Cultural adaptation of a brief motivational intervention for heavy drinking among Hispanics in a medical setting.
Hispanics, particularly men of Mexican origin, are more likely to engage in heavy drinking and experience alcohol-related problems, but less likely to obtain treatment for alcohol problems than non-Hispanic men. Our previous research indicates that heavy-drinking Hispanics who received a brief motivational intervention (BMI) were significantly more likely than Hispanics receiving standard care to reduce subsequent alcohol use. Among Hispanics who drink heavily the BMI effectively reduced alcohol use but did not impact alcohol-related problems or treatment utilization. We hypothesized that an adapted BMI that integrates cultural values and addresses acculturative stress among Hispanics would be more effective. We describe here the protocol for the design and implementation of a randomized (approximately 300 patients per condition) controlled trial evaluating the comparative effectiveness of a culturally adapted (CA) BMI in contrast to a non-adapted BMI (NA-BMI) in a community hospital setting among men of Mexican origin. Study participants will include men who were hospitalized due to an alcohol related injury or screened positive for heavy drinking. By accounting for risk and protective factors of heavy drinking among Hispanics, we hypothesize that CA-BMI will significantly decrease alcohol use and alcohol problems, and increase help-seeking and treatment utilization. This is likely the first study to directly address alcohol related health disparities among non-treatment seeking men of Mexican origin by comparing the benefits of a CA-BMI to a NA-BMI. This study stands to not only inform interventions used in medical settings to reduce alcohol-related health disparities, but may also help reduce the public health burden of heavy alcohol use in the United States. Trial registration clinicaltrials.gov identifier NCT02429401; Registration date: April 28, 2015.


Redifferentiation of human gastric cancer cells induced by ascorbic acid and sodium selenite.
To explore the effects and mechanisms of ascorbic acid (AA) and sodium selenite (SS) on growth inhibition and redifferentiation in human gastric cancer cells. In the present study, trypan blue dye exclusion method was used to determine the cell growth curve and mitotic index, cell electrophoresis and colonogenic potential were used as the indexes of redifferentiation. In order to find out the mechanisms of redifferentiation, the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) were assayed, the content of malondialdehyde (MDA), reduced glutathione (GSH) and H2O2 were evaluated. After treatment with AA 3 mol/L + SS 2 mu mol/L, the growth rate and mitotic index of human gastric cancer cells (MGc-803) decreased remarkably. The indexes related with cell malignancy were alleviated. For example, cell surface charge was obviously decreased, the electrophoresis rate was dropped from 2.21 to 1.15 mu m.s-1.V-1.cm-1. The indexes related with cell redifferentiation were promoted. For example, the colonogenic potential was decreased to 93.5%. These results indicated that redifferentiation of human gastric cancer cells was successfully induced by AA + SS. The activities of SOD and GPX were significantly higher, while the activity of CAT was slower in treated group than that in the control. The content of MDA was slightly decreased, GSH was sharply decreased, and H2O2 content was dramatically increased. These results indicated that combination of ascorbic acid and sodium selenite may induce the redifferentiation of human gastric cancer cells and inhibit cell growth by virtue of enhancing the activities of antioxidative enzymes and inducing the formation of H2O2, and altering the cell redox status. Combination of ascorbic acid and sodium selenite may be a potent anticancer agent for human gastric cancer.


The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study.
This placebo-controlled randomized trial was conducted to ascertain the value of calcium citrate supplementation in averting bone loss in 63 postmenopausal women, 57 of whom were early postmenopausal (five years after menopause) and six of whom were mid-postmenopausal (five to ten years after menopause). Bone density data were available for 25 women who took 800 mg of calcium citrate daily and 31 women who received placebo for one to two years. The two groups were similar in baseline age, years postmenopause (3.3 in the calcium citrate group vs 2.7 in the placebo group), height, weight, calcium intake, and L2-L4 bone density. L2-L4 bone density did not change during calcium citrate treatment (+ 1.03% after two years), whereas it declined significantly by -2.38% after two years on placebo (P < .001). Femoral neck bone density did not change in either group. Radial shaft bone density did not change in the calcium citrate group (-0.02% after two years), but it declined significantly in the placebo group (-1.79% after one year and -3.03% after two years, P < .01). The difference in bone density of the L2-L4 vertebrae and radial shaft after two years of treatment was significant between the two groups. An analysis of covariance disclosed no significant effect of calcium citrate on L2-L4 bone density during the first three years after menopause, but a protective effect after three years. Although serum PTH did not change, serum and urinary calcium increased and serum calcitriol and urinary phosphorus decreased in the calcium citrate group, indicative of parathyroid suppression. Serum bone-specific alkaline phosphatase and osteocalcin, and urinary hydroxyproline and N-telopeptide decreased during some calcium citrate treatment periods, indicative of a reduction in bone turnover. Thus, calcium citrate supplementation (400 mg of calcium twice daily) averted bone loss and stabilized bone density in the spine, femoral neck, and radial shaft in women relatively soon after menopause. This bone-sparing action was probably due to the inhibition of bone resorption from parathyroid suppression.


The Veterans Affairs Low Vision Intervention Trial (LOVIT): design and methodology.
Visual impairment is a major public health problem. Vision rehabilitation programs have the potential to restore independence and improve quality of life for persons with permanent vision loss, and few have been evaluated in randomized controlled trials. The Veterans Affairs (VA) Low Vision Intervention Trial is a multicenter randomized clinical trial to evaluate the effectiveness of a new outpatient low vision rehabilitation program. 126 patients with moderate and severe vision loss due to macular diseases are randomized to low vision treatment in an outpatient setting or a usual care control group at two VA facilities in Hines, Illinois, and Salisbury, North Carolina. The primary outcome is the change in visual reading ability from baseline to four months measured with the Veterans Affairs Low Vision Visual Functioning Questionnaire-48 (VA LV VFQ-48). Secondary outcomes compare the mean change in visual ability measured with the VA LV VFQ-48 (overall ability, mobility, visual information processing, visual motor skills) for the treatment and control groups. Costs and cost effectiveness of outpatient treatment are evaluated. The low vision rehabilitation setting, use of a waiting list control group to address ethical issues, development of the treatment protocol, development of a vision function questionnaire for patients to self-report the difficulty they experience performing daily activities, and the use of Rasch analysis to develop and estimate this outcome measure are described. If the new low vision rehabilitation program is proven effective, studies will be needed to determine which of the multiple aspects of the intervention are necessary and sufficient. The challenges of conducting clinical trials in a rehabilitation setting and use of a waiting list (deferred treatment) control group extend beyond LOVIT. The design and methods of LOVIT may be applicable to other trials of rehabilitation services and to outcomes for which reliable and valid measurement tools must be developed.


Deaths due to Plasmodium knowlesi malaria in Sabah, Malaysia: association with reporting as Plasmodium malariae and delayed parenteral artesunate.
The simian parasite Plasmodium knowlesi is recognized as a common cause of severe and fatal human malaria in Sabah, Malaysia, but is morphologically indistinguishable from and still commonly reported as Plasmodium malariae, despite the paucity of this species in Sabah. Since December 2008 Sabah Department of Health has recommended intravenous artesunate and referral to a general hospital for all severe malaria cases of any species. This paper reviews all malaria deaths in Sabah subsequent to the introduction of these measures. Reporting of malaria deaths in Malaysia is mandatory. Details of reported malaria deaths during 2010-2011 were reviewed to determine the proportion of each Plasmodium species. Demographics, clinical presentations and management of severe malaria caused by each species were compared. Fourteen malaria deaths were reported, comprising seven Plasmodium falciparum, six P. knowlesi and one Plasmodium vivax (all PCR-confirmed). Of the six P. knowlesi deaths, five were attributable to knowlesi malaria and one was attributable to P. knowlesi-associated enterobacter sepsis. Patients with directly attributable P. knowlesi deaths (N = 5) were older than those with P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p = 0.06). Complications in fatal P. knowlesi included respiratory distress (N = 5, 100%), hypotension (N = 4, 80%), and renal failure (N = 4, 80%). All patients with P. knowlesi were reported as P. malariae by microscopy. Only two of five patients with severe knowlesi malaria on presentation received immediate parenteral anti-malarial treatment. The patient with P. vivax-associated severe illness did not receive parenteral treatment. In contrast six of seven patients with severe falciparum malaria received immediate parenteral treatment. Plasmodium knowlesi was responsible, either directly or through gram-negative bacteraemia, for almost half of malaria deaths in Sabah. Patients with severe non-falciparum malaria were less likely to receive immediate parenteral therapy. This highlights the need in Sabah for microscopically diagnosed P. malariae to be reported as P. knowlesi to improve recognition and management of this potentially fatal species. Clinicians need to be better informed of the potential for severe and fatal malaria from non-falciparum species, and the need to treat all severe malaria with immediate intravenous artesunate.


Differential Production of Type I IFN Determines the Reciprocal Levels of IL-10 and Proinflammatory Cytokines Produced by C57BL/6 and BALB/c Macrophages.
Pattern recognition receptors detect microbial products and induce cytokines, which shape the immunological response. IL-12, TNF-α, and IL-1β are proinflammatory cytokines, which are essential for resistance against infection, but when produced at high levels they may contribute to immunopathology. In contrast, IL-10 is an immunosuppressive cytokine, which dampens proinflammatory responses, but it can also lead to defective pathogen clearance. The regulation of these cytokines is therefore central to the generation of an effective but balanced immune response. In this study, we show that macrophages derived from C57BL/6 mice produce low levels of IL-12, TNF-α, and IL-1β, but high levels of IL-10, in response to TLR4 and TLR2 ligands LPS and Pam3CSK4, as well as Burkholderia pseudomallei, a Gram-negative bacterium that activates TLR2/4. In contrast, macrophages derived from BALB/c mice show a reciprocal pattern of cytokine production. Differential production of IL-10 in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages was due to a type I IFN and ERK1/2-dependent, but IL-27-independent, mechanism. Enhanced type I IFN expression in LPS-stimulated C57BL/6 macrophages was accompanied by increased STAT1 and IFN regulatory factor 3 activation. Furthermore, type I IFN contributed to differential IL-1β and IL-12 production in B. pseudomallei and LPS-stimulated C57BL/6 and BALB/c macrophages via both IL-10-dependent and -independent mechanisms. These findings highlight key pathways responsible for the regulation of pro- and anti-inflammatory cytokines in macrophages and reveal how they may differ according to the genetic background of the host.


Protecting the public: state medical board licensure policies for active and inactive physicians.
The purpose of this research was to explore state physician licensing board policies and regulation of active, inactive, and retired licenses. We conducted structured telephone interviews from January to March 2007 with representatives of all 64 state allopathic and osteopathic medical licensing boards in the United States. All of the licensing boards participated. Only 34% of state licensing boards query physicians regarding clinical activity at both initial licensure and renewal. The majority of boards allow physicians to hold or renew an unrestricted active license to practice medicine, although they may not have cared for a patient in years. Only 1 board requires a minimum number of patient visits to maintain an active license. Five boards allow physicians with inactive licenses to practice some form of medicine, whereas 7 boards allow physicians with retired licenses to practice. Few states have any mechanism to assess the competency of clinically inactive physicians who return to active practice. The number of inactive physicians in the United States is growing. Currently, state medical board policies do not address the issue of continuing competence in license renewal. Greater medical safety concerns on the part of the public will likely lead to calls for greater accountability by state licensing authorities.


Membrane protein changes in an L1210 leukemia cell line with a translocation defect in the methotrexate-tetrahydrofolate cofactor transport carrier.
We report on membrane protein changes in an L1210 leukemia cell line with a highly specific defect in the function of the methotrexate (MTX)-tetrahydrofolate cofactor transport carrier. This clonal line, MTXrA, made 100-fold resistant to MTX, was derived in a single step and exhibited stable resistance over 120 generations in the absence of drug. The transport defect was associated with a 10-fold decrease in influx Vmax without a change in influx Km. There was no difference between the MTXrA and parent lines in the levels or affinities of specific cell surface binders for MTX nor in the labeling of the 44-kDa membrane protein upon treatment with the specific affinity label, N-hydroxysuccinimide ester of tritiated MTX. Consistent with impaired carrier function was the observation that trans-stimulation of MTX influx by intracellular 5-formyltetrahydrofolate observed in the parent line was not demonstrated in the MTXrA line. The transport defect was highly specific for the MTX-tetrahydrofolate cofactor transport carrier. Initial uptake rates for 5-fluoro-2'-deoxyuridine and 2-deoxyglucose were unchanged and influx and net transport of alpha-aminoisobutyric acid were, in fact, increased. There was no cross-resistance of this line to phenylalanine mustard or cytosine arabinoside, agents that utilize specific amino acid and nucleoside transport carriers, respectively. SDS-polyacrylamide gel electrophoresis of purified plasma membrane preparations stained with Coomassie Blue revealed several protein differences between the parental and MTXrA lines. Most prominent is a band at approximately 190 kDa which ran with slightly greater mobility than a lesser staining band in the parent line. [3H]Borohydride labeling of cells also identified a distinct protein peak in the MTXrA line at approximately 190 kDa eliminated by prior treatment of cells with neuraminidase. Absence of expression of protein or mRNA related to the multidrug resistance gene as well as lack of cross-resistance to daunorubicin or trimetrexate indicate that this mechanism of resistance to MTX is completely unrelated to the multidrug resistance phenomenon observed with high molecular weight heterocyclic compounds. These data represent the first demonstration of membrane protein differences in a highly resistant L1210 murine leukemia cell line with a marked unique defect in MTX transport which appears to be related to impaired mobility of the tetrahydrofolate-cofactor carrier. Further studies are now required to elucidate the possible role of one or more of these proteins in the transport defect.


The frequency and complication rates of hysterectomy accompanying cesarean delivery.
To estimate the frequency, indications, and complications of cesarean hysterectomy. This was a prospective, 2-year observational study at 13 academic medical centers conducted between January 1, 1999, and December 31, 2000, on all women who underwent a hysterectomy at the time of cesarean delivery. Data were abstracted from the medical record by study nurses. The outcomes included procedure frequency, indications, and complications. A total of 186 cesarean hysterectomies (0.5%) were performed from a cohort of 39,244 women who underwent cesarean delivery. The leading indications for hysterectomy were placenta accreta (38%) and uterine atony (34%). Of the hysterectomy cases with a diagnosis recorded as accreta, 18% accompanied a primary cesarean delivery, and 82% had a prior procedure (P<.001). Of the hysterectomy cases with atony recorded as a diagnosis, 59% complicated primary cesarean delivery, whereas 41% had a prior cesarean (P<.001). Major maternal complications of cesarean hysterectomy included transfusion of red blood cells (84%) and other blood products (34%), fever (11%), subsequent laparotomy (4%), ureteral injury (3%), and death (1.6%). Accreta hysterectomy cases were more likely than atony hysterectomy cases to require ureteral stents (14% compared with 3%, P=.03) and to instill sterile milk into the bladder (23% compared with 8%, P=.02). The rate of cesarean hysterectomy has declined modestly in the past decade. Despite the use of effective therapies and procedures to control hemorrhage at cesarean delivery, a small proportion of women continue to require hysterectomy to control hemorrhage from both uterine atony and placenta accreta. II.


Antigenicity and Immunogenicity in HIV-1 Antibody-Based Vaccine Design.
Neutralizing antibodies can protect from infection by immunodeficiency viruses. However, the induction by active vaccination of antibodies that can potently neutralize a broad range of circulating virus strains is a goal not yet achieved, despite more than 2 decades of research. Here we review progress made in the field, from early empirical studies to today's rational structure-based vaccine antigen design. We discuss the existence of broadly neutralizing antibodies, their implications for epitope discovery and recent progress made in antigen design. Finally, we consider the relationship between antigenicity and immunogenicity for B cell recognition and antibody production, a major hurdle for rational vaccine design to overcome.


The pinocytic rate of activated macrophages.
Peritoneal macrophages from mice injected 4 days previously with Brewer's thioglycollate medium have a pinocytic rate, in culture, of 190 ng horseradish peroxidase (HRP)/100 mug cell protein/h, compared to the rate of resident peritoneal cells of 53 ng HRP/100 mug cell protein/h. Mice injected with endotoxin or with only certain of the components of the Brewer's medium show an intermediate level of stimulation. The rate of unstimulated, endotoxin-stimulated, or thioglycollate-stimulated cells shows little change over several days in culture. The pinocytic rate of thioglycollate-stimulated cells can, however, be further increased by exposure of concanavalin A. Although cells may show transient increases in their pinocytic rate in many situations, a sustained increase in pinocytic rate is a sign of the "activated" state of macrophages.


Fluid resuscitation strategies: a systematic review of animal trials.
Our objective was to systematically review randomized, controlled trials of fluid resuscitation in animal models of uncontrolled hemorrhage and to explore potential sources of heterogeneity. We conducted an electronic bibliographic search of published research, reviewed reference lists of included trials, and contacted authors about unpublished studies. We included all unconfounded, randomized, controlled trials of fluid resuscitation (timing, volume, or resuscitation targets) in animal models of uncontrolled hemorrhage. The outcome measure was mortality at the end of the scheduled follow-up period of the trial. Two reviewers independently applied the selection criteria to the trial reports. A third reviewer resolved disagreements. Forty-four trials compared fluid versus no fluid resuscitation. There was marked heterogeneity in the effect of fluid resuscitation on the risk of death, much of which was explained by the hemorrhage model used. In aortic injury models, the adjusted relative risk of death with fluid resuscitation was 0.48 (95% confidence interval [CI], 0.33-0.71). In organ incision models, the adjusted relative risk of death was 0.76 (95% CI, 0.49-1.18). In tail resection models, the adjusted relative risk of death was 0.69 (95% CI, 0.38-1.25) if 50% or more was removed and 1.86 (95% CI, 1.13-3.07) if less than 50% was removed. In other vascular injury models, the adjusted relative risk of death with fluid resuscitation was 1.70 (95% CI, 1.01-2.85), respectively. Nine trials compared hypotensive versus normotensive resuscitation. The relative risk of death with hypotensive resuscitation was 0.37 (95% CI, 0.27-0.50). Fluid resuscitation appears to reduce the risk of death in animal models of severe hemorrhage but increases the risk of death in those with less severe hemorrhage. Excessive fluid resuscitation could therefore be harmful in some situations. Hypotensive resuscitation reduced the risk of death in all the trials investigating it. An evaluation of the potential impact of hypotensive resuscitation in humans could now be warranted.


SMAD 8 binding to mice Msx1 basal promoter is required for transcriptional activation.
The Msx1 gene in mice has been proven to be induced by BMP (bone morphogenetic protein) proteins, and three binding sites for SMAD, an intracellular BMP signalling transducer, have already been identified in its promoter. Gel shift analyses were performed and they demonstrated that the consensus found very near the transcription start site, a region designed BP (basal promoter), is functional for binding nuclear proteins from 10.5, 11.5 and 13.5 dpc (days post-coitum) embryos. Notably, this binding occurs only when the SMAD-binding consensus sequence is maintained, suggesting that it is required for the formation of a protein complex over BP. Binding of purified SMAD 1 and SMAD 4 as well as supershift assay with SMAD 1/SMAD 5/SMAD 8 antibody proved that a SMAD protein is present in this complex. Transfection assays in cell cultures with fragments from BP driving the expression of luciferase confirmed that only in the presence of the SMAD consensus site is Msx1 expression activated. A proteomic analysis of the complex components after immunoprecipitation identified several proteins necessary to activate transcription including SMAD 8. Our results suggest that BMP2/BMP4 signalling through SMAD 8 is required for transcriptional activation of the mouse Msx1 gene.


Missed opportunities? Coercion or commitment: policies of prevention.
The DOTS strategy (directly observed therapy, short course) has been the cornerstone of international TB control policy since the early 1990s. This strategy has provided the international community with an advocacy tool to harness funds for TB as well as a method for helping country programs to achieve high cure rates for TB. But as much as the strategy is seen as successful by some, it is perceived as unsuccessful by others. This paper looks at the results of the introduction of DOTS into control programs and discusses research relating to direct observation of treatment. It asks how policies like DOTS are created, and how they are administered and transferred from the international to the national and finally to the local level. The discipline of public health policy is used to interrogate the creation and history of the DOTS strategy in order to find ways of aiding the transfer of the policy to national and local levels. Finally, the paper asks whether the concepts of "control" and "elimination" continue to be useful in the management of infectious diseases. We ask whether it is time to change the perspective to policies that focus more on the context of implementation and the importance of the development of care, integration, and flexibility rather than cure, targets, and short-term solutions.


A probable genetic origin for pitting enamel hypoplasia on the molars of Paranthropus robustus.
We report the frequencies of linear enamel hypoplasia (LEH) and, specifically, pitting enamel hypoplasia (PEH) defects in the teeth of Paranthropus robustus, for comparison with four other South African hominin species and three extant nonhuman primate species. Unlike LEH, the lesser known PEH is characterized by multiple circular depression defects across a tooth crown and is often difficult to interpret in terms of developmental timing and etiology. Teeth in all samples were examined macroscopically with type, position and number of defects recorded. Frequencies of teeth with LEH vary among hominin species, but the differences in PEH are considerable. That is, P. robustus has much higher rates of pitting defects, with 47% of deciduous teeth and 14% of permanent teeth affected, relative to 6.7% and 4.3%, respectively, for all other hominin teeth combined; none of the extant primate samples evidences comparable rates. The defects on P. robustus molars are unlike those in other species, with entire crowns often covered in small circular depressions. The PEH is most consistent with modern human examples of amelogenesis imperfecta. Additionally, the defects are: 1) not found on anterior teeth, 2) uniform in shape and size, and 3) similar in appearance/severity on all molars. Therefore, this form of PEH may have been a side effect of selection on another trait that shares the same coding gene(s), i.e., these defects have a genetic origin. We discuss a possible scenario that may explain how this form of PEH evolved to become so common in the Paranthropus genus.


Training Dogs to Feel Good: Embodying Well-being in Multispecies Relations.
Social science concepts of well-being are largely premised on notions of a common humanity with shared physical needs and broadly legible experiences of the world. While medical anthropologists have interrogated ideas of universal bodily subjectivities, articulations of well-being across species boundaries remain underexplored. This article offers a conceptualization of well-being that attends to species difference. Drawing on ethnographic research with an animal rescue organization, I argue that in the context of partially connected bodily experiences, rescue workers navigate distinctions between dogs' internal feelings and external actions, and they train their bodies alongside dogs' bodies to cultivate canine well-being. A multispecies perspective complicates ideals of autonomy and self-actualization long associated with well-being and opens up avenues for considering well-being as an intercorporeal relationship conditioned in unequal bodies and embodied interactions.


Competing exchange interactions in magnetic multilayers.
We have studied alloying of the nonmagnetic spacer layer with a magnetic material as a method of tuning the interlayer coupling in magnetic multilayers. We have specifically studied the Fe/V(100) system by alloying the spacer V with various amounts of Fe. For some Fe concentrations in the spacer, it is possible to create a competition between antiferromagnetic Ruderman-Kittel-Kasuya-Yoshida exchange and direct ferromagnetic exchange coupling. The exchange coupling and transport properties for a large span of systems with different spacer concentrations and thicknesses were calculated and measured experimentally and good agreement between observations and theory was observed. A reduction in magnetoresistance of about 50% was observed close to the switchover from antiferromagnetic to ferromagnetic coupling.


The use of unmanned aerial vehicles for health purposes: a systematic review of experimental studies.
Unmanned aircraft vehicles (UAVs) have had a rapid escalation in manageability and affordability, which can be exploited in healthcare. We conducted a systematic review examining the use of drones for health-related purposes. A search was conducted in Medline, Embase, Global Health, Scopus, CINAHL and SciELO. Experimental studies were selected if the population included human subjects, the intervention was the use of UAVs and there was a health-related outcome. Of 500 results, five met inclusion criteria during an initial search. An updated search yielded four additional studies. Nine studies, all in high-income countries, were included for systematic syntheses: four studies addressed out-of-hospital cardiac arrest emergencies, three assessed drones for identification of people after accidents, one used drones to transport blood samples and one used drones to improve surgical procedures in war zones. Research on the use of drones in healthcare is limited to simulation scenarios, and this review did not retrieve any studies from low- and middle-income countries.


Fast Crystallization of the Phase Change Compound GeTe by Large-Scale Molecular Dynamics Simulations.
Phase change materials are of great interest as active layers in rewritable optical disks and novel electronic nonvolatile memories. These applications rest on a fast and reversible transformation between the amorphous and crystalline phases upon heating, taking place on the nanosecond time scale. In this work, we investigate the microscopic origin of the fast crystallization process by means of large-scale molecular dynamics simulations of the phase change compound GeTe. To this end, we use an interatomic potential generated from a Neural Network fitting of a large database of ab initio energies. We demonstrate that in the temperature range of the programming protocols of the electronic memories (500-700 K), nucleation of the crystal in the supercooled liquid is not rate-limiting. In this temperature range, the growth of supercritical nuclei is very fast because of a large atomic mobility, which is, in turn, the consequence of the high fragility of the supercooled liquid and the associated breakdown of the Stokes-Einstein relation between viscosity and diffusivity.


A statistical model for assessing performance standards for quantitative and semiquantitative disinfectant test methods.
A performance standard for a disinfectant test method can be evaluated by quantifying the (Type I) pass-error rate for ineffective products and the (Type II) fail-error rate for highly effective products. This paper shows how to calculate these error rates for test methods where the log reduction in a microbial population is used as a measure of antimicrobial efficacy. The calculations can be used to assess performance standards that may require multiple tests of multiple microbes at multiple laboratories. Notably, the error rates account for among-laboratory variance of the log reductions estimated from a multilaboratory data set and the correlation among tests of different microbes conducted in the same laboratory. Performance standards that require that a disinfectant product pass all tests or multiple tests on average, are considered. The proposed statistical methodology is flexible and allows for a different acceptable outcome for each microbe tested, since, for example, variability may be different for different microbes. The approach can also be applied to semiquantitative methods for which product efficacy is reported as the number of positive carriers out of a treated set and the density of the microbes on control carriers is quantified, thereby allowing a log reduction to be calculated. Therefore, using the approach described in this paper, the error rates can also be calculated for semiquantitative method performance standards specified solely in terms of the maximum allowable number of positive carriers per test. The calculations are demonstrated in a case study of the current performance standard for the semiquantitative AOAC Use-Dilution Methods for Pseudomonas aeruginosa (964.02) and Staphylococcus aureus (955.15), which allow up to one positive carrier out of a set of 60 inoculated and treated carriers in each test. A simulation study was also conducted to verify the validity of the model's assumptions and accuracy. Our approach, easily implemented using the computer code provided, offers a quantitative decision-making tool for assessing a performance standard for any disinfectant test method for which log reductions can be calculated.


Serum Levels of Infliximab and Anti-Infliximab Antibodies in Brazilian Patients with Crohn's Disease.
The aim of this study was to evaluate the quantitative serum level of infliximab (IFX) as well as the detection of anti-infliximab antibodies (ATIs) in patients with Crohn's disease (CD). Forty patients with CD under treatment at a tertiary center in southeastern Brazil were evaluated. Their use of infliximab was continuous and regular. We analyzed and compared the differences in the IFX and ATI levels between the patients with active CD (CDA) and those with CD in remission (CDR). There was no difference in the IFX level between the CDA and CDR groups (p>0.05). Eighty percent of all patients had IFX levels above the therapeutic concentration (6-10 μg/mL). Two (9%) of the 22 patients with active disease and four (22.2%) of the 18 patients in remission had undetectable levels of IFX. Four (66.6%) of the six patients with undetectable levels of IFX had positive ATI levels; three of these patients were in remission, and one had active disease. In addition, the other two patients with undetectable levels of IFX presented ATI levels close to positivity (2.7 and 2.8 AU/ml). None of the patients with therapeutic or supratherapeutic IFX levels had positive ATI levels. The undetectable levels of IFX correlated with the detection of ATIs, which was independent of disease activity. Immunogenicity was not the main factor for the loss of response to IFX in our study, and the majority of patients in both groups (CDA and CDR) had supratherapeutic levels of IFX.


Computational prediction of binding affinity for CYP1A2-ligand complexes using empirical free energy calculations.
Predicting binding affinities for receptor-ligand complexes is still one of the challenging processes in computational structure-based ligand design. Many computational methods have been developed to achieve this goal, such as docking and scoring methods, the linear interaction energy (LIE) method, and methods based on statistical mechanics. In the present investigation, we started from an LIE model to predict the binding free energy of structurally diverse compounds of cytochrome P450 1A2 ligands, one of the important human metabolizing isoforms of the cytochrome P450 family. The data set includes both substrates and inhibitors. It appears that the electrostatic contribution to the binding free energy becomes negligible in this particular protein and a simple empirical model was derived, based on a training set of eight compounds. The root mean square error for the training set was 3.7 kJ/mol. Subsequent application of the model to an external test set gives an error of 2.1 kJ/mol, which is remarkably good, considering the simplicity of the model. The structures of the protein-ligand interactions are further analyzed, again demonstrating the large versatility and plasticity of the cytochrome P450 active site.


An Update on the Reversal of Non-Vitamin K Antagonist Oral Anticoagulants.
Non-vitamin K antagonist oral anticoagulants (NOACs) include thrombin inhibitor dabigatran and coagulation factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and betrixaban. NOACs have several benefits over warfarin, including faster time to the achieve effect, rapid onset of action, fewer documented food and drug interactions, lack of need for routine INR monitoring, and improved patient satisfaction. Local hemostatic measures, supportive care, and withholding the next NOAC dose are usually sufficient to achieve hemostasis among patients presenting with minor bleeding. The administration of reversal agents should be considered in patients on NOAC's with major bleeding manifestations (life-threatening bleeding, or major uncontrolled bleeding), or those who require rapid anticoagulant reversal for an emergent surgical procedure. The Food and Drug Administration (FDA) has approved two reversal agents for NOACs: idarucizumab for dabigatran and andexanet alfa for apixaban and rivaroxaban. The American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) have released an updated guideline for the management of patients with atrial fibrillation that provides indications for the use of these reversal agents. In addition, the final results of the ANNEXA-4 study that evaluated the efficacy and safety of andexanet alfa were recently published. Several agents are in different phases of clinical trials, and among them, ciraparantag has shown promising results. However, their higher cost and limited availability remains a concern. Here, we provide a brief review of the available reversal agents for NOACs (nonspecific and specific), recent updates on reversal strategies, lab parameters (including point-of-care tests), NOAC resumption, and agents in development.


Chemistry. The motions of an enzyme soloist.
Dynamics of proteins are crucial to their function. In his Perspective, Orrit stresses the advantages of studying these dynamics with single-molecule methods--which require no synchronization--rather than with conventional ensemble measurements. He highlights the report by Yang et al., who follow the fluorescence of a single enzyme molecule. Electron transfer from the fluorophore to a quencher induces fluctuations of the fluorescence lifetime along with the fluorophore-quencher distance. The wide range of characteristic times of those fluctuations reveals the complexity of the protein's potential energy landscape. As a new molecular ruler, electron transfer complements other single-molecule methods such as energy transfer (FRET) for distances shorter than a few nanometers.


Conflict of interest and signal interference lead to the breakdown of honest signaling.
Animals use signals to coordinate a wide range of behaviors, from feeding offspring to predator avoidance. This poses an evolutionary problem, because individuals could potentially signal dishonestly to coerce others into behaving in ways that benefit the signaler. Theory suggests that honest signaling is favored when individuals share a common interest and signals carry reliable information. Here, we exploit the opportunities offered by bacterial signaling to test these predictions with an experimental evolution approach. We show that: (1) reduced relatedness leads to the relative breakdown of signaling, (2) signaling breaks down by the invasion of mutants that show both reduced signaling and reduced response to signal, (3) the genetic route to signaling breakdown is variable, and (4) the addition of artificial signal, to interfere with signal information, also leads to reduced signaling. Our results provide clear support for signaling theory, but we did not find evidence for previously predicted coercion at intermediate relatedness, suggesting that mechanistic details can alter the qualitative nature of specific predictions. Furthermore, populations evolved under low relatedness caused less mortality to insect hosts, showing how signal evolution in bacterial pathogens can drive the evolution of virulence in the opposite direction to that often predicted by theory.


Coeliac disease causing symptomatic hypocalcaemia, osteomalacia and coagulapathy.
A 36-year-old gentleman presented with 6 months of poor energy, tingling in fingers and weight loss with a change in bowel habit. He appeared cachectic and had clubbing, demineralisation of teeth, pectus carinatus, kyphosis, spinal tenderness, proximal muscle weakness and generalised muscle atrophy. Chvostek's and Trosseau's signs were positive. His haemoglobin (Hb) was 8.7 g/dl, MCV 64.7 fl with low iron. Calcium corrected was 1.30 nmol/l, parathyroid hormone 440.4 ng/l, vitamin D <12.5 nmol/l; INR was 2.7 with coagulation inhibitor studies negative. Radiographs of spine and pelvis commented on osteopenia with thoracic kyphosis and mild anterior wedging of thoracic vertebrae. Antitissue transglutaminase was 145 U/ml, and antiendomysial antibodies were positive. An oesophagogastroduodenoscopy was consistent with coeliac disease. A diagnosis of osteomalacia and coagulopathy secondary to coeliac disease was made. The hypocalcaemia was treated with calcium gluconate infusions with symptomatic relief. Coagulopathy was treated with vitamin K intravenously with normalisation of INR. Following treatment with coeliac diet, calcium slowly normalised.


Overestimating Self-Blame for Stressful Life Events and Adolescents' Latent Trait Cortisol: The Moderating Role of Parental Warmth.
Cognitive interpretations of stressful events impact their implications for physiological stress processes. However, whether such interpretations are related to trait cortisol-an indicator of individual differences in stress physiology-is unknown. In 112 early adolescent girls (M age = 12.39 years), this study examined the association between self-blame estimates for past year events and latent trait cortisol, and whether maternal warmth moderated effects. Overestimating self-blame (versus objective indices) for independent (uncontrollable) events was associated with lower latent trait cortisol, and maternal warmth moderated the effect of self-blame estimates on latent trait cortisol for each dependent (at least partially controllable) and interpersonal events. Implications for understanding the impact of cognitive and interpersonal factors on trait cortisol during early adolescence are discussed.


Exploring differences in referrals to a hospice at home service in two socio-economically distinct areas of Manchester, UK.
In order to provide equitable access to hospice at home palliative care services, it is important to identify the socio-economic factors associated with poorer access. In this population-based study we aimed to test the inverse care law by exploring how socio-economic status and other key demographic indicators were associated with referral rates in two distinct areas (Salford and Trafford) served by the same service. Secondary data from the UK National Census 2001, North West Cancer Intelligence Service (2004) and hospice at home service referral data (2004-06) was collated for both areas. Descriptive analysis profiled electoral ward characteristics whilst simple correlations and regression modelling estimated associations with referral rates. Referral rates were lower and cancer mortality higher in the most deprived areas (Salford). Referral rates were significantly associated with deprivation, particularly multiple deprivation, but not significantly associated with cancer mortality (service model and resources available were held constant). At the population level, the socio-economic characteristics of those referred to hospice at home rather than service provision strongly predicted referral rates. This has implications for the allocation and targeting of resources and contributes important findings to future work exploring equitable access at organizational and professional levels.


Families' perspectives on the effect of constipation and fecal incontinence on quality of life.
Understanding families' quality of life can be important for interdisciplinary treatment planning. The present study examined child and parent perspectives about how constipation and fecal incontinence affect families' quality of life. Semistructured interviews were conducted with 8 children/adolescents and 8 caregivers. All of the children met Rome II criteria for functional constipation. Interviews were analyzed by an interdisciplinary team using a content analysis approach, which included developing a coding manual that described emergent themes from the interview transcripts. Qualitative and quantitative responses revealed the varied experiences of participating families. Child and parent views may be misaligned, which can affect treatment planning and effectiveness. Families described variable satisfaction with the treatment recommendations they had been offered and experienced difficulty finding appropriate care. Children's social and family functioning were significantly affected by constipation and fecal incontinence difficulties. Both children and parents described the challenges of discussing the problems with others. Multiple domains of individual and family functioning are affected by children's constipation and fecal incontinence difficulties, thereby affecting the quality of life of both children and their parents. The findings underscore the need for providers to consider the influence of symptoms on adjustment to both the medical condition and treatment adherence and discuss concerns with children and parents. The results provide the foundation for developing a standardized tool for quantitative assessment of quality of life for children with constipation.


Integrative Review of Exercise at Altitude during Pregnancy.
Many competitive and elite athletes continue to train throughout their pregnancies and many visit or live at altitude. The purpose of this integrative review is to synthesize, analyze and critique published studies regarding the safety of serious recreational or elite athletes exercising at altitude while pregnant. Seven databases were searched, and 157 documents were located, which were screened for appropriateness and reduced to seven articles that met the criteria. The studies were analyzed based on maternal and fetal outcomes. Current recommendations for exercising at altitude were based on sedentary individuals who frequently did not have the expected physiological responses based on research on pregnancy and altitude. It is unknown whether competitive and elite athletes would have similar responses to exercise at altitude. More research on exercise at altitude on individuals with a variety of fitness levels is needed.


Opioids, chronic pain, and addiction in primary care.
Research has largely ignored the systematic examination of physicians' attitudes towards providing care for patients with chronic noncancer pain. The objective of this study was to identify barriers and facilitators to opioid treatment of chronic noncancer pain patients by office-based medical providers. We used a qualitative study design using individual and group interviews. Participants were 23 office-based physicians in New England. Interviews were audiotaped, transcribed, and systematically coded by a multidisciplinary team using the constant comparative method. Physician barriers included absence of objective or physiological measures of pain; lack of expertise in the treatment of chronic pain and coexisting disorders, including addiction; lack of interest in pain management; patients' aberrant behaviors; and physicians' attitudes toward prescribing opioid analgesics. Physician facilitators included promoting continuity of patient care and the use of opioid agreements. Physicians' perceptions of patient-related barriers included lack of physician responsiveness to patients' pain reports, negative attitudes toward opioid analgesics, concerns about cost, and patients' low motivation for pain treatment. Perceived logistical barriers included lack of appropriate pain management and addiction referral options, limited information regarding diagnostic workup, limited insurance coverage for pain management services, limited ancillary support for physicians, and insufficient time. Addressing these barriers to pain treatment will be crucial to improving pain management service delivery. This article demonstrates that perceived barriers to treating patients with chronic noncancer pain are common among office-based physicians. Addressing these barriers in physician training and in existing office-based programs might benefit both noncancer chronic pain patients and their medical providers.


Diagnosis and management of gastric emptying disorders.
In summary, although gastric emptying disorders are relatively uncommon, they are potentially devastating conditions resulting from pathophysiologic motor disturbances. Rapid gastric emptying of liquids is the hallmark of the dumping syndrome and occurs after operations, including vagotomy. Vagal denervation abolishes receptive relaxation and accommodation in the proximal stomach (the storage site for ingested liquids) resulting in increased intragastric pressure which forces liquids through an ablated or bypassed pylorus. Dumping symptoms may occur in up to 50% of postgastrectomy patients, but most patients are treated satisfactorily by dietary manipulation or, in the rare incapacitated patient, by the long-acting somatostatin analogue octreotide. Reconstructive gastric surgery may rarely be indicated to slow gastric emptying and alleviate the dumping syndrome. Reoperative procedures include pyloric reconstruction after pyloroplasty, small intestinal pouches, interposed isoperistaltic and antiperistaltic jejunal segments, and a Roux-en-Y gastrojejunostomy. Interposed jejunal loops and the Roux-en-Y gastrojejunostomy provide the most satisfactory results. Delayed gastric emptying may occur in the acute postoperative period or be a late complication of gastric surgery. Loss of vagal input to the gastric antrum and resection of the antrum with vagotomy may produce an atonic stomach or atonic gastric remnant, respectively, which fails to grind and propel solids into the small intestine. Scintigraphic imaging of both the liquid and solid components of the meal is a valuable diagnostic adjunct. Gastric ileus occurring in the early postoperative period generally resolves within 6 weeks of operation, and the temptation to reoperate on a nonobstructed stomach should be avoided. Pharmacologic therapy of chronic gastric stasis with the benzamide prokinetic agents (metoclopramide, cisapride, renzapride), domperidone, and the motilin agonist erythromycin, may be effective initially, but long-term results are still undefined, and postvagotomy and postgastrectomy patients have not been studied adequately. Persistent postoperative gastric atony and the Roux stasis syndrome should be managed surgically by near-total gastrectomy which should result in symptomatic improvement in two thirds of patients.


Challenges with scale-up of GeneXpert MTB/RIF® in Uganda: a health systems perspective.
Many high burden countries are scaling-up GeneXpert® MTB/RIF (Xpert) testing for tuberculosis (TB) using a hub-and-spoke model. However, the effect of scale up on reducing TB has been limited. We sought to characterize variation in implementation of referral-based Xpert TB testing across Uganda, and to identify health system factors that may enhance or prevent high-quality implementation of Xpert testing services. We conducted a cross-sectional study triangulating quantitative and qualitative data sources at 23 community health centers linked to one of 15 Xpert testing sites between November 2016 and May 2017 to assess health systems infrastructure for hub-and-spoke Xpert testing. Data sources included a standardized site assessment survey, routine TB notification data, and field notes from site visits. Challenges with Xpert implementation occurred at every step of the diagnostic evaluation process, leading to low overall uptake of testing. Of 2192 patients eligible for TB testing, only 574 (26%) who initiated testing were referred for Xpert testing. Of those, 54 (9.4%) were Xpert confirmed positive just under half initiated treatment within 14 days (n = 25, 46%). Gaps in required infrastructure at 23 community health centers to support the hub-and-spoke system included lack of refrigeration (n = 14, 61%) for sputum testing and lack of telephone/mobile communication (n = 21, 91%). Motorcycle riders responsible for transporting sputum to Xpert sites operated variable with trips once, twice, or three times a week at 10 (43%), nine (39%) and four (17%) health centers, respectively. Staff recorded Xpert results in the TB laboratory register at only one health center and called patients with positive results at only two health centers. Of the 15 Xpert testing sites, five (33%) had at least one non-functioning module. The median number of tests per day was 3.57 (IQR 2.06-4.54), and 10 (67%) sites had error/invalid rates > 5%. Although Xpert devices are now widely distributed throughout Uganda, health system factors across the continuum from test referral to results reporting and treatment initiation preclude effective implementation of Xpert testing for patients presenting to peripheral health centers. Support for scale up of innovative technologies should include support for communication, coordination and health systems integration.


Cigarette smoke enhances abdominal aortic aneurysm formation in angiotensin II-treated apolipoprotein E-deficient mice.
Cigarette smoke, hyperlipidemia, and hypertension with the risk of development and progression of atherosclerosis and associated pathologies such as abdominal aortic aneurysm (AAA) are correlated. We examined the interaction of cigarette mainstream smoke (MS) and angiotensin-II (Ang II)-induced hypertension in the atherosclerotic process using hyperlipidemic apolipoprotein E-knockout (ApoE(-/-)) mice. ApoE(-/-) mice were treated with Ang II for 4 weeks and then further exposed to MS or to fresh air for 4 weeks. AAA formation was observed in all mice treated with Ang II, regardless of smoke exposure; however, smoke exposure increased the incidence of AAA in these mice. Ang II treatment resulted in higher gene expression of matrix metalloproteinases (MMP)-2, -3, -8, -9, and -12 in the abdominal aortas, which was further increased by MS exposure. The proteolytic activity of MMP-2 and MMP-9 was also enhanced in Ang II-treated mice exposed to MS, but only minor changes were seen with either smoke exposure or Ang II treatment alone. This study shows for the first time that both formation and severity of AAA in hypertensive ApoE(-/-) mice are accelerated by exposure to MS and that the proteolytic activity of MMPs is enhanced by the combination of Ang II and MS.


Differences in genetic diversity of nonecapsulated Haemophilus influenzae from various diseases.
Genetic relationships among 80 isolates of nonencapsulated Haemophilus influenzae recovered from different disease types were determined by multilocus enzyme electrophoresis (MEE) at 13 enzyme loci in an attempt to assess the association between multilocus genotype and disease. The isolates were obtained from 15 patients with meningitis, 10 with otitis media, 19 with chronic bronchitis, 20 with cystic fibrosis, and 16 were obtained from healthy carriers. The 80 isolates were assigned to 69 electrophoretic types (ETs) falling into 5 groups. Isolates from each disease entity were represented by a variety of genotypes; however, cluster analysis from a matrix of genetic distances between ETs revealed that the ETs of the otitis media and meningitis isolates were all clustered within a genetic distance of 0.55 (group I). In addition, no genotypes were shared between H. influenzae carrier isolates and isolates from cases of disease, H. influenzae isolates from healthy individuals were distributed significantly differently from those from chronic bronchitis meningitis and otitis media patients. The genetic diversity (H) of carrier strains was greatest, although not statistically different from that of isolates from patients with disease. It was concluded that the genetic distribution of acute disease isolates is not random over the five ET groups, although the genetic diversity within the groups is not different. The effect of bacterial persistence in the host on the genetic diversity of H. influenzae is discussed.


The Philosophy of Nosology.
Many scholars believe that psychiatric nosology is undergoing a crisis of confidence. Some of the issues up for debate hark back to the introduction of the natural history approach to classification in the seventeenth century. Natural histories map sameness and difference rather than speculate about causes. In contrast, the natural classification approach aspires to carve nature at the joints by demarcating classifications by causes. Natural classifications are more ideal scientifically, but speculation about causality has had a poor track record in psychiatric nosology. A natural classification of psychiatric disorders may have the added burden of requiring normative assumptions in addition to the discovery of fact. In the natural classification tradition, the epistemic iteration perspective, the Research Domain Criteria (RDoC) initiative, and dimensional models offer different views about the criteria of naturalness (or validity). Also in this tradition, some thinkers believe that causes can be empirically indexed by latent variable models, especially if the latent variables are moderately heritable, but these assumptions may be neither statistically nor genetically warranted.


Integration of in silico and in vitro platforms for pharmacokinetic-pharmacodynamic modeling.
Pharmacokinetic-pharmacodynamic (PK-PD) modeling enables quantitative prediction of the dose-response relationship. Recent advances in microscale technology enabled researchers to create in vitro systems that mimic biological systems more closely. Combination of mathematical modeling and microscale technology offers the possibility of faster, cheaper and more accurate prediction of the drug's effect with a reduced need for animal or human subjects. This article discusses combining in vitro microscale systems and PK-PD models for improved prediction of drug's efficacy and toxicity. First, we describe the concept of PK-PD modeling and its applications. Different classes of PK-PD models are described. Microscale technology offers an opportunity for building physical systems that mimic PK-PD models. Recent progress in this approach during the last decade is summarized. This article is intended to review how microscale technology combined with cell cultures, also known as 'cells-on-a-chip', can confer a novel aspect to current PK-PD modeling. Readers will gain a comprehensive knowledge of PK-PD modeling and 'cells-on-a-chip' technology, with the prospect of how they may be combined for synergistic effect. The combination of microscale technology and PK-PD modeling should contribute to the development of a novel in vitro/in silico platform for more physiologically-realistic drug screening.


Helping smokers make decisions: the enhancement of brief intervention for general medical practice.
Primary care clinicians are often encouraged by government agencies to intervene systematically with all smokers. Pressure of time and pessimism about their own efficacy and patients' capacity to change are some of the reasons why clinicians do not feel it is appropriate to always advise every patient about unhealthy behaviours. Developments in patient centred approaches to the consultation and progress in the addictions field suggest that new consulting methods could be constructed which are more satisfying than giving brief advice to change. The aim of this study was to develop a structured, teachable and acceptable intervention for clinicians to help patients consider their smoking during general medical consultations. Patient centred strategies derived from the stages of change model and motivational interviewing and its adaptations were explored in experimental consultations with 20 volunteer smokers. Feedback from them and from general practice registrars trained in the use of the method informed its development. Acceptability to clinicians was assessed by semi structured telephone interviews with 24 general practice registrars who participated in a randomised controlled trial assessing the effectiveness of the method. Anonymous, written questionnaires were also completed by 20 of the registrars who recruited ten or more patients into the trial. The method is described. Key components are: establishing rapport, assessing motivation and confidence, and then depending on the response, asking standard scaling questions, asking about pros and cons of smoking, non-judgmental information sharing, brainstorming solutions and negotiating attainable goals and follow-up. The clinicians used the method with a total of 270 smokers, taking an average of 9.69 min with each patient. Evaluation reveals that it is acceptable to the group of general practice registrars. Longer consultation time was seen as the main drawback. We conclude that acceptable methods for opportunistic health promotion can be developed by taking into account patient centred approaches to the consultation, developments from the addictions field and the practical problems faced by clinicians. The process can be further enhanced by considering feedback from those who are likely to receive and use the interventions.


Assessment of methane emissions from the U.S. oil and gas supply chain.
Methane emissions from the U.S. oil and natural gas supply chain were estimated by using ground-based, facility-scale measurements and validated with aircraft observations in areas accounting for ~30% of U.S. gas production. When scaled up nationally, our facility-based estimate of 2015 supply chain emissions is 13 ± 2 teragrams per year, equivalent to 2.3% of gross U.S. gas production. This value is ~60% higher than the U.S. Environmental Protection Agency inventory estimate, likely because existing inventory methods miss emissions released during abnormal operating conditions. Methane emissions of this magnitude, per unit of natural gas consumed, produce radiative forcing over a 20-year time horizon comparable to the CO2 from natural gas combustion. Substantial emission reductions are feasible through rapid detection of the root causes of high emissions and deployment of less failure-prone systems.


Functional traits help to explain half-century long shifts in pollinator distributions.
Changes in climate and land use can have important impacts on biodiversity. Species respond to such environmental modifications by adapting to new conditions or by shifting their geographic distributions towards more suitable areas. The latter might be constrained by species' functional traits that influence their ability to move, reproduce or establish. Here, we show that functional traits related to dispersal, reproduction, habitat use and diet have influenced how three pollinator groups (bees, butterflies and hoverflies) responded to changes in climate and land-use in the Netherlands since 1950. Across the three pollinator groups, we found pronounced areal range expansions (>53%) and modelled range shifts towards the north (all taxa: 17-22 km), west (bees: 14 km) and east (butterflies: 11 km). The importance of specific functional traits for explaining distributional changes varied among pollinator groups. Larval diet preferences (i.e. carnivorous vs. herbivorous/detritivorous and nitrogen values of host plants, respectively) were important for hoverflies and butterflies, adult body size for hoverflies, and flight period length for all groups. Moreover, interactions among multiple traits were important to explain species' geographic range shifts, suggesting that taxon-specific multi-trait analyses are needed to predict how global change will affect biodiversity and ecosystem services.


Safety and tolerability of lamotrigine: results from 12 placebo-controlled clinical trials and clinical implications.
The mechanism of action of lamotrigine depends on voltage-sensitive sodium channels by which the neuronal membrane is stabilized and the release of excitatory neurotransmitters, such as glutamate and aspartate, is inhibited. Lamotrigine is indicated for maintenance treatment of bipolar I disorder to delay the time to the occurrence of mood episodes for those treated for acute mood episodes with standard therapy. There are significant gaps between clinical practices and research settings; data from controlled clinical trials of lamotrigine provide essential information about safety in bipolar populations because they result from large samples of patients with a specific disease and include comparisons with placebo or other comparators with randomized designs. In addition, lamotrigine's safety and tolerability data differ slightly in relation to disease entities, age ranges of the patients taking lamotrigine, and treatment conditions. For example, the incidence of serious rashes, including Stevens-Johnson syndrome, is approximately 0.8% (8/1000) in pediatric patients (2-16 years of age) receiving lamotrigine as adjunctive therapy for epilepsy and 0.3% (3/1000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8/1000) in adult patients receiving lamotrigine as initial monotherapy and 0.13% (1.3/1000) in adult patients receiving lamotrigine as adjunctive therapy. Hence, in this study, we focus on the data regarding the safety and tolerability of lamotrigine in the treatment of bipolar disorder gathered from 12 placebo-controlled trials, regardless of publication status, that were sponsored by GlaxoSmithKline. We also inform clinicians of practical issues in safety and tolerability in the use of lamotrigine in the treatment of bipolar disorders.


Theoretical limits on errors and acquisition rates in localizing switchable fluorophores.
A variety of recent imaging techniques are able to beat the diffraction limit in fluorescence microcopy by activating and localizing subsets of the fluorescent molecules in the specimen, and repeating this process until all of the molecules have been imaged. In these techniques there is a tradeoff between speed (activating more molecules per imaging cycle) and error rates (activating more molecules risks producing overlapping images that hide information on molecular positions), and so intelligent image processing approaches are needed to identify and reject overlapping images. We introduce here a formalism for defining error rates, derive a general relationship between error rates, image acquisition rates, and the performance characteristics of the image processing algorithms, and show that there is a minimum acquisition time irrespective of algorithm performance. We also consider algorithms that can infer molecular positions from images of overlapping blurs, and derive the dependence of the minimum acquisition time on algorithm performance.


Arterial patterns of the deep and superficial palmar arches.
The vascular patterns of the palmar arches and their interconnecting branches present a complex and challenging area of study. Improvements in microsurgical techniques have made a better understanding of vascular patterns and vessel diameters more important. Forty-five fresh limbs from cadavers were amputated at the level of the midhumerus. Ward's red latex or Batson's compound was injected under pressure to visualize the arterial system in the hand. After hardening of the injected material, the skin, subcutaneous tissues, and tendons were removed. The specimens were digested in concentrated potassium or sodium hydroxide leaving the bony elements and a cast of the arterial system. The superficial palmar arch is most easily classified into two categories: complete or incomplete. An arch is considered to be complete if an anastomosis is found between the vessels constituting it. An incomplete arch has an absence of a communication or anastomosis between the vessels constituting the arch. Complete superficial palmar arches were seen in 84.4% of specimens. In the most common type, the superficial arch was formed by anastomosis between the superficial volar branch of the radial artery and the ulnar artery. This was seen in 35.5% of specimens. In 31.1%, the arch was formed entirely of the ulnar artery. Incomplete superficial arches were seen in 15.5% of specimens. In 11.1%, the ulnar artery forms the superficial arch but does not contribute to the blood supply to the thumb and index finger. The deep palmar arch was found to be less variable with 44.4% formed by an anastomosis between the deep volar branch of the radial artery and the inferior deep branch of the ulnar artery. Injection followed by chemical debridement allows direct visualization and measurement of the arches and the smaller arterial branches that are visualized poorly with other techniques. Based on the vessel measured, vessels of the superficial and deep arches are of sufficient size to allow microvascular repair, although repair of the communicating branches, the dorsal carpal rete, and its branches, probably is not feasible because of their small size.


Recognition by symmetry derivatives and the generalized structure tensor.
We suggest a set of complex differential operators that can be used to produce and filter dense orientation (tensor) fields for feature extraction, matching, and pattern recognition. We present results on the invariance properties of these operators, that we call symmetry derivatives. These show that, in contrast to ordinary derivatives, all orders of symmetry derivatives of Gaussians yield a remarkable invariance: They are obtained by replacing the original differential polynomial with the same polynomial, but using ordinary coordinates x and y corresponding to partial derivatives. Moreover, the symmetry derivatives of Gaussians are closed under the convolution operator and they are invariant to the Fourier transform. The equivalent of the structure tensor, representing and extracting orientations of curve patterns, had previously been shown to hold in harmonic coordinates in a nearly identical manner. As a result, positions, orientations, and certainties of intricate patterns, e.g., spirals, crosses, parabolic shapes, can be modeled by use of symmetry derivatives of Gaussians with greater analytical precision as well as computational efficiency. Since Gaussians and their derivatives are utilized extensively in image processing, the revealed properties have practical consequences for local orientation based feature extraction. The usefulness of these results is demonstrated by two applications: 1) tracking cross markers in long image sequences from vehicle crash tests and 2) alignment of noisy fingerprints.


Managing the data deluge: data-driven GO category assignment improves while complexity of functional annotation increases.
The available curated data lag behind current biological knowledge contained in the literature. Text mining can assist biologists and curators to locate and access this knowledge, for instance by characterizing the functional profile of publications. Gene Ontology (GO) category assignment in free text already supports various applications, such as powering ontology-based search engines, finding curation-relevant articles (triage) or helping the curator to identify and encode functions. Popular text mining tools for GO classification are based on so called thesaurus-based--or dictionary-based--approaches, which exploit similarities between the input text and GO terms themselves. But their effectiveness remains limited owing to the complex nature of GO terms, which rarely occur in text. In contrast, machine learning approaches exploit similarities between the input text and already curated instances contained in a knowledge base to infer a functional profile. GO Annotations (GOA) and MEDLINE make possible to exploit a growing amount of curated abstracts (97 000 in November 2012) for populating this knowledge base. Our study compares a state-of-the-art thesaurus-based system with a machine learning system (based on a k-Nearest Neighbours algorithm) for the task of proposing a functional profile for unseen MEDLINE abstracts, and shows how resources and performances have evolved. Systems are evaluated on their ability to propose for a given abstract the GO terms (2.8 on average) used for curation in GOA. We show that since 2006, although a massive effort was put into adding synonyms in GO (+300%), our thesaurus-based system effectiveness is rather constant, reaching from 0.28 to 0.31 for Recall at 20 (R20). In contrast, thanks to its knowledge base growth, our machine learning system has steadily improved, reaching from 0.38 in 2006 to 0.56 for R20 in 2012. Integrated in semi-automatic workflows or in fully automatic pipelines, such systems are more and more efficient to provide assistance to biologists. DATABASE URL: http://eagl.unige.ch/GOCat/


Multimodal mechanisms of human socially reinforced learning across neurodegenerative diseases.
Social feedback can selectively enhance learning in diverse domains. Relevant neurocognitive mechanisms have been studied mainly in healthy persons, yielding correlational findings. Neurodegenerative lesion models, coupled with multimodal brain measures, can complement standard approaches by revealing direct multidimensional correlates of the phenomenon. To this end, we assessed socially reinforced and non-socially reinforced learning in 40 healthy participants as well as persons with behavioural variant frontotemporal dementia (n = 21), Parkinson's disease (n = 31) and Alzheimer's disease (n = 20). These conditions are typified by predominant deficits in social cognition, feedback-based learning and associative learning, respectively, although all three domains may be partly compromised in the other conditions. We combined a validated behavioural task with ongoing EEG signatures of implicit learning (medial frontal negativity) and offline MRI measures (voxel-based morphometry). In healthy participants, learning was facilitated by social feedback relative to non-social feedback. In comparison with controls, this effect was specifically impaired in behavioural variant frontotemporal dementia and Parkinson's disease, while unspecific learning deficits (across social and non-social conditions) were observed in Alzheimer's disease. EEG results showed increased medial frontal negativity in healthy controls during social feedback and learning. Such a modulation was selectively disrupted in behavioural variant frontotemporal dementia. Neuroanatomical results revealed extended temporo-parietal and fronto-limbic correlates of socially reinforced learning, with specific temporo-parietal associations in behavioural variant frontotemporal dementia and predominantly fronto-limbic regions in Alzheimer's disease. In contrast, non-socially reinforced learning was consistently linked to medial temporal/hippocampal regions. No associations with cortical volume were found in Parkinson's disease. Results are consistent with core social deficits in behavioural variant frontotemporal dementia, subtle disruptions in ongoing feedback-mechanisms and social processes in Parkinson's disease and generalized learning alterations in Alzheimer's disease. This multimodal approach highlights the impact of different neurodegenerative profiles on learning and social feedback. Our findings inform a promising theoretical and clinical agenda in the fields of social learning, socially reinforced learning and neurodegeneration.


Obesity and food away from home: What drives the socioeconomic gradient in excess body weight?
Rising obesity rates are one of the most challenging public health issues in many emerging economies. To what extent food away from home (FAFH) and its nutritional components are behind this rise is not yet well understood. To address the issue, this paper combines a representative restaurant survey that includes detailed information on the diet quality of the most widely consumed meals and their nutritional components from 1605 restaurants and a representative household survey with anthropometric measures of adult women living in 40 neighborhoods in the Lima Metropolitan Area. One important advantage of the dataset is the fact that nutrition professionals observed the preparation of the meals and that they were subject to a detailed laboratory analysis. Exploiting this data, we examine the differences in nutritional quality of FAFH among 40 neighborhoods of various socioeconomic groups and explore whether these differences can explain part of the observed socioeconomic gradient in excess body weight. The findings indicate that less healthy food in restaurants located in the food environment of the households is significantly associated with higher rates of obesity and overweight. In particular, the high supply and intake of sodium potentially drives higher excess body weight. The study also finds that up to 15 percent of the socioeconomic gradient in obesity is attributable to the restaurant food quality in the food environment of the households.


Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes.
Nicotinic acetylcholine receptors present on cultured hippocampal neurons from fetal rats were characterized by means of whole-cell patch-clamp technique, using a number of structurally divergent agonists and highly selective antagonists. Based upon the decay kinetics of the currents elicited by 3 mM acetylcholine (ACh) and their sensitivities to agonists and antagonists, the neurons were shown to exhibit four current types, IA, IB, II and III. Rapidly decaying currents (type IA) that were blocked by alpha-bungarotoxin (10 nM), kappa-bungarotoxin (10 nM) and methyllycaconitine (MLA, 1 nM) were the most frequent and were found in 83% of the neurons tested. Type II currents (found in 5% of the neurons) were blocked by dihydro-beta-erythroidine (10 nM), and by high concentrations of MLA and kappa-bungarotoxin (100 nM each) but not by alpha-bungarotoxin (100 nM). Type III currents (elicited in 2% of the neurons) decayed slowly and were blocked by (+/-)-mecamylamine (1 microM) but not by alpha-bungarotoxin, kappa-bungarotoxin or MLA (each at 100 nM). Some of the cells (10% of the neurons) had mixed responses (named type IB), which were only partially blocked by MLA (1 nM) or dihydro-beta-erythroidine (10 nM) alone and were completely blocked by combination of the two agents. The order of potency of agonists in activating the currents was the following: for type IA, (+)-anatoxin-a >> 1,1-dimethyl-4-phenyl-piperazinium > (-)-nicotine > cystisine > ACh > carbachol > (+)-nicotine > arecoline > suberyldicholine; for type II, ACh > (+)-anatoxin-a > (-)-nicotine > 1,1-dimethyl-4-phenyl-piperazinium > carbachol > cytisine > (+)-nicotine > suberyldicholine > arecoline. Certain agonists were particularly useful in discriminating among the various types of currents: ACh, carbachol, (-)-nicotine and suberyldicholine for type II, and cytisine for type III currents. The EC50 of ACh was approximately 130 microM for type IA and approximately 2 microM for type II currents. A marked inward rectification was observed with type II, whereas type IA currents showed very little inward rectification. Differences observed in the pharmacological and functional properties of the nicotinic currents imply the expression of at least three structurally distinct nicotinic acetylcholine receptor subtypes in hippocampal neurons. The possible involvement of these currents in the transduction of signals is discussed.


Incidence of Venous Thromboembolism in cancer patients treated with Cisplatin based chemotherapy - a cohort study.
Cancer related thrombosis not only increases morbidity and mortality but also poses a significant financial burden on health care system. Risk of venous thromboembolism (VTE) in these patients substantially increases with the addition of chemotherapy. Lately, cisplatin has been implicated as an independent factor. There is little data estimating the risk of venous thromboembolism in patients receiving cisplatin based chemotherapy when compared to other chemotherapeutic agents. Patients who had received chemotherapy between November 2010 and October 2012 were retrospectively identified from a single institute cancer registry. 200 patients who had received cisplatin based chemotherapy were identified as the exposed group while 200 patients who had received non-Cisplatin based regimens were identified as the non-exposed group. Patients were followed for development of VTE throughout the entire duration of therapy and one month thereafter. Cox proportional hazard model was used to compute relative risks with 95% confidence intervals. The baseline characteristics were similar in the two groups. Mean age for the entire cohort was 55.4 ± 10.7 years and male to female ratio was almost 1:1. On univariate analysis, cisplatin based chemotherapy, presence of central venous catheter, female gender, poor performance status, high risk stratification according to the Khorana model and use of granulocyte colony stimulating factor were all significantly associated with the development of VTE. The crude relative risk for the incidence of VTE in cisplatin group was 2.8 (95% CI, 1.4 - 4.2) times compared to the non-Cisplatin group. When the relative risk was adjusted for the above variables in multivariable analysis, it increased to 3.3 (95% CI, 1.6 - 6.8) compared to the control group. A high incidence of VTE in patients receiving cisplatin based chemotherapy was demonstrated in this study. Prospective studies are warranted to establish this observation with certainty and to explore the possible use of thromboprophylaxis in patients receiving cisplatin based chemotherapeutic regimens.


Comparing genomes to computer operating systems in terms of the topology and evolution of their regulatory control networks.
The genome has often been called the operating system (OS) for a living organism. A computer OS is described by a regulatory control network termed the call graph, which is analogous to the transcriptional regulatory network in a cell. To apply our firsthand knowledge of the architecture of software systems to understand cellular design principles, we present a comparison between the transcriptional regulatory network of a well-studied bacterium (Escherichia coli) and the call graph of a canonical OS (Linux) in terms of topology and evolution. We show that both networks have a fundamentally hierarchical layout, but there is a key difference: The transcriptional regulatory network possesses a few global regulators at the top and many targets at the bottom; conversely, the call graph has many regulators controlling a small set of generic functions. This top-heavy organization leads to highly overlapping functional modules in the call graph, in contrast to the relatively independent modules in the regulatory network. We further develop a way to measure evolutionary rates comparably between the two networks and explain this difference in terms of network evolution. The process of biological evolution via random mutation and subsequent selection tightly constrains the evolution of regulatory network hubs. The call graph, however, exhibits rapid evolution of its highly connected generic components, made possible by designers' continual fine-tuning. These findings stem from the design principles of the two systems: robustness for biological systems and cost effectiveness (reuse) for software systems.


A candidate gene association study further corroborates involvement of contactin genes in autism.
Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.


Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets.
Mitochondrial dysfunction is an important factor contributing to tissue damage in both severe traumatic brain injury and ischemic stroke. This experimental study explores the possibility to diagnose the condition bedside by utilising intracerebral microdialysis and analysis of chemical variables related to energy metabolism. Mitochondrial dysfunction was induced in piglets and evaluated by monitoring brain tissue oxygen tension (PbtO2 ) and cerebral levels of glucose, lactate, pyruvate, glutamate, and glycerol bilaterally. The biochemical variables were obtained by microdialysis and immediate enzymatic analysis. Mitochondrial function was blocked by unilateral infusion of NaCN/KCN (0.5 mol/L) through the microdialysis catheter (N = 5). As a reference, NaCl (0.5 mol/L) was infused by intracerebral microdialysis in one group of animals (N = 3). PbtO2 increased during cyanide infusion and returned to baseline afterwards. The lactate/pyruvate (LP) ratio increased significantly following cyanide infusion because of a marked increase in lactate level while pyruvate remained within normal limits. Glutamate and glycerol increased after cyanide infusion indicating insufficient energy metabolism and degradation of cellular membranes, respectively. Mitochondrial dysfunction is characterised by an increased LP ratio signifying a shift in cytoplasmatic redox state at normal or elevated PbtO2 . The condition is biochemically characterised by a marked increase in cerebral lactate with a normal or elevated pyruvate level. The metabolic pattern is different from cerebral ischemia, which is characterised by simultaneous decreases in intracerebral pyruvate and PbtO2 . The study supports the hypothesis that cerebral ischemia and mitochondrial dysfunction may be identified and separated at the bedside by utilising intracerebral microdialysis.


A comparative assessment of avoidable blindness and visual impairment in seven Latin American countries: prevalence, coverage, and inequality.
To conduct a comparative analysis of social inequalities in eye health and eye health care and generate baseline evidence for seven Latin American countries as a benchmarking exercise for monitoring progress toward three goals of the regional Plan of Action for the Prevention of Blindness and Visual Impairment: increasing eye health service coverage, minimizing barriers, and reducing eye health-related disease burden. Results from cross-sectional eye health surveys conducted in six Latin American countries (Argentina, El Salvador, Honduras, Panama, Peru, and Uruguay) from 2011 to 2013 and recently published national surveys in Paraguay were analyzed. The magnitude of absolute and relative inequalities between countries in five dimensions of eye health across the population gradient defined by three equity stratifiers (educational attainment, literacy, and wealth) were explored using standard exploratory data analysis techniques. Overall prevalence of blindness in people 50 years old and older varied from 0.7% (95% CI: 0.4-1.0) in Argentina to 3.0% (95% CI: 2.3-3.6) in Panama. Overall prevalence of visual impairment (severe plus moderate) varied from 8.0% (95% CI: 6.5-11.0) in Uruguay to 14.3% (95% CI: 13.9-14.7) in El Salvador. The main reported cause of blindness was unoperated cataract and most cases of visual impairment were caused by uncorrected refractive error. Three countries had cataract surgical coverage of more than 90% for blind persons, and two-thirds of cataract-operated patients had good visual acuity. Blindness and moderate visual impairment prevalence were concentrated among the most socially disadvantaged, and cataract surgical coverage and cataract surgery optimal outcome were concentrated among the wealthiest. There is a need for policy action to increase services coverage and quality to achieve universality.


The serum/PDGF-dependent "melanogenic" role of the minute level of the oncogenic kinase PAK1 in melanoma cells proven by the highly sensitive kinase assay.
We previously demonstrated that the oncogenic kinase PAK4, which both melanomas and normal melanocytes express at a very high level, is essential for their melanogenesis. In the present study, using the highly sensitive "Macaroni-Western" (IP-ATP-Glo) kinase assay, we investigated the melanogenic potential of another oncogenic kinase PAK1, which melanoma (B16F10) cells express only at a very minute level. After transfecting melanoma cells with PAK1-shRNA for silencing PAK1 gene, melanin content, tyrosinase activity, and kinase activity of PAK1 were compared between the wild-type and transfectants. We found that (i) PAK1 is significantly activated by melanogenic hormones such as IBMX (3-isobutyl-1-methyl xanthine) and α-MSH (melanocyte-stimulating hormone), (ii) silencing the endogenous PAK1 gene in melanoma cells through PAK1-specific shRNA reduces both melanin content and tyrosinase activity in the presence of both serum and melanogenic hormones to the basal level, (iii) the exogenously added wild-type PAK1 in the melanoma cells boosts the α-MSH-inducible melanin level by several folds without affecting the basal, and (iv) α-MSH/IBMX-induced melanogenesis hardly takes place in the absence of either serum or PAK1, clearly indicating that PAK1 is essential mainly for serum- and α-MSH/IBMX-dependent melanogenesis, but not the basal, in melanoma cells. The outcome of this study might provide the first scientific basis for explaining why a wide variety of herbal PAK1-blockers such as CAPE (caffeic acid phenethyl ester), curcumin and shikonin in cosmetics are useful for skin-whitening.


Systemic hyalinosis: a distinctive early childhood-onset disorder characterized by mutations in the anthrax toxin receptor 2 gene (ANTRX2).
We sought to further characterize the phenotype and facilitate clinical recognition of systemic hyalinosis in children who present with chronic pain and progressive contractures in early childhood. We report on 3 children who presented in infancy with symptoms and signs that initially were not recognized to be those of systemic hyalinosis. Although the children were evaluated for a variety of problems, including lysosomal storage disorders and nonaccidental trauma, all eventually underwent genetic analysis of the anthrax toxin receptor 2 gene (ANTRX2) and were diagnosed as having systemic hyalinosis. We describe the recognizable but variable clinical phenotype of systemic hyalinosis and associated mutations in ANTRX2. Affected individuals presented in early infancy with severe pain and progressive contractures. Initial diagnostic evaluations were unrevealing; however, hyperpigmented skin over bony prominences, skin nodules, and fleshy perianal masses suggested a diagnosis of systemic hyalinosis. ANTRX2 analysis confirmed the diagnosis in each case. Although 2 of the children died in infancy as a result of complications of chronic diarrhea, the third child has survived into midchildhood. These data suggest that some ANTRX2 mutations, such as that identified in the long-term survivor, may be associated with a less severe course of disease. Although some aspects of systemic hyalinosis may resemble lysosomal storage disorders, the clinical features of systemic hyalinosis are distinctive, and detection of an ANTRX2 mutation can confirm the diagnosis. Early recognition of affected individuals should allow for aggressive pain control and expectant management of the multiple associated problems, including gastrointestinal dysfunction.


Outcome of revision anterior cruciate ligament reconstruction: a systematic review.
Revision anterior cruciate ligament (ACL) reconstruction is believed to have an inferior outcome compared with primary ACL reconstruction. The available literature on the outcome of revision ACL reconstruction is sparse compared with that for primary reconstruction. The purpose of this systematic review was to test the hypothesis that the outcome of revision ACL reconstruction compares unfavorably with the historical outcome of primary ACL reconstruction. A systematic review of studies evaluating the outcome of revision ACL reconstructions with a minimum of two years of follow-up was performed. Pooled data were collected when appropriate and a mixed-effect-model meta-analysis was performed for important outcome measures that were reported in several studies (objective graft failure, Lysholm score, International Knee Documentation Committee [IKDC] subjective score, and IKDC objective score). Objective failure was defined as repeat revision, a side-to-side difference of >5 mm measured with use of a KT1000 arthrometer, or a pivot-shift grade of 2+ or 3+. Twenty-one studies were included, and 863 of the 1004 patients in these studies had a minimum of two years of follow-up and were analyzed. The pooled mean age of the patients at the time of the revision procedure was 30.6 years, and 66% were male. Objective failure occurred in 13.7% ± 2.7% of the patients (95% confidence interval, 8.0% to 19.4%). The mean Lysholm score in 491 patients was 82.1 ± 3.3 (95% confidence interval, 74.6 to 89.5) according to a mixed-model meta-analysis. The mean IKDC subjective score in 202 patients was 74.8 ± 4.4 (95% confidence interval, 62.5 to 87.0). Revision ACL reconstruction resulted in a worse outcome compared with primary ACL reconstruction. Patient-reported outcome scores were inferior to previously published results of primary ACL reconstruction, but these differences may not be clinically important. A dramatically elevated failure rate was noted after revision ACL reconstruction; this rate was nearly three to four times the failure rate in prospective series of primary ACL reconstructions.


Impact of herbivore identity on algal succession and coral growth on a Caribbean reef.
Herbivory is an important top-down force on coral reefs that regulates macroalgal abundance, mediates competitive interactions between macroalgae and corals, and provides resilience following disturbances such as hurricanes and coral bleaching. However, reductions in herbivore diversity and abundance via disease or over-fishing may harm corals directly and may indirectly increase coral susceptibility to other disturbances. In two experiments over two years, we enclosed equivalent densities and masses of either single-species or mixed-species of herbivorous fishes in replicate, 4 m(2) cages at a depth of 17 m on a reef in the Florida Keys, USA to evaluate the effects of herbivore identity and species richness on colonization and development of macroalgal communities and the cascading effects of algae on coral growth. In Year 1, we used the redband parrotfish (Sparisoma aurofrenatum) and the ocean surgeonfish (Acanthurus bahianus); in Year 2, we used the redband parrotfish and the princess parrotfish (Scarus taeniopterus). On new substrates, rapid grazing by ocean surgeonfish and princess parrotfish kept communities in an early successional stage dominated by short, filamentous algae and crustose coralline algae that did not suppress coral growth. In contrast, feeding by redband parrotfish allowed an accumulation of tall filaments and later successional macroalgae that suppressed coral growth. These patterns contrast with patterns from established communities not undergoing primary succession; on established substrates redband parrotfish significantly reduced upright macroalgal cover while ocean surgeonfish and princess parrotfish allowed significant increases in late successional macroalgae. This study further highlights the importance of biodiversity in affecting ecosystem function in that different species of herbivorous fishes had very different impacts on reef communities depending on the developmental stage of the community. The species-specific effects of herbivorous fishes suggest that a species-rich herbivore fauna can be critical in providing the resilience that reefs need for recovery from common disturbances such as coral bleaching and storm damage.