Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.
To assess the clinical effectiveness and cost-effectiveness of pemetrexed disodium in combination with cisplatin for the treatment of unresectable pleural mesothelioma in chemotherapy-naive patients. Electronic databases were searched up to May 2005. The systematic review was conducted following accepted guidelines. An assessment of the economic submission received from the manufacturer of pemetrexed was also carried out. This comprised two sections, each employing an economic model. One of these models was then reformulated in order to carry out a separate exploration of economic performance. One randomised controlled trial comparing pemetrexed and cisplatin with cisplatin alone, and involving a total study population of 448 patients, met the inclusion criteria. Pemetrexed in combination with cisplatin in this trial showed a 2.8-month gain in median survival compared with cisplatin alone in an intention-to-treat (ITT) population (12.1 and 9.3 months, respectively, p = 0.020, hazard ratio of 0.77). During the trial, increased reporting of severe toxicity in the pemetrexed arm led to a change in the protocol to add folic acid and vitamin B12 supplementation to therapy. For fully supplemented patients (n = 331) the hazard ratio for median survival in favour of pemetrexed plus cisplatin was also comparable (0.75), but of borderline significance between treatment arms (p = 0.051). The trial inclusion criteria restricted recruitment to those with a Karnofsky performance status of 70 or greater (equivalent to ECOG/WHO 0 or 1 scales more widely used in the UK). Quality of life scores using the Lung Cancer Symptom Scale demonstrated significantly greater improvement for pain and dyspnoea for patients in the combination group compared with those in the cisplatin group. In the ITT population, the incidence of serious toxicities with pemetrexed plus cisplatin was higher compared with cisplatin alone. However, the grade 3/4 toxicities of the combination arm, particularly leucopenia, neutropenia and diarrhoea, were found to be greatly improved by the addition of vitamin B12 and folic acid. The existing published economic literature was very limited. The economic evaluation conducted by the study (and that submitted by the manufacturer) suggested that pemetrexed is unlikely to be considered cost-effective at conventionally accepted thresholds in the UK for all patients, mainly because of the high cost of pemetrexed itself compared with cisplatin. These findings were better for some patient subgroups, e.g. especially for fully supplemented (FS) patients with good performance status (0/1) and advanced disease (AD). These findings seem robust. The estimated cost-effectiveness results were for the FS population, incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained = pound59,600; for the FS with AD population, ICER per QALY = pound47,600; for the FS with performance status 0/1 population, ICER per QALY = pound49,800; and for the FS with performance status 0/1 and AD population, ICER per QALY = pound36,700. The new therapy examined in this document demonstrates an extension of life expectancy and palliation, as measured by time to progression of disease and other end-points. However, the absolute benefit obtained is small, and it needs to be weighed against the benefits of effective palliative care services. The limited benefit was also at the expense of considerable toxicity to patients. The economic evaluation conducted in this study and that of the manufacturers suggest that pemetrexed is not cost-effective at conventional thresholds for all patients. Cost-effectiveness seems better for some patient subgroups, e.g. especially for patients with good performance status and with advanced diseases, where it is estimated the ICER per QALY would be pound36,700. Given the relatively small number of patients with mesothelioma, albeit increasing, the overall budget impact of pemetrexed would be unlikely to be more than pound5 million per year at present costs. Much more research is needed into the optimum chemotherapy for patients with mesothelioma and a clear definition of what constitutes best supportive care.


Socioeconomic Status, Sex, Age and Access to Medications for COPD in Ontario, Canada.
Disparities in COPD health outcomes have been found with older individuals, men and those of lower socioeconomic status doing worse. We sought to determine if this was due to differences in access to COPD medications. We conducted a retrospective cohort study using population health administrative data from Ontario, Canada, a province with universal prescription drug coverage for older adults. All individuals with COPD aged 67 years and older in 2008 who were not taking inhaled long-acting bronchodilators or inhaled corticosteroids were followed for 2 years. Poisson regression was used to determine the effects of age, sex, and socioeconomic status on the likelihood of initiating one of these medications, after adjusting for potential confounders. Over the study period, 54,050 of 185,698 (29.1%) older individuals with COPD not previously taking any inhaled long-acting bronchodilators or corticosteroids were initiated on one or more of these medications. After adjustment, individuals of low socioeconomic status, measured using neighborhood income level quintiles, were slightly more likely to initiate COPD medications than those of high socioeconomic status (relative risk (RR) 1.05; 95% confidence interval (95% CI) 1.02-1.08). While men received COPD medication at a consistent rate across all age groups, the likelihood that a woman received medication decreased with increasing age. With the exception of older women, there was minimal disparity in prescription for COPD medications. Disparity in health outcomes among Ontario COPD patients is not clearly explained by differences in medication access by socioeconomic status, sex or age.


The role of changes in contraceptive use in the decline of induced abortion in Turkey.
The induced abortion rate in Turkey declined from a peak of 4.5 abortions per 100 women in 1988 to 2.4 in 1998. This study examines the extent to which the decline in abortion in Turkey can be attributed to increased use of modern contraceptives. Trends in induced abortion rates and in contraceptive use are examined among Turkish women together with fertility preferences, changes in the contraceptive behavior associated with abortion, and changes in the propensity to abort unwanted pregnancies. The analysis includes a number of simulations that examine what abortion levels might be in different contraceptive-use scenarios. Results indicate that the decline in abortion is due to a decrease in the number of abortions associated with traditional method failure. This decrease is related to three factors: a shift from traditional method use to modern method use, a decline in the traditional method failure rate, and a decline in the proportion of pregnancies resulting from traditional method failures that are aborted.


Comparative study of fiber-optic guided tracheal intubation through intubating laryngeal mask airway LMA Fastrach™ and i-gel in adult paralyzed patients.
The i-gel is a novel and innovative supraglottic airway management device used both as an airway rescue device and as a conduit for fiberoptic intubation. In this prospective randomized study, we compared fiberoptic-guided tracheal intubation through the i-gel and LMA Fastrach™ in adult paralyzed patients. After ethical committee approval and written informed consent, 60 patients of either sex were randomly allocated to either group of supraglottic airway device (SGAD). After successful insertion of the SGAD, the fiberoptic bronchoscope (FOB)-guided tracheal intubation was done through the respective SGAD. The primary objectives were the ease and time taken for fiberoptic-guided intubation in either group. Secondary variables included time taken for successful placement of SGAD, ease of insertion of SGAD, airway seal pressure, ease and time of removal of SGAD, variation in hemodynamic parameters, and complications if any. Time taken for tracheal intubation in LMA Fastrach™ group was 69.53 ± 5.09 s and for the i-gel group it was 72.33 ± 6.73 s. It was seen that it was easy to insert the endotracheal tube (ETT) in 93.3% patients in the LMA Fastrach™ group and 96.7% patients in the i-gel group. Airway seal pressure was higher for the LMA Fastrach™ group. Both the SGADs were comparable in the number of attempts of insertion, ease of insertion, and insertion time. In addition, the hemodynamic variables noted did not show any increase after insertion of SGAD. There was no difficulty encountered in removal of either SGAD. I-gel may be a reliable and cost-effective alternative to LMA Fastrach™ for fibreoptic-guided tracheal intubation.


Baseline in vitro activities of the antimalarials pyronaridine and methylene blue against Plasmodium falciparum isolates from Kenya.
We have analyzed the in vitro activities of pyronaridine and methylene blue against 59 Plasmodium falciparum isolates from Kenya in association with polymorphisms in Pfcrt (codon 76), Pfmdr1 (codon 86), and Pfnhe (full sequence). The median inhibitory concentrations that kill 50% of parasites were 13.5 and 3.3 nM for pyronaridine and methylene blue, respectively. Their activities were not associated with polymorphisms in these genes. The drugs' high in vitro activities indicate that they would be efficacious against Kenyan isolates in vivo.


Decreased Metabolic Rate in the Mole Crabs, Emerita analoga, Infected with the Acanthocephalan Profilicollis altmani.
The relationship between a parasite and its host will have an energy cost for the host at some point; however, this basic hypothesis has seldom been evaluated. Using Emerita analoga as a model species, we investigated the aerobic metabolism, ammonia excretion rate, and locomotor performance patterns of crabs both uninfected and infected with the acanthocephalan Profilicollis altmani. Our results show that infected Emerita had a lower metabolic rate compared to uninfected ones. Whether or not this decrease is a result of the pathology of the parasite infection or due to manipulation of the host by the parasite is still unknown. We discuss the importance of using anaerobic and aerobic metabolism and more-complex scenarios in order to understand the effects on host fitness and not only on the immediate response of the host.


[Validity assessment of a food frequency questionnaire by comparison with a 4-day diet record].
When dietary methods are used to evaluate nutritional intake, it is important to know which methods are most appropriate to ensure validity in nutrient intake studies. Our main objective was to assess the validity of a semi-quantitative food-frequency questionnaire (FFQ) developed for Portuguese adults by comparing nutrient intake (energy and 44 nutrients) assessed by FFQ with the nutritional data from a four-day diet record (DR). The FFQ was developed by the Epidemiology Department, Faculty of Medicine, University of Porto, and allowed the subjects to indicate their daily, weekly or monthly intake of 89 foods. Subjects were 246 university students (159 females and 87 males, aged 18 to 29 years). Mean intakes from the FFQ were generally higher than those from the DR. Pearson correlation coefficients between FFQ and DR ranged from 0.21 for vitamin D, to 0.73, for iodine. When energy-adjusted, this coefficients ranged from 0.20, for selenium, to 0.75 for iodine. Misclassification in opposite extreme quintiles varied from 0% to 16%, and the proportion of subjects correctly classified within the lowest two quintiles ranged between 52% and 84%. The distribution of those correctly classified within the highest two quintiles ranged between 51% and 88%. Exact classification in the same quintile of ingestion varied from 26% and 41%. These data suggest that this FFQ provides valid estimates of intakes for major nutrients, comparable to those reported from other studies in the literature.


Effects of Plant-Based Diets on Outcomes Related to Glucose Metabolism: A Systematic Review.
According to the rising prevalence of obesity and metabolic disorders leading to impaired glucose metabolism, effective strategies to prevent and/or delay the onset of disease are of great need. A plant-based diet has been suggested as an effective lifestyle change that may reduce the degree of obesity and improve outcomes related to glucose metabolism. This systematic review aimed to evaluate the effect of a plant-based diet on outcomes related to glucose metabolism. A literature search was conducted in the database PubMed until January 30, 2020. Randomized controlled trials investigating the effect of a plant-based dietary intervention on outcomes related to glucose metabolism in human subjects compared to an omnivorous diet were eligible for inclusion. Of 65 publications identified, nine trials on subjects with overweight/obesity, type 2 diabetes mellitus, or cardiovascular disease were included. Five studies reported that the plant-based intervention significantly improved markers of glycemic control from baseline to end point, of which four revealed a significant improvement in the intervention group compared to the control intervention. The remaining four studies did not observe a significant effect of a plant-based intervention on outcomes related to glucose metabolism. Our findings suggest that a shift to a plant-based diet may lead to favorable effects on glycemic control in individuals diagnosed with type 2 diabetes mellitus and/or obesity. The data were however somewhat conflicting, and the included trials reported results based on different intervention diets and study populations. Overall, no clear conclusions regarding effects of different plant-based diets can be drawn based on the current findings alone.


Relationships Between Potentiation Effects After Ballistic Half-Squats and Bilateral Symmetry.
The purposes of this study were to examine the effect of ballistic concentric-only half-squats (COHS) on subsequent squat-jump (SJ) performances at various rest intervals and to examine the relationships between changes in SJ performance and bilateral symmetry at peak performance. Thirteen resistance-trained men performed an SJ immediately and every minute up to 10 min on dual force plates after 2 ballistic COHS repetitions at 90% of their 1-repetition-maximum COHS. SJ peak force, peak power, net impulse, and rate of force development (RFD) were compared using a series of 1-way repeated-measures ANOVAs. The percent change in performance at which peak performance occurred for each variable was correlated with the symmetry index scores at the corresponding time point using Pearson correlation coefficients. Statistical differences in peak power (P = .031) existed between rest intervals; however, no statistically significant pairwise comparisons were present (P > .05). No statistical differences in peak force (P = .201), net impulse (P = .064), and RFD (P = .477) were present between rest intervals. The relationships between changes in SJ performance and bilateral symmetry after the rest interval that produced the greatest performance for peak force (r = .300, P = .319), peak power (r = -.041, P = .894), net impulse (r = -.028, P = .927), and RFD (r = -.434, P = .138) were not statistically significant. Ballistic COHS may enhance SJ performance; however, the changes in performance were not related to bilateral symmetry.


Nature, Incidence, and Symptomatology of Viruses Infecting Vanilla tahitensis in French Polynesia.
A survey was carried out to identify the viruses infecting vanilla in French Polynesia and to assess their incidence. Virus identification was based on enzyme-linked immunosorbent assay (ELISA) and, for potyviruses, on the sequence of part of the coat protein and inoculation assays. Between 1998 and 1999, 3,610 vanilla plants from 49 plots in the Society Islands were indexed. Cymbidium mosaic virus (CymMV) was detected in 500 vines from 10 plots in the Leeward Islands. The data suggest that this virus has spread widely since its first detection in French Polynesia in 1986, most likely through the dissemination of symptomless infected cuttings. Viruses belonging to the Potyvirus genus were found in 674 plants from 27 plots in the four islands surveyed. Three distinct potyviruses have been identified: (i) Vanilla mosaic virus, (ii) Watermelon mosaic virus, and (iii) and a virus related to Bean common mosaic virus. The symptoms induced on Vanilla tahitensis by the three potyviruses can be differentiated from each other and from those due to CymMV. A significant proportion of the plants surveyed (97/476) were symptomatic but tested negative by ELISA for CymMV and the Potyvirus group. Odontoglossum ringspot virus was not detected in any sample tested.


Targeting accurate object extraction from an image: a comprehensive study of natural image matting.
With the development of digital multimedia technologies, image matting has gained increasing interests from both academic and industrial communities. The purpose of image matting is to precisely extract the foreground objects with arbitrary shapes from an image or a video frame for further editing. It is generally known that image matting is inherently an ill-posed problem because we need to output three images out of only one input image. In this paper, we provide a comprehensive survey of the existing image matting algorithms and evaluate their performance. In addition to the blue screen matting, we systematically divide all existing natural image matting methods into four categories: 1) color sampling-based; 2) propagation-based; 3) combination of sampling-based and propagation-based; and 4) learning-based approaches. Sampling-based methods assume that the foreground and background colors of an unknown pixel can be explicitly estimated by examining nearby pixels. Propagation-based methods are instead based on the assumption that foreground and background colors are locally smooth. Learning-based methods treat the matting process as a supervised or semisupervised learning problem. Via the learning process, users can construct a linear or nonlinear model between the alpha mattes and the image colors using a training set to estimate the alpha matte of an unknown pixel without any assumption about the characteristics of the testing image. With three benchmark data sets, the various matting algorithms are evaluated and compared using several metrics to demonstrate the strengths and weaknesses of each method both quantitatively and qualitatively. Finally, we conclude this paper by outlining the research trends and suggesting a number of promising directions for future development.


The incidence and patterns of illness at the Sochi 2014 Winter Paralympic Games: a prospective cohort study of 6564 athlete days.
To describe the epidemiology of illness at the Sochi 2014 Winter Paralympic Games. A total of 547 athletes from 45 countries were monitored daily for 12 days over the Sochi 2014 Winter Paralympic Games (6564 athlete days). Illness data were obtained daily from teams without their own medical support (13 teams, 37 athletes) and teams with their own medical support (32 teams, 510 athletes) through electronic data capturing systems. The total number of illnesses reported was 123, with an illness incidence rate (IR) of 18.7 per 1000 athlete days (95% CI 15.1% to 23.2%). The highest IR was reported for wheelchair curling (IR of 20.0 (95% CI 10.1% to 39.6%)). Illnesses in the respiratory system (IR of 5.6 (95% CI 3.8% to 8.0%)), eye and adnexa (IR of 2.7 (95% CI 1.7% to 4.4%)) and digestive system (IR of 2.4 (95% CI 1.4% to 4.2%)) were the most common. Older athletes (35-63 years) had a significantly higher IR than younger athletes (14-25 years, p=0.049). The results of this study indicate that Paralympic athletes report higher illness incidence rates compared to Olympic athletes at similar competitions. The highest rates of illness were reported for the respiratory and digestive systems, eye and adnexa, respectively. Thus, the results of this study form a basis for the identification of physiological systems at higher risk of illness, which can in turn inform illness prevention and management programmes with eventual policy change to promote athlete safety in future editions of the Winter Paralympic Games.


An Enhanced Energy Balanced Data Transmission Protocol for Underwater Acoustic Sensor Networks.
This paper presents two new energy balanced routing protocols for Underwater Acoustic Sensor Networks (UASNs); Efficient and Balanced Energy consumption Technique (EBET) and Enhanced EBET (EEBET). The first proposed protocol avoids direct transmission over long distance to save sufficient amount of energy consumed in the routing process. The second protocol overcomes the deficiencies in both Balanced Transmission Mechanism (BTM) and EBET techniques. EBET selects relay node on the basis of optimal distance threshold which leads to network lifetime prolongation. The initial energy of each sensor node is divided into energy levels for balanced energy consumption. Selection of high energy level node within transmission range avoids long distance direct data transmission. The EEBET incorporates depth threshold to minimize the number of hops between source node and sink while eradicating backward data transmissions. The EBET technique balances energy consumption within successive ring sectors, while, EEBET balances energy consumption of the entire network. In EEBET, optimum number of energy levels are also calculated to further enhance the network lifetime. Effectiveness of the proposed schemes is validated through simulations where these are compared with two existing routing protocols in terms of network lifetime, transmission loss, and throughput. The simulations are conducted under different network radii and varied number of nodes.


Multivariate analyses of inflammatory cytokines in eyes with branch retinal vein occlusion: relationships to bevacizumab treatment.
To characterize the differential expression of intraocular inflammatory cytokines in eyes with branch retinal vein occlusion (BRVO) and to assess their roles as prognostic determinants of BRVO. A prospective cohort study of 38 eyes with BRVO. Aqueous humor samples were collected just before the intravitreal injection of bevacizumab and were assessed for 18 cytokines, chemokines, and growth factors. For control, aqueous humor was collected from 28 eyes before cataract surgery. In the aqueous of eyes with BRVO, the IL-23, IL-8, IL-6, IL-15, IL-12, and IL-17 levels were significantly higher than that in control eyes. Pretreatment visual acuity was significantly correlated with the concentrations of IL-8, IL-10, IL-2, IL-1β, IL-5, IL-6, IL-23, IL-4, MCP-1, IL-1α, IL-12, IL-13, IFN-γ, and IL-15. The pretreatment nonperfused area (NPA) was significantly correlated with the concentrations of IL-8, IL-2, MCP-1, and IL-6. Logistic regression analyses revealed significant associations between the BRVO and the concentrations of IL-8, IL-23, IL-12, IL-15, IL-10, IL-1β, and IL-13. IL-8 had the highest odds ratio (OR) and was significantly associated with NPA, central retinal thickness (CRT), and visual acuity. Bevacizumab treatment significantly improved visual acuity and CRT after 1 month. Refractoriness to bevacizumab (defined as CRT recovery 1 month after treatment by <90%) was significantly associated with the IL-12 level. Of the induced cytokines in eyes with BRVO, IL-8 was the most significantly associated with the disease parameters of BRVO. IL-12 is most likely a factor that blocks the effect of bevacizumab treatment. (www.umin.ac.jp/ctr number, UMIN000003854.).


[Children and motor competence].
Recently, the topic of motor competence has figured prominently in the media. The claims made are many, but the research that support the statements is seldom cited. The aim of this review article is to address that deficiency by documenting what is really known about the motor competence of children. Motor competence not only allows children to carry out everyday practical tasks, but it is also an important determinant of their level of self-esteem and of their popularity and status in their peer group. While many studies have shown a significant correlation between motor problems and other problems in the social sphere, it has been difficult to establish causal relationships with any degree of confidence, as there appear to be several interactions which need to be taken into account. Research has shown that 6-10% of Norwegian children in the 7 to 10 year age group have a motor competence well below the norm. It is unusual for motor problems to simply disappear over time. In the absence of intervention the syndrome is likely to continue to manifest itself. More recent research points to some of the circularity in this causal network, children with motor problems having been shown to be less physically active than their peers. In a larger health perspective this in itself can have very serious consequences for the child.


Minimally invasive surgical techniques versus open myomectomy for uterine fibroids.
Fibroids are common benign tumours arising in the uterus. Myomectomy is the surgical treatment of choice for women with symptomatic fibroids who prefer or want uterine conservation. Myomectomy can be performed by conventional laparotomy, by mini-laparotomy or by minimal access techniques such as hysteroscopy and laparoscopy. To determine the benefits and harms of laparoscopic or hysteroscopic myomectomy compared with open myomectomy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (inception to July 2014), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of Controlled Trials (inception to July 2014), MEDLINE(R) (inception to July 2014), EMBASE (inception to July 2014), PsycINFO (inception to July 2014) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (inception to July 2014) to identify relevant randomised controlled trials (RCTs). We also searched trial registers and references from selected relevant trials and review articles. We applied no language restriction in these searches. All published and unpublished randomised controlled trials comparing myomectomy via laparotomy, mini-laparotomy or laparoscopically assisted mini-laparotomy versus laparoscopy or hysteroscopy in premenopausal women with uterine fibroids diagnosed by clinical and ultrasound examination were included in the meta-analysis. We conducted study selection and extracted data in duplicate. Primary outcomes were postoperative pain, reported in six studies, and in-hospital adverse events, reported in eight studies. Secondary outcomes included length of hospital stay, reported in four studies, operating time, reported in eight studies and recurrence of fibroids, reported in three studies. Each of the other secondary outcomes-improvement in menstrual symptoms, change in quality of life, repeat myomectomy and hysterectomy at a later date-was reported in a single study. Odds ratios (ORs), mean differences (MDs) and 95% confidence intervals (CIs) were calculated and data combined using the fixed-effect model. The quality of evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. We found 23 potentially relevant trials, of which nine were eligible for inclusion in this review. The nine trials included in our meta-analysis had a total of 808 women. The overall risk of bias of included studies was low, as most studies properly reported their methods.Postoperative pain: Postoperative pain was measured on a visual analogue scale (VAS), with zero meaning 'no pain at all' and 10 signifying 'pain as bad as it could be.' Postoperative pain was significantly less, as determined by subjectively assessed pain score at six hours (MD -2.40, 95% CI -2.88 to -1.92, one study, 148 women, moderate-quality evidence) and 48 hours postoperatively (MD -1.90, 95% CI -2.80 to -1.00, two studies, 80 women, I² = 0%, moderate-quality evidence) in the laparoscopic myomectomy group compared with the open myomectomy group. This means that among women undergoing laparoscopic myomectomy, mean pain score at six hours and 48 hours would be likely to range from about three points lower to one point lower on a VAS zero-to-10 scale. No significant difference in postoperative pain score was noted between the laparoscopic and open myomectomy groups at 24 hours (MD -0.29, 95% CI -0.7 to 0.12, four studies, 232 women, I² = 43%, moderate-quality evidence). The overall quality of these findings is moderate; therefore further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.In-hospital adverse events: No evidence suggested a difference in unscheduled return to theatre (OR 3.04, 95% CI 0.12 to 75.86, two studies, 188 women, I² = 0%, low-quality evidence) and laparoconversion (OR 1.11, 95% CI 0.44 to 2.83, eight studies, 756 women, I² = 53%, moderate-quality evidence) when open myomectomy was compared with laparoscopic myomectomy. Only one study including 148 women reported injury to pelvic organs (no events were described in other studies), and no significant difference was noted between laparoscopic myomectomy and laparoscopically assisted mini-laparotomy myomectomy (OR 3.04, 95% CI 0.12 to 75.86). Significantly lower risk of postoperative fever was observed in the laparoscopic myomectomy group compared with groups treated with all types of open myomectomy (OR 0.44, 95% CI 0.26 to 0.77, I² = 0%, six studies, 635 women). This indicates that among women undergoing laparoscopic myomectomy, the risk of postoperative fever is 50% lower than among those treated with open surgery. No studies reported immediate hysterectomy, uterine rupture, thromboembolism or mortality. Six studies including 549 women reported haemoglobin drop, but these studies were not pooled because of extreme heterogeneity (I² = 97%) and therefore could not be included in the analysis. Laparoscopic myomectomy is a procedure associated with less subjectively reported postoperative pain, lower postoperative fever and shorter hospital stay compared with all types of open myomectomy. No evidence suggested a difference in recurrence risk between laparoscopic and open myomectomy. More studies are needed to assess rates of uterine rupture, occurrence of thromboembolism, need for repeat myomectomy and hysterectomy at a later stage.


Determinants of affinity and activity of the anti-sigma factor AsiA.
The AsiA protein is a T4 bacteriophage early gene product that regulates transcription of host and viral genes. Monomeric AsiA binds tightly to the sigma(70) subunit of Escherichia coli RNA polymerase, thereby inhibiting transcription from bacterial promoters and phage early promoters and coactivating transcription from phage middle promoters. Results of structural studies have identified amino acids at the protomer-protomer interface in dimeric AsiA and at the monomeric AsiA-sigma(70) interface and demonstrated substantial overlap in the sets of residues that comprise each. Here we evaluate the contributions of individual interfacial amino acid side chains to protomer-protomer affinity in AsiA homodimers, to monomeric AsiA affinity for sigma(70), and to AsiA function in transcription. Sedimentation equilibrium, dynamic light scattering, electrophoretic mobility shift, and transcription activity measurements were used to assess affinity and function of site-specific AsiA mutants. Alanine substitutions for solvent-inaccessible residues positioned centrally in the protomer-protomer interface of the AsiA homodimer, V14, I17, and I40, resulted in the largest changes in free energy of dimer association, whereas alanine substitutions at other interfacial positions had little effect. These residues also contribute significantly to AsiA-dependent regulation of RNA polymerase activity, as do additional residues positioned at the periphery of the interface (K20 and F21). Notably, the relative contributions of a given amino acid side chain to RNA polymerase inhibition and activation (MotA-independent) by AsiA are very similar in most cases. The mainstay for intermolecular affinity and AsiA function appears to be I17. Our results define the core interfacial residues of AsiA, establish roles for many of the interfacial amino acids, are in agreement with the tenets underlying protein-protein interactions and interfaces, and will be beneficial for a general, comprehensive understanding of the mechanistic underpinnings of bacterial RNA polymerase regulation.


Therapeutic Immune Recovery and Reduction of CXCR4-Tropic HIV-1.
In the absence of therapy, CXCR4 (X4)-tropic human immunodeficiency virus type 1 (HIV-1) increases over time, associated with accelerated disease progression. In contrast, the majority of patients receiving long-term combination antiretroviral therapy (cART) present with CCR5 (R5)-tropic HIV-1 variants. It is unclear whether cART itself mediates the reduction of X4-tropic HIV-1. The current study aimed at assessing the tropism of viral integrates in patients' blood during fully suppressive cART. The relative frequencies of X4-tropic proviral HIV-1 variants were determined by means of next-generation sequencing (False Positive Rate (FPR), 3.5%; R5- or X4 tropic variants occurring at less than 2% of the total virus population) for 35 treated patients in the Swiss HIV Cohort Study and followed longitudinally over time. Full viral suppression and a continuous CD4 T-cell recovery during cART were documented for all patients. Viral phylogenetic changes and sequence evolution were analyzed. The majority of patients (80%) experienced no frequency increase in X4-tropic proviruses during therapy. Although some proviral sequence evolution was demonstrable in >50% of these patients during therapy, this growing viral diversity was in no case paralleled by the emergence or expansion of X4-tropic provirus variants. In the remaining 20% of patients, the documented expansion of X4-tropic provirus was based on the outgrowth of single viral variants from minority populations already present before therapy initiation. Our study demonstrates that X4-tropic HIV sharply declines in most patients during successful therapy, which indicates a preferential tropism-dependent provirus elimination in the immunocompetent host. The recently implemented World Health Organization strategies of immediate therapy initiation are fully in line with this gradual loss of X4 tropism during therapy. Moreover, the early use of coreceptor antagonists against the remaining CCR5-tropic viruses may be indicated.


Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency.
Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD. We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerability because (1) periadolescent HFD (pHFD) selectively downregulates prefrontal RELN+ cells and (2) augmenting mPFC RELN levels using transgenesis or prefrontal pharmacology prevents the pHFD-induced prefrontal cognitive deficits. We further identify N-methyl-d-aspartate-dependent long-term depression (NMDA-LTD) at prefrontal excitatory synapses as a synaptic signature of this association because pHFD abolishes NMDA-LTD, a function that is restored by RELN overexpression. We believe this study provides the first mechanistic insight into the vulnerability of the adolescent mPFC towards nutritional stress, such as HFDs. Our findings have primary relevance to obese individuals who are at an increased risk of developing neurological cognitive comorbidities, and may extend to multiple neuropsychiatric and neurological disorders in which RELN deficiency is a common feature.


Left atrial 4D flow cardiovascular magnetic resonance: a reproducibility study in sinus rhythm and atrial fibrillation.
Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows sophisticated quantification of left atrial (LA) blood flow, and could yield novel biomarkers of propensity for intra-cardiac thrombus formation and embolic stroke. As reproducibility is critically important to diagnostic performance, we systematically investigated technical and temporal variation of LA 4D flow in atrial fibrillation (AF) and sinus rhythm (SR). Eighty-six subjects (SR, n = 64; AF, n = 22) with wide-ranging stroke risk (CHA2DS2VASc 0-6) underwent LA 4D flow assessment of peak and mean velocity, vorticity, vortex volume, and stasis. Eighty-five (99%) underwent a second acquisition within the same session, and 74 (86%) also returned at 30 (27-35) days for an interval scan. We assessed variability attributable to manual contouring (intra- and inter-observer), and subject repositioning and reacquisition of data, both within the same session (same-day scan-rescan), and over time (interval scan). Within-subject coefficients of variation (CV) and bootstrapped 95% CIs were calculated and compared. Same-day scan-rescan CVs were 6% for peak velocity, 5% for mean velocity, 7% for vorticity, 9% for vortex volume, and 10% for stasis, and were similar between SR and AF subjects (all p > 0.05). Interval-scan variability was similar to same-day scan-rescan variability for peak velocity, vorticity, and vortex volume (all p > 0.05), and higher for stasis and mean velocity (interval scan CVs of 14% and 8%, respectively, both p < 0.05). Longitudinal changes in heart rate and blood pressure at the interval scan in the same subjects were associated with significantly higher variability for LA stasis (p = 0.024), but not for the remaining flow parameters (all p > 0.05). SR subjects showed significantly greater interval-scan variability than AF patients for mean velocity, vortex volume, and stasis (all p < 0.05), but not peak velocity or vorticity (both p > 0.05). LA peak velocity and vorticity are the most reproducible and temporally stable novel LA 4D flow biomarkers, and are robust to changes in heart rate, blood pressure, and differences in heart rhythm.


Challenges for achieving safe and effective radical cure of Plasmodium vivax: a round table discussion of the APMEN Vivax Working Group.
The delivery of safe and effective radical cure for Plasmodium vivax is one of the greatest challenges for achieving malaria elimination from the Asia-Pacific by 2030. During the annual meeting of the Asia Pacific Malaria Elimination Network Vivax Working Group in October 2016, a round table discussion was held to discuss the programmatic issues hindering the widespread use of primaquine (PQ) radical cure. Participants included 73 representatives from 16 partner countries and 33 institutional partners and other research institutes. In this meeting report, the key discussion points are presented and grouped into five themes: (i) current barriers for glucose-6-phosphate deficiency (G6PD) testing prior to PQ radical cure, (ii) necessary properties of G6PD tests for wide scale deployment, (iii) the promotion of G6PD testing, (iv) improving adherence to PQ regimens and (v) the challenges for future tafenoquine (TQ) roll out. Robust point of care (PoC) G6PD tests are needed, which are suitable and cost-effective for clinical settings with limited infrastructure. An affordable and competitive test price is needed, accompanied by sustainable funding for the product with appropriate training of healthcare staff, and robust quality control and assurance processes. In the absence of quantitative PoC G6PD tests, G6PD status can be gauged with qualitative diagnostics, however none of the available tests is currently sensitive enough to guide TQ treatment. TQ introduction will require overcoming additional challenges including the management of severely and intermediately G6PD deficient individuals. Robust strategies are needed to ensure that effective treatment practices can be deployed widely, and these should ensure that the caveats are outweighed by the benefits of radical cure for both the patients and the community. Widespread access to quality controlled G6PD testing will be critical.


Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes.
Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA. ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated. Mean (standard deviation) serum apoM concentration (μmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68). We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics.


Experimental viral evolution to specific host MHC genotypes reveals fitness and virulence trade-offs in alternative MHC types.
The unprecedented genetic diversity found at vertebrate MHC (major histocompatibility complex) loci influences susceptibility to most infectious and autoimmune diseases. The evolutionary explanation for how these polymorphisms are maintained has been controversial. One leading explanation, antagonistic coevolution (also known as the Red Queen), postulates a never-ending molecular arms race where pathogens evolve to evade immune recognition by common MHC alleles, which in turn provides a selective advantage to hosts carrying rare MHC alleles. This cyclical process leads to negative frequency-dependent selection and promotes MHC diversity if two conditions are met: (i) pathogen adaptation must produce trade-offs that result in pathogen fitness being higher in familiar (i.e., host MHC genotype adapted to) vs. unfamiliar host MHC genotypes; and (ii) this adaptation must produce correlated patterns of virulence (i.e., disease severity). Here we test these fundamental assumptions using an experimental evolutionary approach (serial passage). We demonstrate rapid adaptation and virulence evolution of a mouse-specific retrovirus to its mammalian host across multiple MHC genotypes. Critically, this adaptive response results in trade-offs (i.e., antagonistic pleiotropy) between host MHC genotypes; both viral fitness and virulence is substantially higher in familiar versus unfamiliar MHC genotypes. These data are unique in experimentally confirming the requisite conditions of the antagonistic coevolution model of MHC evolution and providing quantification of fitness effects for pathogen and host. These data help explain the unprecedented diversity of MHC genes, including how disease-causing alleles are maintained.


Influence of biochars on plant uptake and dissipation of two pesticides in an agricultural soil.
This study investigated the influence of two types of biochars on the bioavailability of two soil-applied insecticides (chlorpyrifos and fipronil) to Chinese chives ( Allium tuberosum ) and dissipation of the pesticides in the biochar-amended soils. The biochars (BC450 and BC850) prepared from the burning of cotton ( Gossypium spp.) straw chips at two different temperatures (450 and 850 degrees C) were thoroughly mixed into a soil to achieve 0, 0.1, 0.5, and 1% by soil dry weight. Chinese chives were grown for 5 weeks in the biochar-amended soils spiked with 50 mg kg(-1) of each pesticide. The loss of both pesticides in soils decreased significantly with increasing amounts of the biochars in the soil. After 35 days of incubation, 58-68% of the pesticides was lost from the control soil, whereas in the soil amended with 1.0% BC850 only 34% of chlorpyrifos and 32% of fipronil were dissipated. More losses of the pesticides were found in the soils with plants due to plant uptake and enhanced microbial degradation. Despite greater persistence of the two pesticide residues in the biochar-amended soils, plant uptake of the two pesticides from the amended soils decreased markedly with increasing biochar content in the soil. With the amendment of 1% of BC850 in the soil, the total chlorpyrifos and fipronil residues in plant biomass decreased to 19 and 48% of those in the control treatment, respectively. Thus, biochar BC850 was found to be effective in reducing the bioavailability of both pesticides from the soil. Biochar could be applied to sequester pesticide residues in contaminated soils and to reduce plant uptake.


Determination of hydroxylated polycyclic aromatic hydrocarbons by HPLC-photoionization tandem mass spectrometry in wood smoke particles and soil samples.
A simple and fast method for analysis of hydroxylated polycyclic aromatic hydrocarbons using pressurized liquid extraction and high performance liquid chromatography utilizing photoionization tandem mass spectrometry was developed. Simultaneous separation and determination of nine hydroxylated polycyclic aromatic hydrocarbons and two hydroxy biphenyls could be performed in negative mode with a run time of 12 min, including equilibration in 5 min. The calibration curves were in two concentration ranges; 1-50 ng/mL and 0.01-50 μg/mL, with coefficients of correlation R (2) > 0.997. The limits of detection and method quantification limits were in the range of 9-56 pg and 5-38 ng/g, respectively. A two-level full factorial experimental design was used for screening of conditions with the highest impact on the extraction. The extraction procedure was automated and suitable for a large number of samples. The extraction recoveries ranged from 70 to 102 % and the matrix effects were between 92 and 104 %. The overall method was demonstrated on wood smoke particles and soil samples with good analytical performance, and five OH-PAHs were determined in the concentration range of 0.19-210 μg/g. As far as we know, hydroxylated polycyclic aromatic hydrocarbons were determined in wood smoke and soil samples using photoionization mass spectrometry for the first time in this present study. Accordingly, this study shows that high performance liquid chromatography photoionization tandem mass spectrometry can be a good option for the determination of hydroxylated polycyclic aromatic hydrocarbons in complex environmental samples. Graphical Abstract The method developed in this study was used to determine hydroxylated polycyclic aromatic hydrocarbons in wood smoke and soil.


Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24.
Off-target binding of hydrophobic drugs can lead to unwanted side effects, either through specific or non-specific binding to unintended membrane protein targets. However, distinguishing the binding of drugs to membrane proteins from that of detergents, lipids and cofactors is challenging. Here, we use high-resolution mass spectrometry to study the effects of HIV protease inhibitors on the human zinc metalloprotease ZMPSTE24. This intramembrane protease plays a major role in converting prelamin A to mature lamin A. We monitored the proteolysis of farnesylated prelamin A peptide by ZMPSTE24 and unexpectedly found retention of the C-terminal peptide product with the enzyme. We also resolved binding of zinc, lipids and HIV protease inhibitors and showed that drug binding blocked prelamin A peptide cleavage and conferred stability to ZMPSTE24. Our results not only have relevance for the progeria-like side effects of certain HIV protease inhibitor drugs, but also highlight new approaches for documenting off-target drug binding.


The effects of Goldblatt hypertension on development of the glomerular lesions of diabetes mellitus in the rat.
Rats with classic Goldblatt (two-kidney) hypertension had diabetes induced by streptozotocin. After four months of diabetes, glomeruli of the unclipped kidney of hypertensive diabetic rats had markedly increased diabetic changes, including mesangial matrix thickening and mesangial immunoglobulin (IgG and IgM) and complement (C3) localization, when compared with glomeruli of the contralateral-clipped kidneys. Further, glomeruli of the unclipped kidneys of hypertensive diabetic animals had more mesangial thickening and IgG and IgM staining than glomeruli of normotensive diabetic rats. Although glomeruli of clipped kidneys in hypertensive diabetic rats had less mesangial thickening than glomeruli of normotensive diabetic rats, this did not reach statistical significance. However, these glomeruli did have significantly less IgG, IgM, and C3 staining compared with glomeruli of normotensive diabetic animals. Mesangial thickness in glomeruli of clipped and unclipped nondiabetic hypertensive rats did not differ from that in normal animals. However, there was less mesangial IgG staining in clipped than in unclipped kidneys of nondiabetic hypertensive rats or in kidneys of normal animals. We have interpreted these results to imply that alterations in nephron hemodynamics combine with the diabetic state to influence the rate of development of diabetic glomerulopathy in rats.


Gentamicin-induced nephrotoxicity in rats ameliorated and healing effects of resveratrol.
In this study, we aimed to investigate the possible protective effect of resveratrol on gentamicin induced nephrotoxicity. Experiments were carried out in male Wistar rats weighing 200-250 g. Gentamicin sulfate (80 mg/kg per day i.p.), resveratrol (10 mg/kg per day i.p.) and gentamicin together with resveratrol were administered for 6 d. The animals were sacrificed 24 h after the last injection. Urine, blood samples and tissue samples were collected from the animals on the seventh day of the treatment before they were sacrificed. Kidneys were collected for histopathological studies and fixed in 10% buffered formalin solution. Tissue samples were stored at -70 degrees C in liquid nitrogen for the determination of glutathione (GSH), glutathione-S-transferase (GST), malondialdehyde (MDA) and catalase (CAT). Glutathione assay was determined by the method of Beutler et al. GST amounts were measured by the method of Habig et al. Catalase activity was tested by Aebi's method and MDA was determined according to Thayer's method. Blood urea level was significantly increased in the gentamicin treated group. The study showed lowered levels of urea and creatinine levels in resveratrol administered groups when compared with gentamicin administered rats, and the difference was statistically significant. It has been determined that resveratrol caused statistically significant decrease in lipid peroxidation and reduced the level of catalase. Histopathological examination showed that resveratrol prevented partly gentamicin induced tubular damage. The results histopathologically demonstrated that resveratrol has a protective effect against gentamicin induced nephrotoxicity, lipid peroxidation and cellular damage in rats.


Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm.
Disturbances in peripheral norepinephrine release or removal by neuronal and extraneuronal uptake may have pathogenetic significance in cardiovascular disease states. We investigated the mechanisms of removal of norepinephrine in the forearm of healthy subjects under basal conditions, using measurements of arterial and venous plasma norepinephrine concentrations, blood pressure, heart rate, and forearm blood flow. The specific inhibitor of neuronal uptake, desipramine, was infused intra-arterially into the brachial artery of five subjects. Net norepinephrine overflow from the forearm increased markedly, revealing considerable local release of norepinephrine. Six other subjects received four intra-arterial infusions of norepinephrine, 1.18 pmol/kg/min, with various doses of desipramine and the extraneuronal uptake-inhibiting drug hydrocortisone. The forearm extraction rate for circulating norepinephrine decreased with increasing doses of desipramine (from 69.4 +/- 3.0 [SEM] to 35.3 +/- 8.4%; p less than 0.001). Increasing doses of hydrocortisone during continued inhibition of neuronal uptake resulted in decreased forearm extraction of norepinephrine (from 63.3 +/- 4.9 to 40.6 +/- 4.4%; p less than 0.01). In six other subjects who received the highest dose of hydrocortisone without concomitant inhibition of neuronal uptake, forearm extraction of norepinephrine decreased from 57.1 +/- 4.9 to 51.5 +/- 4.7% (p less than 0.05). These results suggest that neuronal uptake contributes markedly to the removal of circulating and endogenously released norepinephrine in the forearm. For circulating norepinephrine, a corticosteroid-sensitive mechanism of extraneuronal uptake was also demonstrated. These results indicate that neuronal and extraneuronal uptake can be estimated separately in this vascular bed. Similar organ-specific studies in patients may reveal disturbances in mechanisms of norepinephrine removal.


Action anticipation and motor resonance in elite basketball players.
We combined psychophysical and transcranial magnetic stimulation studies to investigate the dynamics of action anticipation and its underlying neural correlates in professional basketball players. Athletes predicted the success of free shots at a basket earlier and more accurately than did individuals with comparable visual experience (coaches or sports journalists) and novices. Moreover, performance between athletes and the other groups differed before the ball was seen to leave the model's hands, suggesting that athletes predicted the basket shot's fate by reading the body kinematics. Both visuo-motor and visual experts showed a selective increase of motor-evoked potentials during observation of basket shots. However, only athletes showed a time-specific motor activation during observation of erroneous basket throws. Results suggest that achieving excellence in sports may be related to the fine-tuning of specific anticipatory 'resonance' mechanisms that endow elite athletes' brains with the ability to predict others' actions ahead of their realization.


Compliance of Si photodiodes with Talbot's law.
For accurate measurements of chopped radiation, it is important that the photoelectric instrumentation complies with Talbot's law, that is, measures the time average. Two different photoelectric measuring systems were investigated for their compliance with Talbot's law: (1) Si photodiode with an integrating digital voltmeter (IDVM) system, and (2) Si photodiode with a lock-in amplifier. The test consisted in comparing values predicted from the amplitude and the duty factor of the chopper with values measured by both systems. It was found that the IDVM system showed satisfactory compliance with Talbot's law, whereas the lock-in system did not. However, a Fourier analysis of the signal wave shape produced correction factors for the lock-in system data which then yielded satisfactory compliance with Talbot's law.


SYT1-associated neurodevelopmental disorder: a case series.
Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.


A long and winding road: federally qualified health centers, community variation and prospects under reform.
Community health centers have evolved from fringe providers to mainstays of many local health care systems. Those designated as federally qualified health centers (FQHCs), in particular, have largely established themselves as key providers of comprehensive, efficient, high-quality primary care services to low-income people, especially Medicaid and uninsured patients. The Center for Studying Health System Change's (HSC's) site visits to 12 nationally representative metropolitan communities since 1996 document substantial growth in FQHC capacity, based on growing numbers of Medicaid enrollees and uninsured people, increased federal support, and improved managerial acumen. At the same time, FQHC development has varied considerably across communities because of several important factors, including local health system characteristics and financial and political support at federal, state and local levels. Some communities--Boston; Syracuse, N.Y.; Miami; and Seattle--have relatively extensive FQHC capacity for their Medicaid and uninsured populations, while other communities--Lansing, Mich.; northern New Jersey; Indianapolis; and Greenville, S.C.--fall in the middle. FQHC growth in Phoenix; Little Rock, Ark.; Cleveland; and Orange County, Calif.; has lagged in comparison. Today, FQHCs seem poised to play a key role in federal health care reform, including coverage expansions and the emphasis on primary care and medical homes.


Evolution of coagulation abnormalities following Russell's viper bite in Burma.
The evolution of coagulation abnormalities was studied in Russell's viper bite victims who, on admission to hospital, showed no clinical signs of systemic envenoming. Based on the laboratory results and subsequent clinical course, three groups were distinguished. The first group, consisting of five cases, showed no activation of coagulation at any stage. The second group, consisting of six cases, developed mild to moderate abnormalities in some tests, particularly in the aPTT and factor V assay, which corrected to normal without treatment. The third group, consisting of nine patients, developed haemostatic abnormalities as early as 1-2 h after the bite, which progressed to severe defibrination 4-8 h later at which time antivenom was given. Comparison of the haemostatic abnormalities in the three groups suggested that serial monitoring of the serum FDP concentration may be of value in predicting the likelihood of systemic envenoming and progression to complete defibrination.


Effect of geometrical parameters on rebound of impacting droplets on leaky superhydrophobic meshes.
When a droplet impacts a superhydrophobic sieve, a part of the droplet penetrates through it when the dynamic pressure (ρU2) of the impinging droplet exceeds the breakthrough pressure (γΓ/A). At higher impact velocities, the ejected-jet breaks and separates from the main droplet. The remaining part of the droplet bounces off the surface showing different modes (normal bouncing as a vertically elongated drop or pancake bouncing). In this work, we have studied the effect of different geometrical parameters of superhydrophobic copper meshes on different modes of droplet rebound. We observe three different effects in our study. Firstly, we observe pancake like bouncing, which is attributed to the capillary energy of the rebounding interface formed after the breaking of the ejected-jet. Secondly, we observe leakage of the droplet volume and kinetic energy due to the breaking of the ejected-jet, which leads to reduction in the contact times. Finally, we observe that for flexible meshes, the transition to pancake type bouncing is induced at lower Weber numbers. Flexibility also leads to a reduction in the volume loss from the ejected-jet. This study will be helpful in the design of superhydrophobic meshes for use under impact scenarios.


Assembly associated with the cytomatrix.
Assembly in vivo has been studied both for endogenous cytoskeletal proteins and for several classes of viruses. Autoradiography of cytoskeletal proteins has shown that many associate with the cytoskeletal framework close to the time and place of synthesis. The cytoskeletal proteins rearrange after association with the cytoskeletal framework. Rearrangement in symmetrical giant cells occurs in a centrifugal and coherent pattern. Many of the cytoskeletal proteins associate cotranslationally, as shown by their puromycin resistance in a cell-free translation system. The assembly of several groups of viruses has been shown to be associated with various components of the cytoskeleton; whether such assembly is cotranslational has not yet been addressed directly.


The skinny on brain-derived neurotrophic factor: evidence from animal models to GWAS.
Obesity and its sequelae constitute a major international healthcare problem. The obesity epidemic is due in part to higher calorie diets and reduced exercise over the past 30 years; however, increasing evidence has established genetic regulation of body weight as a major contributor to obesity. Brain-derived neurotrophic factor (BDNF) regulates development and plasticity of the central nervous system, and recent work has established a clear role for signaling through BDNF and its receptor TrkB in the control of body weight. Here we review research findings from animal models and human populations indicating that BDNF is a negative regulator of appetitive behavior and body weight.


Assessment of Infection by Fusarium pseudograminearum in Wheat Seedling Tissues Using Quantitative PCR and a Visual Discoloration Scale.
Assessment among cereal genotypes of relative seedling resistance to the crown rot pathogen Fusarium pseudograminearum has been primarily based on visual discoloration of the leaf sheaths. This study is the first to investigate the relationship between the widely used visual rating of seedling leaf sheath discoloration and the degree of colonization of these tissues by the pathogen, based on quantitative polymerase chain reaction (qPCR) of fungal DNA using primers specific for the translation elongation factor α sequence. Fourteen-day-old seedlings of four hard white spring wheat genotypes which differ in their degree of resistance to the pathogen, based on the expression of visible symptoms, were inoculated using a droplet method and assessed weekly from 7 to 35 days after inoculation (dai) for both discoloration and fungal DNA content per unit of tissue weight. Both visual assessment of disease symptoms and qPCR of fungal biomass indicated significant differences between the partially resistant and susceptible wheat genotypes from 14 dai. Visual discoloration of leaf sheath tissues was strongly correlated with fungal biomass estimated by qPCR in all four genotypes; however, this correlation became weaker with increasing time after inoculation. Significant correlations between these parameters were indicated at 14, 21, and 28 dai whereas, by 35 dai, the correlation was not significant. Evaluation of plants at 14 dai provided a rapid test which gave clear discrimination between lines for both parameters and was the time point of closest correlation between fungal colonization and disease symptoms. Symptom expression at all times following inoculation was accompanied by tissue infection, and at no time was symptomless infection observed under this screening environment. These qPCR results confirm that visual assessments of disease symptoms reflect the extent of tissue colonization by the pathogen in recently colonized tissues and confirm the validity of visual assessments for disease rating in high-throughput screening of breeding materials.


Coagulopathy following lethal and non-lethal envenoming of humans by the South American rattlesnake (Crotalus durissus) in Brazil.
The South American tropical rattlesnake (Crotalus durissus subspp) is responsible for approximately 10% of bites from venomous snakes in Brazil. We studied 24 victims of bites by this species over 3 years, in south-eastern Brazil, particularly investigating haemostatic alterations. Thirteen patients were defined as moderately envenomed and 11 as severe. There were two deaths, which were not attributed to venom-induced haemostatic disturbances. However, envenoming by C. durissus is frequently associated with haemostatic disorders, which are probably attributable mainly to the action of the thrombin-like enzyme, with possible additional effects secondary to the powerful myotoxic activity of the venom.


Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol alone or a sedation protocol and daily interruption.
Mechanically ventilated patients may receive more sedation during the night than during the day, potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration in adult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolized sedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses were associated with liberation from mechanical ventilation. This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine and opioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, we compared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariable logistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, and spontaneous breathing trial (SBT) conduct, SBT success, and extubation. Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (mean difference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356 mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, and was at target (3.2 vs 3.3, 95 % CI -0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the night and day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were more unintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases in nighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and the decision not to extubate the patient despite successful SBT. Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses were associated with SBT failure and delayed extubation. ClinicalTrials.gov NCT00675363 . Registered 7 May 2008.


The effect of an inhibitive weight-bearing splint on tone and function: a single-case study.
This single-case study was designed to duplicate Smelt's (1989) study of the effects of the application of an inhibitive weight-bearing splint on upper-extremity muscle tone and function in a child with cerebral palsy. Data on tone were collected by tracing the hand when weight bearing in the extended arm posture. Data on function were collected by observing block play for active grasp and voluntary release and ball play. Results indicate that after the application of an inhibitive weight-bearing splint, tone changed minimally, fine motor functional task changes were variable, and arm-hand position improved. Subjective reports by family and other caregivers, however, suggest that tone decreased and function increased. The results of this study suggest the need to find more accurate means of measuring changes of tone and function in children with cerebral palsy. Selection criteria for suitable candidates for the weight-bearing splint are presented.


Charge translocation by the Na+/K+-ATPase investigated on solid supported membranes: rapid solution exchange with a new technique.
Adsorption of Na+/K+-ATPase containing membrane fragments from pig kidney to lipid membranes allows the detection of electrogenic events during the Na+/K+-ATPase reaction cycle with high sensitivity and time resolution. High stability preparations can be obtained using solid supported membranes (SSM) as carrier electrodes for the membrane fragments. The SSMs are prepared using an alkanethiol monolayer covalently linked to a gold surface on a glass substrate. The hydrophobic surface is covered with a lipid monolayer (SAM, self-assembled monolayer) to obtain a double layer system having electrical properties similar to those of unsupported bilayer membranes (BLM). As we have previously shown (, Biophys. J. 64:384-391), the Na+/K+-ATPase on a SSM can be activated by photolytic release of ATP from caged ATP. In this publication we show the first results of a new technique which allows rapid solution exchange at the membrane surface making use of the high mechanical stability of SSM preparations. Especially for substrates, which are not available as a caged substance-such as Na+ and K+-this technique is shown to be capable of yielding new results. The Na+/K+-ATPase was activated by rapid concentration jumps of ATP and Na+ (in the presence of ATP). A time resolution of up to 10 ms was obtained in these experiments. The aim of this paper is to present the new technique together with the first results obtained from the investigation of the Na+/K+-ATPase. A comparison with data taken from the literature shows considerable agreement with our experiments.


Normal pre-attentive and impaired attentive processing of lexical tones in Cantonese-speaking congenital amusics.
The neural underpinnings of congenital amusia, an innate neurogenetic disorder of musical pitch processing, are not well understood. Previous studies suggest that amusia primarily impairs attentive processing (P300) of small pitch deviations in music, leaving pre-attentive pitch processing (mismatch negativity or MMN) more or less intact. However, it remains unknown whether the same neuro-dynamic mechanism of deficiency underlies pitch processing in speech, where amusics also often show impairment behaviorally. The current study examined how lexical tones are processed in pre-attentive (MMN) and attentive (P300) conditions in 24 Cantonese-speaking amusics and 24 matched controls. At the pre-attentive level, Cantonese-speaking amusics exhibited normal MMN responses to lexical tone changes, even for tone pairs with small pitch differences (mid level vs. low level tone; high rising vs. low rising tone). However, at the attentive level, amusics exhibited reduced P3a amplitude for all tone pairs, and further reduced P3b amplitude for tone pairs with small pitch differences. These results suggest that the amusic brain detects tone changes normally pre-attentively, but shows impairment in consciously detecting the same tone differences. Consistent with previous findings in nonspeech pitch processing, this finding provides support for a domain-general neuro-dynamic mechanism of deficient attentive pitch processing in amusia.


PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab.
Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. In sensitive cell lines, cetuximab induced a G(0)-G(1) arrest without inducing apoptosis. Notably, cetuximab-sensitive but not cetuximab-resistant cell lines were preferentially responsive to EGF-stimulated growth. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTEN-expressing cell lines (14 +/- 5.0% versus 38.5 +/- 6.4% growth inhibition, mean +/- SE; P = 0.008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared with PIK3CA WT controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss (10.8 +/- 4.3% versus 38.8 +/- 5.9% growth inhibition, respectively; P = 0.002), indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy.


Templating carbohydrate-functionalised polymer-scaffolded dynamic combinatorial libraries with lectins.
A conceptually new approach to the design of macromolecular receptors for lectins is outlined. Carbohydrate-functionalised Polymer-Scaffolded Dynamic Combinatorial Libraries (PS-DCLs) have been prepared in aqueous solution by the reversible conjugation of carbohydrates possessing acylhydrazide functionalities in their aglycone on to an aldehyde-functionalised polymer scaffold. PS-DCLs have been shown to undergo compositional change in response to the addition of lectin templates, with polymer scaffolds preferentially incorporating carbohydrate units which recognise the lectin added. This compositional change has been shown to generate polymers of significantly enhanced affinity for the lectin added, with enhancements in free energy of binding in the range of 5.2-8.8 kJ mol(-1) observed. Experiments indicate that these enhancements are not only as a consequence of increased display of the preferred carbohydrate upon the polymer scaffold, but that templation also reorganises key residues into strategic positions in order to interact more strongly with the target.


Anatomical basis for the intrahepatic glissonian approach during hepatectomies.
Anatomical liver resections are based on some basic technical principles such as vascular control, ischemic area delineation to be resected and maximum parenchymal preservation. These aspects are achieved by the intrahepatic glissonian approach, which consists in accessing the pedicles of hepatic segments within the hepatic parenchyma. Small incisions on well-defined anatomical landmarks are performed to approach the pedicles, making dissection of the hilar plate unnecessary. Analyze parameters in liver anatomy related to intrahepatic surgical technique to glissonians pedicles, to set the normal anatomy related to the procedure and thereby facilitate the attainment of this technique. Anatomical parameters related to the intrahepatic glissonian approach were studied in 37 cadavers. Measurements were performed with precision instruments. Data were expressed as mean±standard deviation. The subjects were divided into groups according to gender and liver weight and groups were compared statistically. Twenty-five cadavers were male and 12 female. No statistically significant difference was observed in virtually all parameters when groups were compared. This demonstrates the consistency of the anatomical parameters related to the intrahepatic glissonian approach. The results obtained in this study made possible major technical advances in the realization of open and laparoscopic hepatectomies with intrahepatic glissonian approach, and can help surgeons to perform liver resections by this method.


Global land change from 1982 to 2016.
Land change is a cause and consequence of global environmental change1,2. Changes in land use and land cover considerably alter the Earth's energy balance and biogeochemical cycles, which contributes to climate change and-in turn-affects land surface properties and the provision of ecosystem services1-4. However, quantification of global land change is lacking. Here we analyse 35 years' worth of satellite data and provide a comprehensive record of global land-change dynamics during the period 1982-2016. We show that-contrary to the prevailing view that forest area has declined globally5-tree cover has increased by 2.24 million km2 (+7.1% relative to the 1982 level). This overall net gain is the result of a net loss in the tropics being outweighed by a net gain in the extratropics. Global bare ground cover has decreased by 1.16 million km2 (-3.1%), most notably in agricultural regions in Asia. Of all land changes, 60% are associated with direct human activities and 40% with indirect drivers such as climate change. Land-use change exhibits regional dominance, including tropical deforestation and agricultural expansion, temperate reforestation or afforestation, cropland intensification and urbanization. Consistently across all climate domains, montane systems have gained tree cover and many arid and semi-arid ecosystems have lost vegetation cover. The mapped land changes and the driver attributions reflect a human-dominated Earth system. The dataset we developed may be used to improve the modelling of land-use changes, biogeochemical cycles and vegetation-climate interactions to advance our understanding of global environmental change1-4,6.


Using community-based participatory research to develop the PARTNERS youth violence prevention program.
School-based violence prevention programs have shown promise for reducing aggression and increasing children's prosocial behaviors. Prevention interventions within the context of urban after-school programs provide a unique opportunity for academic researchers and community stakeholders to collaborate in the creation of meaningful and sustainable violence prevention initiatives. This paper describes the development of a collaborative between academic researchers and community leaders to design a youth violence prevention/leadership promotion program (PARTNERS Program) for urban adolescents. Employing a community-based participatory research (CBPR) model, this project addresses the needs of urban youth, their families, and their community. Multiple strategies were used to engage community members in the development and implementation of the PARTNERS Program. These included focus groups, pilot testing the program in an after-school venue, and conducting organizational assessments of after-school sites as potential locations for the intervention. Community members and academic researchers successfully worked together in all stages of the project development. Community feedback helped the PARTNERS team redesign the proposed implementation and evaluation of the PARTNERS Program such that the revised study design allows for all sites to obtain the intervention over time and increases the possibility of building community capacity and sustainability of programs. Despite several challenges inherent to CBPR, the current study provides a number of lessons learned for the continued development of relationships and trust among researchers and community members, with particular attention to balancing the demand for systematic implementation of community-based interventions while being responsive to the immediate needs of the community.


Arthroplasty versus internal fixation of femoral neck fractures: a clinical decision analysis.
The optimal surgical management of displaced femoral neck fractures in the elderly remains controversial. Treatment alternatives include arthroplasty and internal fixation. Options for arthroplasty include total hip arthroplasty and hemiarthroplasty, whereas options for internal fixation include multiple screws and sliding hip screws. We sought to compare arthroplasty and internal fixation alternatives and determine the key factors influencing final outcomes using a clinical decision analysis. We constructed a decision analytic model representing potential outcomes after arthroplasty and internal fixation alternatives. Probabilities of events following each procedure were systematically derived from a literature review. Relative outcome preferences were estimated using health utility questionnaires with surgeons and lay persons. Sensitivity analyses determined threshold values that would alter the preferred decision. In the arthroplasty comparison, patients treated with total hip arthroplasty achieved higher expected utility values than patients treated with hemiarthroplasty (0.80 versus 0.74). In the internal fixation analysis, sliding hip screw fixation yielded higher expected utility values than multiple screws (0.76 versus 0.73). Overall, total hip arthroplasty achieved higher expected utility values than either approach to internal fixation. The superiority of arthroplasty over internal fixation was maintained over a wide range of probabilities and utilities. When outcomes and their values are considered in a systematic manner, arthroplasty results in better patient outcomes when compared to internal fixation in the management of displaced hip fractures in the elderly.


Mid-term results of endoscopic perforator vein interruption for chronic venous insufficiency: lessons learned from the North American subfascial endoscopic perforator surgery registry. The North American Study Group.
The safety, feasibility, and early efficacy of subfascial endoscopic perforator surgery (SEPS) for the treatment of chronic venous insufficiency were established in a preliminary report. The long-term clinical outcome and the late complications after SEPS are as yet undetermined. The North American Subfascial Endoscopic Perforator Surgery registry collected information on 148 SEPS procedures that were performed in 17 centers in the United States and Canada between August 1, 1993, and February 15, 1996. The data analysis in this study focused on mid-term outcome in 146 patients. One hundred forty-six patients (79 men and 67 women; mean age, 56 years; range, 27 to 87 years) underwent SEPS. One hundred and one patients (69%) had active ulcers (class 6), and 21 (14%) had healed ulcers (class 5). One hundred and three patients (71%) underwent concomitant venous procedures (stripping, 70; high ligation, 17; varicosity avulsion alone, 16). There were no deaths or pulmonary embolisms. One deep venous thrombosis occurred at 2 months. The follow-up periods averaged 24 months (range, 1 to 53 months). Cumulative ulcer healing at 1 year was 88% (median time to healing, 54 days). Concomitant ablation of superficial reflux and lack of deep venous obstruction predicted ulcer healing (P <.05). Clinical score improved from 8.93 to 3.98 at the last follow-up (P <. 0001). Cumulative ulcer recurrence at 1 year was 16% and at 2 years was 28% (standard error, < 10%). Post-thrombotic limbs had a higher 2-year cumulative recurrence rate (46%) than did those limbs with primary valvular incompetence (20%; P <.05). Twenty-eight of the 122 patients (23%) who had class 5 or class 6 ulcers before surgery had an active ulcer at the last follow-up examination. The interruption of perforators with ablation of superficial reflux is effective in decreasing the symptoms of chronic venous insufficiency and rapidly healing ulcers. Recurrence or new ulcer development, however, is still significant, particularly in post-thrombotic limbs. The reevaluation of the indications for SEPS is warranted because operations in patients without previous deep vein thrombosis are successful but operations in those patients with deep vein thrombosis are less successful. Operations on patients with deep vein occlusion have poor outcomes.


Polarization at metal-biomolecular interfaces in solution.
Metal surfaces in contact with water, surfactants and biopolymers experience attractive polarization owing to induced charges. This fundamental physical interaction complements stronger epitaxial and covalent surface interactions and remains difficult to measure experimentally. We present a first step to quantify polarization on even gold (Au) surfaces in contact with water and with aqueous solutions of peptides of different charge state (A3 and Flg-Na3) by molecular dynamics simulation in all-atomic resolution and a posteriori computation of the image potential. Attractive polarization scales with the magnitude of atomic charges and with the length of multi-poles in the aqueous phase such as the distance between cationic and anionic groups. The polarization energy per surface area is similar on aqueous Au {1 1 1} and Au {1 0 0} interfaces of approximately -50 mJ m(-2) and decreases to -70 mJ m(-2) in the presence of charged peptides. In molecular terms, the polarization energy corresponds to -2.3 and -0.1 kJ mol(-1) for water in the first and second molecular layers on the metal surface, and to between -40 and 0 kJ mol(-1) for individual amino acids in the peptides depending on the charge state, multi-pole length and proximity to the surface. The net contribution of polarization to peptide adsorption on the metal surface is determined by the balance between polarization by the peptide and loss of polarization by replaced surface-bound water. On metal surfaces with significant epitaxial attraction of peptides such as Au {1 1 1}, polarization contributes only 10-20% to total adsorption related to similar polarity of water and of amino acids. On metal surfaces with weak epitaxial attraction of peptides such as Au {1 0 0}, polarization is a major contribution to adsorption, especially for charged peptides (-80 kJ mol(-1) for peptide Flg-Na(3)). A remaining water interlayer between the metal surface and the peptide then reduces losses in polarization energy by replaced surface-bound water. Computed polarization energies are sensitive to the precise location of the image plane (within tenths of Angstroms near the jellium edge). The computational method can be extended to complex nanometre and micrometer-size surface topologies.


Phase II trial of the novel sulphonylurea sulofenur in advanced breast cancer.
A total of 18 women with advanced breast cancer were treated with sulofenur [LY186641; N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)-urea], a diarylsulfonylurea that has broad-spectrum activity against a number of murine mammary tumour xenografts. The dosage chosen on the basis of pre-clinical and phase I studies was 700 mg/m2 given orally once daily for 14 days, with treatments being repeated every 3 weeks. There was no response. All patients experienced at least grade 1 anaemia, and two patients developed symptomatic methaemoglobinaemia. Two patients developed grade 4 rises in serum liver-function values along with histological changes consistent with drug-induced toxicity. The mean plasma concentrations of 176 micrograms/ml were lower than the levels required to exert anti-tumour effect in the mouse model.


Controlling alternans in cardiac cells.
Electrical alternans, the alternation in action potential morphology, has been suggested as an important cause of potentially dangerous cardiac rhythm disorders. Previous studies have developed alternans control strategies based on the dynamics of the relationship between action potential duration and the previous diastolic interval. We demonstrate that alternans in a single cardiac cell can also be controlled by directly modifying the underlying ion channel dynamics. Surprisingly, we find that, for a detailed canine ventricular cell model, the best time to apply the control stimulus is not during the repolarization phase of the action potential, but rather during the early plateau phase, when the charge requirements are two orders of magnitude smaller. Computer simulations show that a single control stimulus applied during the early plateau can completely eliminate small-amplitude alternans, while a small number of stimuli can rapidly extinguish large-amplitude alternans. We have also developed an effective control algorithm that uses only the membrane potential as control input and requires no prior detailed knowledge of the cell dynamics. The study suggests that control strategies based on ion channel dynamics can provide new directions for the development of algorithms intended to control dangerous cardiac rhythm disorders.


Automatic measurement of epithelium differentiation and classification of cervical intraneoplasia by computerized image analysis.
The feasibility of evaluating an objective grading of cervical intraneoplasia lesions (CIN) is attempted using an automatic computerized system able to measure several valuable parameters with special reference to epithelium differentiation. 4 groups of 10 images each were selected at random from 68 consensus images coming from 80 archival cervical biopsies, normal (n = 10), CIN 1 (n = 10), CIN 2 (n = 10), CIN 3 (n = 10). Representative images of lesions were captured from the microscopic slides and were analyzed using mathematical morphology, with special reference toVoronoï tessellation and Delaunay triangulation. Epithelium surface, nuclear and cytoplasm area, triangle edge and area, total and upper nuclear index were precisely measured in each lesion, and discriminant coefficients were calculated therewith. A dilation/erosion coefficient was automatically defined using triangle edge length and nuclear radius in order to measure the epithelium ratio of differentiation. A histogram ratio was also automatically established between total nuclei and upper nuclei on top of differentiated epithelium. With the latter two ratios added to the nucleo-cytoplasmic ratio, a cervical score able to classify CIN is proposed. There is a quasi-linear increase of mean cervical score values between normal epithelium and CIN 3: (27) for normal epithelium, (51) for CIN 1, (78) for CIN 2 and (100) for CIN 3, with significant differences (P < 0.05). Our results highlight the possibility of applying a cervical score for the automatic grading of CIN lesions and thereby assisting the pathologist for improvement of grading. The automatic measure of epithelium differentiation ratio appears to be a new interesting parameter in computerized image analysis of cervical lesions.


Enzyme stabilization by glass-derived silicates in glass-exposed aqueous solutions.
To analyze the solutes leaching from glass containers into aqueous solutions, and to show that these solutes have enzyme activity stabilizing effects in very dilute solutions. Enzyme assays with acetylcholine esterase were used to analyze serially succussed and diluted (SSD) solutions prepared in glass and plastic containers. Aqueous SSD preparations starting with various solutes, or water alone, were prepared under several conditions, and tested for their solute content and their ability to affect enzyme stability in dilute solution. We confirm that water acts to dissolve constituents from glass vials, and show that the solutes derived from the glass have effects on enzymes in the resultant solutions. Enzyme assays demonstrated that enzyme stability in purified and deionized water was enhanced in SSD solutions that were prepared in glass containers, but not those prepared in plastic. The increased enzyme stability could be mimicked in a dose-dependent manner by the addition of silicates to the purified, deionized water that enzymes were dissolved in. Elemental analyses of SSD water preparations made in glass vials showed that boron, silicon, and sodium were present at micromolar concentrations. These results show that silicates and other solutes are present at micromolar levels in all glass-exposed solutions, whether pharmaceutical or homeopathic in nature. Even though silicates are known to have biological activity at higher concentrations, the silicate concentrations we measured in homeopathic preparations were too low to account for any purported in vivo efficacy, but could potentially influence in vitro biological assays reporting homeopathic effects.


A Multi-Center, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury.
Acute kidney injury (AKI) is a highly morbid condition in critically ill patients that is associated with high mortality. Previous clinical studies have demonstrated the safety and efficacy of the Selective Cytopheretic Device (SCD) in the treatment of AKI requiring continuous renal replacement therapy in the intensive care unit (ICU). A randomized, controlled trial of 134 ICU patients with AKI, 69 received continuous renal replacement therapy (CRRT) alone and 65 received SCD therapy. No significant difference in 60-day mortality was observed between the treated (27/69; 39%) and control patients (21/59; 36%, with six patients lost to follow up) in the intention to treat (ITT) analysis. Of the 19 SCD subjects (CRRT+SCD) and 31 control subjects (CRRT alone) who maintained a post-filter ionized calcium (iCa) level in the protocol's recommended range (≤ 0.4 mmol/L) for greater or equal to 90% of the therapy time, 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the CRRT alone group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD treated versus control CRRT alone patients maintained for ≥ 90% of the treatment in the protocol's recommended (r) iCa target range of ≤ 0.4 mmol/L with values of, 0% (0/16) and 25% (4/16), respectively (P = 0.10). When the riCa treated and control subgroups were compared for a composite index of 60 day mortality and dialysis dependency, the percentage of SCD treated subjects was 16% versus 58% in the control subjects (p<0.01). The incidence of serious adverse events did not differ between the treated (45/69; 65%) and control groups (40/65; 63%; p = 0·86). SCD therapy may improve mortality and reduce dialysis dependency in a tightly controlled regional hypocalcaemic environment in the perfusion circuit. ClinicalTrials.gov NCT01400893 http://clinicaltrials.gov/ct2/show/NCT01400893.


Hepatocyte transplantation in children with liver cell failure.
Patients with hepatic failure and liver-based metabolic disorders require management which is both costly and complex. Hepatocyte transplantation has been very encouraging as an alternative to organ transplantation for liver disease treatment, and studies in rodents, show that transplants involving isolated liver cells can reverse hepatic failure, and correct various metabolic deficiencies of the liver. This 2016 review is based on a literature search using PubMed including original articles, reviews, cases and clinical guidelines. The search terms were "hepatocyte transplantation", "liver transplantation", "liver cell failure", "metabolic liver disorders", "orthotropic liver transplantation", "hepatocytes" and "stem cell transplantation". The goal of this review is to summarize the significance of hepatocyte transplantation, the sources of hepatocytes and the barriers of hepatocyte transplantation using a detailed review of literature. Our review shows that treatment of patients with liver disease by hepatocyte transplantation has expanded exponentially, especially for patients suffering from liver-based metabolic disorders. Once hepatocyte transplantation has been shown to effectively replace organ transplantation for a portion of patients with life-threatening liver metabolic diseases and those with liver failure it will make cell therapy effective and available for a broad population of patients with liver disorders.