experience any SMM (adjusted odds ratio: 1.38, 95% CI: 1.35-1.41). This finding was consistent in stratified analyses. Black women were also more likely than white women to receive general anesthesia for cesarean delivery (aOR: 1.44, 95% CI: 1.39-1.49) and to receive no analgesia for vaginal delivery (aOR: 1.45, 95% CI: 1.43-1.47). Our findings highlight the differences in outcomes and care for black as compared to white parturients related to SMM and administered anesthesia techniques.


Profiles of neurological outcome prediction among intensivists.
Advances in intensive care medicine have increased survival rates of patients with critical neurological conditions. The focus of prognostication for such patients is therefore shifting from predicting chances of survival to meaningful neurological recovery. This study assessed the variability in long-term outcome predictions among physicians and aimed to identify factors that may account for this variability. Based on a clinical vignette describing a comatose patient suffering from post-anoxic brain injury intensivists were asked in a semi-structured interview about the patient's specific neurological prognosis and about prognostication in general. Qualitative research methods were used to identify areas of variability in prognostication and to classify physicians according to specific prognostication profiles. Quantitative statistics were used to assess for associations between prognostication profiles and physicians' demographic and practice characteristics. Eighteen intensivists participated. Functional outcome predictions varied along an evaluative dimension (fair/good-poor) and a confidence dimension (certain-uncertain). More experienced physicians tended to be more pessimistic about the patient's functional outcome and more certain of their prognosis. Attitudes toward quality of life varied along an evaluative dimension (good-poor) and a "style" dimension (objective-subjective). Older and more experienced physicians were more likely to express objective judgments of quality of life and to predict a worse quality of life for the patient than their younger and less experienced counterparts. Various prognostication profiles exist among intensivists. These may be dictated by factors such as physicians' age and clinical experience. Awareness of these associations may be a first step to more uniform prognostication.


Comparing cost-effectiveness results for a vaccine across different countries worldwide: what can we learn?
Cost-effectiveness analysis (CEA) using country-specific thresholds tied to gross domestic product (GDP) might not be appropriate in countries with low healthcare investment and a high disease burden as a consequence. Using data from previously published CEA of rotavirus vaccination across nine countries worldwide, we calculated the cost neutral price (Pn) for the new intervention that reflects the price resulting in no net increase in health care costs compared with the current situation, and the maximum price (Pm) obtained with an incremental cost-effectiveness ratio (ICER) at the threshold value of 1×GDP/capita. In countries with low GDP/capita, the paradoxical finding for rotavirus vaccination is that the Pm is much higher than in countries with a high GDP/capita. On the other hand, the Pn for the low GDP/capita countries is much lower than for high GDP/capita countries because of the low investment in health care. In countries with low healthcare investment and a high disease burden, the difference between the Pn and Pm for rotavirus vaccine which is the price range within which the ICER is below the World Health Organization (WHO) threshold value, is large. One reason could be that the WHO threshold value may not properly account for the local opportunity cost of health care expenditures. Therefore, either alternative threshold values should be selected or alternative economic assessment tools should be considered, such as budget optimisation or return on investment, if we want to communicate about real economic value of new vaccines in those countries.


Environmental interventions in low-SES neighbourhoods to promote healthy behaviour: enhancing and impeding factors.
Social and physical environments are important drivers of socioeconomic inequalities in health behaviour. Although many interventions aiming to improve such environments are being implemented in underprivileged neighbourhoods, implementation processes are rarely studied. Acquiring insight into successful implementation may improve future interventions. The present study aimed to investigate factors influencing the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) of social and physical environmental interventions aimed at promoting healthy behaviour in underprivileged neighbourhoods in The Netherlands. A large set of theory-based factors of successful implementation was assessed for 18 implemented interventions in three underprivileged neighbourhoods. Expert and target group panels scored the RE-AIM dimensions for each intervention. We analyzed the statistical significance of associations between theory-based factors and the actual RE-AIM in a statistical model, to identify factors associated with increased RE-AIM. Six factors were identified: effectiveness and implementation success were higher when the target group was involved in the planning process, whereas maintenance increased in the absence of competition with other projects. If the current situation was inventoried during intervention development, the effectiveness, adoption and implementation were higher. These dimensions were also higher when the target group was informed before implementation. Involvement of the target group during implementation resulted in higher reach, effectiveness and adoption. Finally, lack of intervention staff worsened the reach. This study contributes to the evidence base for effective implementation of environmental measures aimed at promoting healthy behaviours. In particular, interventions in which the target group was involved in the implementation process were associated with higher RE-AIM outcomes.


Aminoglycoside-induced hair cell death of inner ear organs causes functional deficits in adult zebrafish (Danio rerio).
Aminoglycoside antibiotics, like gentamicin, kill inner ear sensory hair cells in a variety of species including chickens, mice, and humans. The zebrafish (Danio rerio) has been used to study hair cell cytotoxicity in the lateral line organs of larval and adult animals. Little is known about whether aminoglycosides kill the hair cells within the inner ear of adult zebrafish. We report here the ototoxic effects of gentamicin on hair cells in the saccule, the putative hearing organ, and utricle of zebrafish. First, adult zebrafish received a single 30 mg/kg intraperitoneal injection of fluorescently-tagged gentamicin (GTTR) to determine the distribution of gentamicin within inner ear sensory epithelia. After 4 hours, GTTR was observed in hair cells throughout the saccular and utriclar sensory epithelia. To assess the ototoxic effects of gentamicin, adult zebrafish received a single 250 mg/kg intraperitoneal injection of gentamicin and, 24 hours later, auditory evoked potential recordings (AEPs) revealed significant shifts in auditory thresholds compared to untreated controls. Zebrafish were then euthanized, the inner ear fixed, and labeled for apoptotic cells (TUNEL reaction), and the stereociliary bundles of hair cells labeled with fluorescently-tagged phalloidin. Whole mounts of the saccule and utricle were imaged and cells counted. There were significantly more TUNEL-labeled cells found in both organs 4 hours after gentamicin injection compared to vehicle-injected controls. As expected, significantly fewer hair cell bundles were found along the rostral-caudal axis of the saccule and in the extrastriolar and striolar regions of the utricle in gentamicin-treated animals compared to untreated controls. Therefore, as in other species, gentamicin causes significant inner ear sensory hair cell death and auditory dysfunction in zebrafish.


Interaction between replication protein A and p53 is disrupted after UV damage in a DNA repair-dependent manner.
Replication protein A (RPA) is required for both DNA replication and nucleotide excision repair. Previous studies have shown that RPA interacts with the tumor suppressor p53. Herein, we have mapped a 20-amino acid region in the N-terminal part of p53 that is essential for its binding to RPA. This region is distinct from the minimal activation domain of p53 previously identified. We also demonstrate that UV radiation of cells greatly reduces the ability of RPA to bind to p53. Interestingly, damage-induced hyperphosphorylated RPA does not associate with p53. Furthermore, down-regulation of the RPA/p53 interaction is dependent upon the capability of cells to perform global genome repair. On the basis of these data, we propose that RPA may participate in the coordination of DNA repair with the p53-dependent checkpoint control by sensing UV damage and releasing p53 to activate its downstream targets.


Arabidopsis thaliana cells: a model to evaluate the virulence of Pectobacterium carotovorum.
Pectobacterium carotovorum are economically important plant pathogens that cause plant soft rot. These enterobacteria display high diversity world-wide. Their pathogenesis depends on production and secretion of virulence factors such as plant cell wall-degrading enzymes, type III effectors, a necrosis-inducing protein, and a secreted virulence factor from Xanthomonas spp., which are tightly regulated by quorum sensing. Pectobacterium carotovorum also present pathogen-associated molecular patterns that could participate in their pathogenicity. In this study, by using suspension cells of Arabidopsis thaliana, we correlate plant cell death and pectate lyase activities during coinfection with different P. carotovorum strains. When comparing soft rot symptoms induced on potato slices with pectate lyase activities and plant cell death observed during coculture with Arabidopsis thaliana cells, the order of strain virulence was found to be the same. Therefore, Arabidopsis thaliana cells could be an alternative tool to evaluate rapidly and efficiently the virulence of different P. carotovorum strains.


A monoclinic polymorph of sodium birnessite for ultrafast and ultrastable sodium ion storage.
Sodium transition metal oxides with layered structures are attractive cathode materials for sodium-ion batteries due to their large theoretical specific capacities. However, these layered oxides suffer from poor cyclability and low rate performance because of structural instability and sluggish electrode kinetics. In the present work, we show the sodiation reaction of Mn3O4 to yield crystal water free NaMnO2-y-δ(OH)2y, a monoclinic polymorph of sodium birnessite bearing Na/Mn(OH)8 hexahedra and Na/MnO6 octahedra. With the new polymorph, NaMnO2-y-δ(OH)2y exhibits an enlarged interlayer distance of about 7 Å, which is in favor of fast sodium ion migration and good structural stability. In combination of the favorable nanosheet morphology, NaMn2-y-δ(OH)2y cathode delivers large specific capacity up to 211.9 mAh g-1, excellent cycle performance (94.6% capacity retention after 1000 cycles), and outstanding rate capability (156.0 mAh g-1 at 50 C). This study demonstrates an effective approach in tailoring the structural and electrochemical properties of birnessite towards superior cathode performance in sodium-ion batteries.


Kale carotenoids remain stable while flavor compounds respond to changes in sulfur fertility.
Dietary intake of certain carotenoids has been associated with a reduced risk of disease. Kale (Brassica oleracea L. Acephala Group) has the highest levels of carotenoids lutein and beta-carotene, and is an excellent source of minerals among the green leafy vegetable crops. However, Brassica vegetables contain glucosinolate (GS) and S-methylcysteine sulfoxide (MCSO). While these sulfur compounds have medicinal value, they are also responsible for the bitter, acrid flavors that are often regarded as objectionable by consumers. Therefore, the objectives of this study were to investigate the influence of increased S fertility levels on (1) elemental accumulation, (2) GS and MCSO production, and (3) the accumulation patterns of carotenoid pigments in the leaves of three kale cultivars. Winterbor, Redbor, and Toscano kale were greenhouse-grown using nutrient solution culture with S treatment concentrations of 4, 8, 16, 32, and 64 mg of S/L. Decreasing S fertility decreased S leaf content, but increased the levels of Mg and Ca accumulation, two important minerals for human health. Levels of GS and MSCO decreased in response to a decreasing S level in nutrient solution. However, accumulation of lutein and beta-carotene was unaffected by S treatment. Lowering the S fertility in the production of kale should decrease the levels of negative flavors associated with high levels of GS and MCSO without affecting carotenoid pigment levels. Understanding the combined impact of fertility on flavor compounds and carotenoid pigments may help improve consumer acceptance of phytonutritionally enhanced vegetable crops.


The effectiveness of metrifonate in reducing hookworm infection in Kenyan school children.
The reduction in hookworm egg counts was determined in children treated with 1 and 2 doses of metrifonate. Kenyan primary school children were allocated to receive either 10.0 mg (n = 53) or 7.5 mg (n = 53) of metrifonate per kg of body weight (mg/kg) or a placebo (n = 26). Two doses of 10.0 mg/kg reduced hookworm egg counts (from arithmetic means of 4,177 to 438 eggs per gram of feces [epg]) more than did 2 doses of 7.5 mg/kg (from 4,329 to 1,392 epg; P less than 0.01). Two doses of metrifonate reduced egg counts more than did 1 dose (P less than 0.0001). The placebo group did not show a significant change in egg counts. The single dose of 10.0 mg/kg led to a 78% reduction in hookworm egg counts (from 4,177 to 918 epg), a level unlikely to cause iron deficiency anemia. This was as effective as 2 doses of 7.5 mg/kg, and was more easily administered than 2 or 3 doses. The further reduction after a second dose of 10.0 mg/kg (to 438 epg) is probably not of practical importance. This study shows that metrifonate, even in a single dose for treatment of S. haematobium, is also useful in reducing hookworm egg counts.


Pitfalls and Limitations of Radionuclide and Hybrid Cardiac Imaging.
Radionuclide myocardial perfusion imaging (MPI) is an important technique for evaluating the presence and severity of ischemic coronary heart disease that is widespread in the United States and much of the world. This widely used test has excellent diagnostic accuracy and strong risk-stratification utility and plays an important role in guiding patient management. As with all testing modalities, the clinical utility of MPI relies on proper procedure performance as improper techniques can lead to incorrect test interpretation, and thus misdiagnosis with potential adverse effects on patient management and outcome. A variety of potential pitfalls must be understood and recognized. These include minimizing referral of "rarely appropriate" patients for testing, selecting the best imaging procedure for each patient, properly preparing a patient for the test to be performed, skillful performance of stress testing and image acquisition, careful image processing, understanding the strengths and weaknesses of different image display options, recognition of common artifacts that can lead to misdiagnoses, distinguishing normal anatomy from true pathology, recognizing noncoronary cardiac disease, and not missing extracardiac pathology. It is important that physicians who perform and interpret radionuclide MPI be well versed in published guidelines and potential pitfalls to proper test performance and interpretation.


A genetic approach to promoter recognition during trans induction of viral gene expression.
Viral infection of mammalian cells entails the regulated induction of viral gene expression. The induction of many viral genes, including the herpes simplex virus gene encoding thymidine kinase (tk), depends on viral regulatory proteins that act in trans. Because recognition of the tk promoter by cellular transcription factors is well understood, its trans induction by viral regulatory proteins may serve as a useful model for the regulation of eukaryotic gene expression. A comprehensive set of mutations was therefore introduced into the chromosome of herpes simplex virus at the tk promoter to directly analyze the effects of promoter mutations on tk transcription. The promoter domains required for efficient tk expression under conditions of trans induction corresponded to those important for recognition by cellular transcription factors. Thus, trans induction of tk expression may be catalyzed initially by the interaction of viral regulatory proteins with cellular transcription factors.


Prices, policies and youth smoking, May 2001.
Youth smoking continues to be an important public health problem. Many policy tools designed to reduce youth smoking are based on economic principles. This paper describes the economic and policy context of tobacco use aiming at reducing youth smoking and explains the economic rationale for tobacco control tools such as excise tax and price, clean indoor air laws, youth access laws and the broad provision of health information to the public. An overview of economic models of addiction provides the framework for empirical analysis of the impact of these policies. This is followed by a summary of the empirical evidence of the effectiveness of various tobacco control tools that are primarily economic in nature. The most consistent finding in this literature is that higher cigarette prices discourage youth smoking. Compared to the effects of cigarette taxation and price on youth smoking, the evidence on the effectiveness of the youth access laws and clean indoor air laws are still mixed and inconclusive. More research is needed to address issues such as: (1) the effects of gender, age, race and socio-economic status on the relationship between tobacco control policies and youth smoking; (2) better measurement of the outcome variables to account for the multi-dimensional nature of dependence; and (3) the effects of excise taxes and other tobacco control policies with regard to a host of dimensions of smoking such as initiation, cessation, and more generally the trajectories of tobacco use that would include patterns of progression, maintenance, regression, cessation, and relapse. More frequently collected longitudinal data than those currently available are needed to address the above issues. Understanding smoking behavior cannot be achieved without incorporating familial and other social contexts.


Influence of Structural Heterogeneity on Diffusion of CH4 and CO2 in Silicon Carbide-Derived Nanoporous Carbon.
We investigate the influence of structural heterogeneity on the transport properties of simple gases in a Hybrid Reverse Monte Carlo (HRMC) constructed model of silicon carbide-derived carbon (SiC-DC). The energy landscape of the system is determined based on free energy analysis of the atomistic model. The overall energy barriers of the system for different gases are computed along with important properties, such as Henry constant and differential enthalpy of adsorption at infinite dilution, and indicate hydrophobicity of the SiC-DC structure and its affinity for CO2 and CH4 adsorption. We also study the effect of molecular geometry, pore structure and energy heterogeneity considering different hopping scenarios for diffusion of CO2 and CH4 through ultramicropores using the Nudged Elastic Band (NEB) method. It is shown that the energy barrier of a hopping molecule is very sensitive to the shape of the pore entry. We provide evidence for the influence of structural heterogeneity on self-diffusivity of methane and carbon dioxide using molecular dynamics simulation, based on a maximum in the variation of self-diffusivity with loading. A comparison of the MD simulation results with self-diffusivities from quasi-elastic neutron scattering (QENS) measurements and, with macroscopic uptake-based low-density transport coefficients, reveals the existence of internal barriers not captured in MD simulation and QENS experiments. Nevertheless, the simulation and macroscopic uptake-based diffusion coefficients agree within a factor of 2-3, indicating that our HRMC model structure captures most of the important energy barriers affecting the transport of CH4 in the nanostructure of SiC-DC.


Ferulic Acid Alleviates Changes in a Rat Model of Metabolic Syndrome Induced by High-Carbohydrate, High-Fat Diet.
Metabolic syndrome is a cluster of metabolic abnormalities characterized by obesity, insulin resistance, hypertension and dyslipidemia. Ferulic acid (FA) is the major phenolic compound found in rice oil and various fruits and vegetables. In this study, we examined the beneficial effects of FA in minimizing insulin resistance, vascular dysfunction and remodeling in a rat model of high-carbohydrate, high-fat diet-induced metabolic changes, which is regarded as an analogue of metabolic syndrome (MS) in man. Male Sprague-Dawley rats were fed a high carbohydrate, high fat (HCHF) diet and 15% fructose in drinking water for 16 weeks, where control rats were fed with standard chow diet and tap water. FA (30 or 60 mg/kg) was orally administered to the HCHF and control rats during the last six weeks of the study. We observed that FA significantly improved insulin sensitivity and lipid profiles, and reduced elevated blood pressure, compared to untreated controls (p < 0.05). Moreover, FA also improved vascular function and prevented vascular remodeling of mesenteric arteries. The effects of FA in HCHF-induced MS may be realized through suppression of oxidative stress by down-regulation of p47phox, increased nitric oxide (NO) bioavailability with up-regulation of endothelial nitric oxide synthase (eNOS) and suppression of tumor necrosis factor-α (TNF-α). Our results suggest that supplementation of FA may have health benefits by minimizing the cardiovascular complications of MS and alleviating its symptoms.


Applying ethnography to the study of context in healthcare quality and safety.
Translating and scaling healthcare quality improvement (QI) and patient safety interventions remains a significant challenge. Context has been identified as a major factor in this. QI and patient safety research have begun to focus on context, with ethnography seen as a promising methodology for understanding the professional, organisational and cultural aspects of context. While ethnography is used to investigate the context of a variety of QI and safety interventions, the challenges inherent in effectively importing a qualitative methodology and its social science practitioners into this work have been largely unexamined. We explain ethnography as a research practice grounded in theory and dependent on observations gathered and interpreted in particular ways. We then review the approach of health services literature to evaluating this sort of qualitative research. Although the study of context is an interest shared by both social scientists and healthcare QI and safety researchers, we identify three key points at which those 'exporting' ethnography as a methodology and those 'importing' it to deal with QI and safety challenges may diverge. We describe perspectival divergences on the methodology's mission, form and scale. At the level of mission we demonstrate how ethnography has been adapted to a 'describe and feed back' role in the service of QI. At the level of form, we show how the long-term embedded observation at the heart of ethnography can be adapted only so far to accommodate QI interests if both data quality and ethical standards are to be upheld. Finally, at the level of scale, we demonstrate one ethnographic study design that balances breadth of exposure with depth of experience in its observations and so generates a particular type of scalable findings. The effective export of ethnography into QI and safety research requires discussion and negotiation between social scientific and health services research perspectives, as well as creative approaches to producing self-reflexive data that will allow clinicians to understand their own context and so improve their own processes.


Empirical evaluation of humpback whale telomere length estimates; quality control and factors causing variability in the singleplex and multiplex qPCR methods.
Telomeres, the protective cap of chromosomes, have emerged as powerful markers of biological age and life history in model and non-model species. The qPCR method for telomere length estimation is one of the most common methods for telomere length estimation, but has received recent critique for being too error-prone and yielding unreliable results. This critique coincides with an increasing awareness of the potentials and limitations of the qPCR technique in general and the proposal of a general set of guidelines (MIQE) for standardization of experimental, analytical, and reporting steps of qPCR. In order to evaluate the utility of the qPCR method for telomere length estimation in non-model species, we carried out four different qPCR assays directed at humpback whale telomeres, and subsequently performed a rigorous quality control to evaluate the performance of each assay. Performance differed substantially among assays and only one assay was found useful for telomere length estimation in humpback whales. The most notable factors causing these inter-assay differences were primer design and choice of using singleplex or multiplex assays. Inferred amplification efficiencies differed by up to 40% depending on assay and quantification method, however this variation only affected telomere length estimates in the worst performing assays. Our results suggest that seemingly well performing qPCR assays may contain biases that will only be detected by extensive quality control. Moreover, we show that the qPCR method for telomere length estimation can be highly precise and accurate, and thus suitable for telomere measurement in non-model species, if effort is devoted to optimization at all experimental and analytical steps. We conclude by highlighting a set of quality controls which may serve for further standardization of the qPCR method for telomere length estimation, and discuss some of the factors that may cause variation in qPCR experiments.


Validation of thermodesorption method for analysis of semi-volatile organic compounds adsorbed on wafer surface.
To prevent the degradation of the device characteristics it is important to detect the organic contaminants adsorbed on the wafers. In this respect, a reliable qualitative and quantitative analytical method for analysis of semi-volatile organic compounds which can adsorb on wafer surfaces is of paramount importance. Here, we present a new analytical method based on Wafer Outgassing System (WOS) coupled to Automated Thermal Desorber-Gas chromatography-Mass spectrometry (ATD-GC-MS) to identify and quantify volatile and semi-volatile organic compounds from 6", 8" and 12" wafers. WOS technique allows the desorption of organic compounds from one side of the wafers. This method was tested on three important airborne contaminants in cleanroom i.e. tris-(2-chloroethyl) phosphate (TCEP), tris-(2-chloroisopropyl) phosphate (TCPP) and diethyl phthalate (DEP). In addition, we validated this method for the analysis and quantification of DEP, TCEP and TCPP and we estimated the backside organic contamination which may contribute to the front side of the contaminated wafers. We are demonstrating that WOS/ATD-GC-MS is a suitable and highly efficient technique for desorption and quantitative analysis of organophosphorous compounds and phthalate ester which could be found on the wafer surface.


Heterogeneity of human polymorphonuclear leukocyte receptors for leukotriene B4. Identification of a subset of high affinity receptors that transduce the chemotactic response.
Human polymorphonuclear (PMN) leukocytes bound [3H]leukotriene B4 ([3H]-LTB4) specifically, as assessed by the displacement of 88% or more of the bound radioactivity by a 15,000-fold higher concentration of nonradioactive LTB4 or by micromolar concentrations of structural isomers of LTB4. The specific binding of [3H]LTB4 by PMN leukocytes was characterized by rapid association and dissociation, and was saturable at 800 nM LTB4. The results of computer analyses of the concentration dependence of binding of [3H]LTB4 were consistent with the expression of two classes of receptors having respective mean affinities of 3.9 X 10(-10) M and 6.1 X 10(-8) M and mean densities of 4.4 X 10(3) and 2.7 X 10(5) per PMN leukocyte. Structural isomers of LTB4 inhibited the binding of [3H]LTB4 to PMN leukocytes at concentrations similar to those required to elicit chemotaxis, while chemotactic peptides did not inhibit binding. PMN leukocytes that were deactivated by prior exposure to LTB4 lost high affinity binding sites selectively and concurrently with a reduction in the chemotactic response to LTB4. Chemotactic deactivation altered, but did not eliminate, the low affinity receptors for LTB4 and reduced only minimally the lysosomal degranulation elicited by LTB4. The high affinity receptors for LTB4 on normal human PMN leukocytes appear to transduce the chemotaxis evoked by LTB4 without substantially modifying lysosomal degranulation.


Reprogramming of root epidermal cells in response to nutrient deficiency.
Post-embryonic development of the root system is highly plastic to environmental cues, compensating for the sessile lifestyle of plants. The fate of epidermal cells of Arabidopsis roots is particularly responsive to nutritional signals, leading to an increase in the root's surface area in the absence of the essential but immobile minerals iron, phosphate and manganese. The resulting phenotype is characteristic of the respective condition. Growth under nutrient starvation affects the expression of genes involved in cell specification, indicating that environmental signals are perceived at an early stage of cell development. Cell fate decisions are controlled at different levels, probably integrated at the level of chromatin organization.


Inapparent infections and cholera dynamics.
In many infectious diseases, an unknown fraction of infections produce symptoms mild enough to go unrecorded, a fact that can seriously compromise the interpretation of epidemiological records. This is true for cholera, a pandemic bacterial disease, where estimates of the ratio of asymptomatic to symptomatic infections have ranged from 3 to 100 (refs 1-5). In the absence of direct evidence, understanding of fundamental aspects of cholera transmission, immunology and control has been based on assumptions about this ratio and about the immunological consequences of inapparent infections. Here we show that a model incorporating high asymptomatic ratio and rapidly waning immunity, with infection both from human and environmental sources, explains 50 yr of mortality data from 26 districts of Bengal, the pathogen's endemic home. We find that the asymptomatic ratio in cholera is far higher than had been previously supposed and that the immunity derived from mild infections wanes much more rapidly than earlier analyses have indicated. We find, too, that the environmental reservoir (free-living pathogen) is directly responsible for relatively few infections but that it may be critical to the disease's endemicity. Our results demonstrate that inapparent infections can hold the key to interpreting the patterns of disease outbreaks. New statistical methods, which allow rigorous maximum likelihood inference based on dynamical models incorporating multiple sources and outcomes of infection, seasonality, process noise, hidden variables and measurement error, make it possible to test more precise hypotheses and obtain unexpected results. Our experience suggests that the confrontation of time-series data with mechanistic models is likely to revise our understanding of the ecology of many infectious diseases.


Differences in how macaques monitor others: Does serotonin play a central role?
Primates must balance the need to monitor other conspecifics to gain social information while not losing other resource opportunities. We consolidate evidence across the fields of primatology, psychology, and neuroscience to examine individual, population, and species differences in how primates, particularly macaques, monitor conspecifics. We particularly consider the role of serotonin in mediating social competency via social attention, aggression, and dominance behaviors. Finally, we consider how the evolution of variation in social tolerance, aggression, and social monitoring might be explained by differences in serotonergic function in macaques. This article is categorized under: Economics > Interactive Decision-Making Psychology > Comparative Psychology Neuroscience > Behavior Cognitive Biology > Evolutionary Roots of Cognition.


Light-emitting diode-generated red light inhibits keloid fibroblast proliferation.
Red light is part of the visible light spectrum that does not generate DNA adducts associated with skin cancer and photoaging and may represent a safer therapeutic modality for treatment of keloid scars and other fibrotic skin diseases. Our laboratory previously demonstrated that light-emitting diode-generated red light (LED-RL) inhibits proliferation of skin fibroblasts. The effects of LED-RL on keloidal skin are not well characterized. To determine the effect of LED-RL on keloid-derived fibroblast proliferation and viability in vitro. Irradiation of primary keloid-derived human skin fibroblasts using LED-RL panels was performed in vitro, and modulation of proliferation and viability was quantified using trypan blue dye exclusion assay. Statistical analysis was performed using analysis of variance to compare treatment arms and the Student t-test to compare each treatment arm with the paired bench control arm. Keloid fibroblasts treated with LED-RL 240, 320, and 480 J/cm demonstrated statistically significant dose-dependent decreases in relative proliferation rate of 12.4%, 16.5%, and 28.9%, respectively, compared with matched nonirradiated controls (p < .05) and did not significantly alter viability relative to the matched nonirradiated controls. Light-emitting diode-generated red light can inhibit keloid fibroblast proliferation in a dose-dependent manner without altering viability. Light-emitting diode-generated red light has the potential to contribute to the treatment of keloids and other fibrotic skin diseases and is worthy of further translational and clinical investigation.


Blood transfusion and non-Hodgkin lymphoma: lack of association.
Non-Hodgkin lymphoma is the seventh most commonly diagnosed malignant condition worldwide, and its incidence has increased markedly in recent decades. Blood transfusions have been implicated as a possible risk factor for non-Hodgkin lymphoma. To determine whether blood transfusions are associated with an elevated risk for non-Hodgkin lymphoma. Population-based, nested case-control study. Nationwide cohort in Sweden. 361 patients with non-Hodgkin lymphoma and 705 matched controls, nested within a population-based cohort of 96795 patients at risk for blood transfusion between 1970 and 1983. Prospectively collected information on exposure was retrieved from computerized transfusion registries. Odds ratios obtained from conditional logistic regression models were used as measures of relative risks. No association was found between blood transfusions and the risk for non-Hodgkin lymphoma when patients who had received transfusions were compared with patients who had not received transfusions (odds ratio, 0.93 [95% CI, 0.71 to 1.23]). A reduction in risk was seen among persons who received transfusion of blood without leukocyte depletion (odds ratio, 0.72 [CI, 0.53 to 0.97]). Risk was not related to number of transfusions, and no interaction was seen with latency after transfusion. The findings in this study do not support previous observations of an association between blood transfusions and the risk for non-Hodgkin lymphoma.


Sedentary lifestyle related exosomal release of Hotair from gluteal-femoral fat promotes intestinal cell proliferation.
Pioneering epidemiological work has established strong association of sedentary lifestyle and obesity with the risk of colorectal cancer, while the detailed underlying mechanism remains unknown. Here we show that Hotair (HOX transcript antisense RNA) is a pro-adipogenic long non-coding RNA highly expressed in gluteal-femoral fat over other fat depots. Hotair knockout in adipose tissue results in gluteal-femoral fat defect. Squeeze of the gluteal-femoral fat induces intestinal proliferation in wildtype mice, while not in Hotair knockout mice. Mechanistically, squeeze of the gluteal-femoral fat induces exosomal Hotair secretion mainly by transcriptional upregulation of Hotair via NFκB. And increased exosomal Hotair in turn circulates in the blood and is partially endocytosed by the intestine, finally promoting the stemness and proliferation of intestinal stem/progenitor cells via Wnt activation. Clinically, obese subjects with sedentary lifestyle have much higher exosomal HOTAIR expression in the serum. These findings establish that sedentary lifestyle promotes exosomal Hotair release from the gluteal-femoral fat, which in turn facilitates intestinal stem and/or progenitor proliferation, raising a possible link between sedentary lifestyle with colorectal tumorigenesis.


Pre-Statistical Considerations for Harmonization of Cognitive Instruments: Harmonization of ARIC, CARDIA, CHS, FHS, MESA, and NOMAS.
Meta-analyses of individuals' cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear. To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study. We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item's administration and scoring procedures, and score distributions. We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences. Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies.


Surgical treatment of active infective aortic valve endocarditis with associated periannular abscess--11 year results.
The aim of the study was to evaluate the long-term results of allograft and prosthetic valve replacement in the treatment of infective aortic valve endocarditis with periannular abscess. Between March 1988 and March 1996, 65 patients underwent surgery for active aortic valve endocarditis and paravalvular abscess. The indications for surgery were congestive heart failure, systemic emboli and atrioventricular block III. The pre-operative evaluation was performed with transoesophageal echocardiography. Aortic valve replacement was performed with allografts in 47 cases, with mechanical valves in 15, and bioprosthetic valves in three cases. All patients with total ventricular-aortic dehiscence and prosthetic valve endocarditis were treated with allografts. The 30-day mortality rate was 23.5% in the prosthetic group, when compared with 8.5% in the patients treated with allografts. The rate of recurrent valve infections during the 11-year follow-up period was 27.1% in the prosthetic group and 3.2% in the allograft group. The actuarial 11-year survival rate was 82.1% in the allograft group and 64.7% in the prosthetic group. Aortic allografts are an effective treatment for infective aortic valve endocarditis with associated periannular abscess. The operative mortality and recurrent infection rates are lower than in the prosthetic group, resulting in a significantly higher survival rate. Diagnosis and surgical management of these cases should be based on pre-operative transoesophageal echocardiography.


Effects of oncology clinical nurse specialists' interventions on nursing-sensitive outcomes in South Korea.
This study compared outcomes, including pain, fatigue, anxiety, satisfaction, health-related quality of life (HRQOL), ease of access, and unexpected emergency room (ER) visits, for patients with cancer in South Korea who were cared for by an oncology clinical nurse specialist (CNS) with patients with cancer who were not. Self-report questionnaires and semistructured interviews were used to appraise the performance of oncology CNSs, and medical characteristics were obtained through chart review. CNS interventions were found to diminish some intensity scores of pain and fatigue, and to increase HRQOL, satisfaction with trustworthiness, and ease of access. No significant effects were observed on anxiety or unexpected ER visits. The current study provides evidence that oncology CNSs are effective in South Korea, which will be the basis of validating the implementation and expansion of policy for oncology nursing.


Overexpressing centriole-replication proteins in vivo induces centriole overduplication and de novo formation.
Centrosomes have important roles in many aspects of cell organization, and aberrations in their number and function are associated with various diseases, including cancer. Centrosomes consist of a pair of centrioles surrounded by a pericentriolar matrix (PCM), and their replication is tightly regulated. Here, we investigate the effects of overexpressing the three proteins known to be required for centriole replication in Drosophila-DSas-6, DSas-4, and Sak. By directly observing centriole replication in living Drosophila embryos, we show that the overexpression of GFP-DSas-6 can drive extra rounds of centriole replication within a single cell cycle. Extra centriole-like structures also accumulate in brain cells that overexpress either GFP-DSas-6 or GFP-Sak, but not DSas-4-GFP. No extra centrioles accumulate in spermatocytes that overexpress any of these three proteins. Most remarkably, the overexpression of any one of these three proteins results in the rapid de novo formation of many hundreds of centriole-like structures in unfertilized eggs, which normally do not contain centrioles. Our data suggest that the levels of centriolar DSas-6 determine the number of daughter centrioles formed during centriole replication. Overexpression of either DSas-6 or Sak can induce the formation of extra centrioles in some tissues but not others, suggesting that centriole replication is regulated differently in different tissues. The finding that the overexpression of DSas-4, DSas-6, or Sak can rapidly induce the de novo formation of centriole-like structures in Drosophila eggs suggests that this process results from the stabilization of centriole-precursors that are normally present in the egg.


Electroclinical features and long-term therapeutic response in patients with typical absence seizures.
To characterize in detail the electroclinical features of typical absence seizures and elucidate whether EEG or semiology features, alone or in combination, can predict long-term therapeutic outcome. We analysed video-EEG recordings from 213 typical absence seizures from 61 patients with idiopathic generalized epilepsy. We extracted semiological features, in addition to hallmark manifestations (motor/behavioural arrest, non-responsiveness), their location, timing and frequency. We evaluated the duration and frequency of generalized spike-wave discharges and the presence of polyspikes. We used a supervised machine-learning approach (random forest) to search for classifier features for long-term therapeutic outcome (>one year). Besides the hallmark manifestations, additional semiological features were identified in 87% of patients (75% of seizures). The most common additional semiological features were automatisms and eye blinking (observed in 45% and 41.5% of seizures, respectively). Automatisms were associated with longer seizure duration, and oral automatisms occurred earlier compared to limb automatisms (4.03 vs. 6.19 seconds; p=0.005). The mean duration of the ictal spike-wave discharges was nine seconds, and the median frequency was 3 Hz. Polyspikes occurred in 46 seizures (21.6%), in 19 patients (31%). Median follow-up was five years, and 73% of the patients were seizure-free at the end of the follow-up. None of the semiological features, alone or in combination, were predictors of therapeutic outcome. The only significant classifier was the presence of polyspikes, predicting a non-seizure-free outcome with an accuracy of 73% (95% CI: 70-77%), positive predictive value of 92% (95% CI: 84-98%) and negative predictive value of 60% (95% CI: 39-81%). Semiological features, in addition to behavioural arrest and non-responsiveness, are common in typical absence seizures, but they do not predict long-term therapeutic outcome. The presence of polyspikes has a high positive predictive value for unfavourable therapeutic outcome, and their presence should therefore be included when reporting EEGs in patients with typical absence seizures.


Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.
Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.


Hyperbaric oxygen therapy: A new look on treating stroke and traumatic brain injury.
Although hyperbaric oxygen therapy (HBOT) is common as a treatment for injuries, this study aimed to research the ability of HBOT in preconditioning to diminish any potential damage. The hypothesis stated that HBOT preconditioning alleviated the death of cells in primary rat neuronal cells (PRNCs) by transferring mitochondria from astrocytes. In this experiment, PRNCs were given an HBOT treatment before a tumor necrosis factor-alpha or lipopolysaccharide injury which resembled cell death associated with stroke and traumatic brain injury (TBI). After being examined, the study found more cell viability in the PRNCs that had received HBOT precondition and a mitochondrial transfer. The mitochondrial transfer was visualized by a series of images showing the transfer after the HBOT treatment. This study demonstrated the ability of HBOT preconditioning as a treatment for inflammation in stroke and TBI, with the transfer of mitochondria from astrocytes to PRNCs reducing cell death. Along with discussion of the study, this review also focuses on different stroke treatments in comparison with HBOT.


The phenotypic consequences of CFTR mutations.
Cystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.


Resveratrol, a red wine constituent polyphenol, protects gastric tissue against the oxidative stress in cholestatic rats.
This experimental study was designed to determine the effects of resveratrol on the level of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) in gastric tissue after bile duct ligation (BDL). Swiss albino rats were divided into three groups: Group 1, sham (n = 7); Group 2, BDL (BDL only group; n = 7); and Group 3, BDL plus resveratrol (n = 7). Animals in the resveratrol group were treated with 10 mg/kg resveratrol (i.p.) once a day throughout 28 days. In the resveratrol group, levels of MDA and NO in gastric tissue were significantly lower than in the BDL-only group (P < 0.001). The level of GSH in the resveratrol group was significantly higher than in the BDL-only group (P < 0.001). The present study demonstrates that intraperitoneal administration of resveratrol maintains antioxidant defenses and reduces oxidative gastric damage. This effect of resveratrol may be useful to preserve gastric tissue under oxidative stress due to cholestasis.


Vegetarian diets and chronic kidney disease.
While dietary restriction of protein intake has long been proposed as a possible kidney-protective treatment, the effects of changes in the quality of ingested proteins on the prevalence and risk of progression of chronic kidney disease (CKD) have been scarcely studied; these two aspects are reviewed in the present article. The prevalence of hypertension, type 2 diabetes and metabolic syndrome, which are the main causes of CKD in Western countries, is lower in vegetarian populations. Moreover, there is a negative relationship between several components of plant-based diets and numerous factors related to CKD progression such as uraemic toxins, inflammation, oxidative stress, metabolic acidosis, phosphate load and insulin resistance. In fact, results from different studies seem to confirm a kidney-protective effect of plant-based diets in the primary prevention of CKD and the secondary prevention of CKD progression. Various studies have determined the nutritional safety of plant-based diets in CKD patients, despite the combination of a more or less severe dietary protein restriction. As observed in the healthy population, this dietary pattern is associated with a reduced risk of all-cause mortality in CKD patients. We propose that plant-based diets should be included as part of the clinical recommendations for both the prevention and management of CKD.


Deep brain stimulation: eye movements reveal anomalous effects of electrode placement and stimulation.
One of the major difficulties in evaluating the efficacy of deep brain stimulation (DBS), or understanding its mechanism, is the need to distinguish the effects of stimulation itself from those of the lesion inevitably created during surgery. Recent work has shown that DBS of the subthalamic nucleus in Parkinson's disease greatly reduces the time it takes the eyes to make a saccade in response to a visual stimulus. Since this saccadic latency can be rapidly and objectively measured, we used it to compare the effects of surgery and of stimulation. We used a saccadometer to measure the saccadic latencies of 9 DBS patients (1) preoperatively, (2) the day after insertion of subthalamic nucleus electrodes, (3) three weeks later, prior to turning on the stimulator, and (4) after commencement of stimulation. Patients were on their anti-Parkinsonian medication throughout the study. It revealed an entirely unexpected and puzzling finding. As in previous studies an amelioration of symptoms is seen immediately after surgery, and then a further improvement when finally the stimulator is turned on, but in the case of saccadic latency the pattern is different: surgery produces a transient increase in latency, returning to baseline within three weeks, while subsequent stimulation reduced latency. Thus the differential effects of electrode placement and stimulation are completely different for saccades and for more general motor symptoms. This important finding rules out some over-simple interpretations of the mechanism of DBS, and needs to be taken into account in future attempts at modelling the neurophysiology of DBS.


Problems with risk reclassification methods for evaluating prediction models.
For comparing the performance of a baseline risk prediction model with one that includes an additional predictor, a risk reclassification analysis strategy has been proposed. The first step is to cross-classify risks calculated according to the 2 models for all study subjects. Summary measures including the percentage of reclassification and the percentage of correct reclassification are calculated, along with 2 reclassification calibration statistics. The author shows that interpretations of the proposed summary measures and P values are problematic. The author's recommendation is to display the reclassification table, because it shows interesting information, but to use alternative methods for summarizing and comparing model performance. The Net Reclassification Index has been suggested as one alternative method. The author argues for reporting components of the Net Reclassification Index because they are more clinically relevant than is the single numerical summary measure.


Implementation Strategies for Frontline Healthcare Professionals: People, Process Mapping, and Problem Solving.
Implementation science is focused on developing and evaluating methods to reduce gaps between research and practice. As healthcare organizations become increasingly accountable for equity, quality, and value, attention has been directed to identifying specific implementation strategies that can accelerate the adoption of evidence-based therapies into clinical practice. In this perspective, we offer three simple, practical strategies that can be used by frontline healthcare providers who are involved in on-the-ground implementation: people (stakeholder) engagement, process mapping, and problem solving. As a use case example, we describe the iterative application of these strategies to the implementation of a new home sleep apnea testing program for patients in the Veterans Health Administration (VA) healthcare system.


P110β in the ventromedial hypothalamus regulates glucose and energy metabolism.
Phosphoinositide 3-kinase (PI3K) signaling in hypothalamic neurons integrates peripheral metabolic cues, including leptin and insulin, to coordinate systemic glucose and energy homeostasis. PI3K is composed of different subunits, each of which has several unique isoforms. However, the role of the PI3K subunits and isoforms in the ventromedial hypothalamus (VMH), a prominent site for the regulation of glucose and energy homeostasis, is unclear. Here we investigated the role of subunit p110β in steroidogenic factor-1 (SF-1) neurons of the VMH in the regulation of metabolism. Our data demonstrate that the deletion of p110β in SF-1 neurons disrupts glucose metabolism, rendering the mice insulin resistant. In addition, the deletion of p110β in SF-1 neurons leads to the whitening of brown adipose tissues and increased susceptibility to diet-induced obesity due to blunted energy expenditure. These results highlight a critical role for p110β in the regulation of glucose and energy homeostasis via VMH neurons.


End-to-end electronic control of the hospital transfusion process to increase the safety of blood transfusion: strengths and weaknesses.
Incorrect blood component transfused is a frequent serious incident associated with transfusion and often involves misidentification of the patient and/or the unit of blood. This study extended the evaluation of an electronic system involving bar code technology and handheld computers. Electronic control of collection of blood from blood refrigerators was incorporated into a previously described process for blood sample collection and blood administration. Practice was evaluated before and after its introduction in cardiac surgery. The baseline audits revealed poor practice. Significant improvements were found following the introduction of the electronic system, including from 8 percent to 100 percent in checking that the blood group and unit number on the blood pack matched the compatibility label and the pack was in date (p < or = 0.0001). Similar significant improvements were found in blood sample collection, the collection of blood from blood refrigerators, and the documentation of transfusion. Staff found the system easy to operate and preferred it to standard procedures. A bar code patient identification system improved transfusion practice, although areas for improvement were identified. These results provide support for further work on the development of such systems for both transfusion and other procedures requiring patient identification.


Pollen limitation and flower abortion in a wind-pollinated, masting tree.
Pollen limitation is a key assumption of theories that explain mast seeding, which is common among wind-pollinated and woody plants. In particular, the pollen coupling hypothesis and pollination Moran effect hypothesis assume pollen limitation as a factor that synchronizes seed crops across individuals. The existence of pollen limitation has not, however, been unambiguously demonstrated in wind-pollinated, masting trees. We conducted a two-year pollen supplementation experiment on a masting oak species, Quercus lobata. Supplemental pollen increased acorn set in one year but not in the other, supporting the importance of pollen coupling and pollination Moran effect models of mast seeding. We also tracked the fate of female flowers over five years and found that the vast majority of flowers were aborted for reasons unrelated to pollination, even in the presence of excess pollen. Pollen limitation can reduce annual seed set in a wind-pollinated tree, but factors other than pollen limitation cause the majority of flower abortion.


Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries.
Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov).


A Genotypic Analysis of Five P. aeruginosa Strains after Biofilm Infection by Phages Targeting Different Cell Surface Receptors.
Antibiotic resistance constitutes one of the most serious threats to the global public health and urgently requires new and effective solutions. Bacteriophages are bacterial viruses increasingly recognized as being good alternatives to traditional antibiotic therapies. In this study, the efficacy of phages, targeting different cell receptors, against Pseudomonas aeruginosa PAO1 biofilm and planktonic cell cultures was evaluated over the course of 48 h. Although significant reductions in the number of viable cells were achieved for both cases, the high level of adaptability of the bacteria in response to the selective pressure caused by phage treatment resulted in the emergence of phage-resistant variants. To further investigate the genetic makeup of phage-resistant variants isolated from biofilm infection experiments, some of these bacteria were selected for phenotypic and genotypic characterization. Whole genome sequencing was performed on five phage-resistant variants and all of them carried mutations affecting the galU gene as well as one of pil genes. The sequencing analysis further revealed that three of the P. aeruginosa PAO1 variants carry large deletions (>200 kbp) in their genomes. Complementation of the galU mutants with wild-type galU in trans restored LPS expression on the bacterial cell surface of these bacterial strains and rendered the complemented strains to be sensitive to phages. This provides unequivocal evidence that inactivation of galU function was associated with resistance to the phages that uses LPS as primary receptors. Overall, this work demonstrates that P. aeruginosa biofilms can survive phage attack and develop phage-resistant variants exhibiting defective LPS production and loss of type IV pili that are well adapted to the biofilm mode of growth.


Phobos LIFE (Living Interplanetary Flight Experiment).
The Planetary Society's Phobos Living Interplanetary Flight Experiment (Phobos LIFE) flew in the sample return capsule of the Russian Federal Space Agency's Phobos Grunt mission and was to have been a test of one aspect of the hypothesis that life can move between nearby planets within ejected rocks. Although the Phobos Grunt mission failed, we present here the scientific and engineering design and motivation of the Phobos LIFE experiment to assist with the scientific and engineering design of similar future experiments. Phobos LIFE flew selected organisms in a simulated meteoroid. The 34-month voyage would have been the first such test to occur in the high-radiation environment outside the protection of Earth's magnetosphere for more than a few days. The patented Phobos LIFE "biomodule" is an 88 g cylinder consisting of a titanium outer shell, several types of redundant seals, and 31 individual Delrin sample containers. Phobos LIFE contained 10 different organisms, representing all three domains of life, and one soil sample. The organisms are all very well characterized, most with sequenced genomes. Most are extremophiles, and most have flown in low Earth orbit. Upon return from space, the health and characteristics of organisms were to have been compared with controls that remained on Earth and have not yet been opened.


X-ray screening seems to reduce gastric cancer mortality by half in a community-controlled trial in Costa Rica.
X-ray screening of gastric cancer is broadly used in Japan, although no controlled trial has proved its effectiveness. This study evaluates the impact of an X-ray screening demonstrative intervention to reduce gastric cancer mortality in a Costa Rican region. The evaluation follows a quasi-experimental, community-controlled design, with measures before and after. About 7000 individuals participated by invitation in the two-wave screening programme. X-ray screening was followed by videoendoscopy and gastric biopsies. Treatment included resection with or without lymph node dissection. Comparisons with two control groups estimate that gastric cancer mortality was halved in the period from 2 to 7 years after the first screening visit. Validity of X-rays as used in this intervention had 88% sensitivity, 80% specificity, and 3% predictive value for individuals with two screening visits. Incidence in the screened group increased up to four times. Case survival was 85% in the intervention group after 5 years, compared to 12% among the controls before the intervention and 35% among the controls in the same region after the intervention. Although X-ray mass screening seems able to reduce stomach cancer mortality, its high cost may be an obstacle for scaling up this intervention in a non-rich country like Costa Rica.