The immunophenotype of blast transformation of chronic myelogenous leukemia: a high frequency of mixed lineage phenotype in "lymphoid" blasts and A comparison of morphologic, immunophenotypic, and molecular findings.
Immunophenotypic studies have a limited role in the diagnosis of chronic myelogenous leukemia (CML) but are increasingly being used in CML blast transformation (BT). Determination of the cell lineage of CML blasts is clinically important because patients with lymphoid blast transformation have a better response to chemotherapy and longer survival than those with other lineages. We studied the morphologic, cytochemical, immunophenotypic, cytogenetic, and molecular features of 20 patients with Philadelphia chromosome-positive CML and more than 10% blast cells in peripheral blood or bone marrow. The blasts were morphologically heterogeneous. CD33 was expressed in 19 cases (95%), followed by CD13 (85%), CD11c (80%), CD36 (60%), CD117 (40%), and CD15 (30%). Seven cases (35%) had a precursor-B lymphoid immunophenotype, and 13 (65%) had a predominantly myeloid immunophenotype. Of the former group, of which only one had a pure lymphoid phenotype, terminal deoxynucleotidyl transferase (TdT) and CD19 were expressed in 100%, CD10 in 85.7%, and CD20 in 14.3%. Of the latter group, all 13 expressed from 3 to 6 myeloid antigens, with 46.2% myeloperoxidase positive and 69.2% CD61 positive. No cases were interpreted as T lineage, but the T-cell antigens CD3, CD4, CD5, and CD7 were expressed in 5.0, 40.0, 5.3. and 30.0% of all cases, respectively. In most cases, the immunophenotype of the CML blasts could not be predicted from their morphologic features. Polymerase chain reaction showed that 80.0% of the lymphoid group and 37.5% of the myeloid group had immunoglobulin heavy-chain gene rearrangements. The frequent lineage infidelity of the blast cells in CML BT seems to be related to the stem cell origin of this disorder. Such lineage infidelity, however, makes classification of many cases difficult and the significance of and criteria for biphenotypic blast crisis of CML is yet to be determined.


Determining control parameters for dendritic cell-cytotoxic T lymphocyte interaction.
Dendritic cells (DC) are potent immunostimulatory cells facilitating antigen transport to lymphoid tissues and providing efficient stimulation of T cells. A series of experimental studies in mice demonstrated that cytotoxic T lymphocytes (CTL) can be efficiently induced by adoptive transfer of antigen-presenting DC. However, the success of DC-based immunotherapeutic treatment of human cancer, for example, is still limited because the details of the regulation and kinetics of the DC-CTL interaction are not yet completely understood. Using a combination of experimental mouse studies, mathematical modeling, and nonlinear parameter estimation, we analyzed the population dynamics of DC-induced CTL responses. The model integrates a predator-prey-type interaction of DC and CTL with the non-linear compartmental dynamics of T cells. We found that T cell receptor avidity, the half-life of DC, and the rate of CTL-mediated DC-elimination are the major control parameters for optimal DC-induced CTL responses. For induction of high avidity CTL, the number of adoptively transferred DC was of minor importance once a minimal threshold of approximately 200 cells per spleen had been reached. Taken together, our study indicates that the availability of high avidity T cells in the recipient in combination with the optimal application regimen is of prime importance for successful DC-based immunotherapy.


In Silico analysis of perturbed steroidogenesis and gonad growth in fathead minnows (P. promelas) exposed to 17α-ethynylestradiol.
The multi-factorial nature of adverse reproductive effects mediated by endocrine disrupting compounds (or EDCs) makes understanding the mechanistic basis of reproductive dysfunction a highly pertinent area of research. As a consequence, a main motivator for continued research is to integrate 'multi-leveled' complexity (i.e., from genes to phenotype) using mathematical methods capable of encapsulating properties of physiological relevance. In this study, an in silico stoichiometric model of piscine steroidogenesis was augmented with a 'biomass' reaction associating the underlying stoichiometry of steroidogenesis with a reaction representative of gonad growth. The ability of the in silico model to predict perturbed steroidogenesis and subsequent effects on gonad growth was tested by exposing reproductively active male and female fathead minnows (Pimephales promelas) to 88 ng/L of the synthetic estrogen, 17α-ethynylestradiol (EE2). The in silico model was parameterized (or constrained) with experimentally quantified concentrations of selected steroid hormones (using mass spectrometry) and fold changes in gene expression (using RT-qPCR) for selected steroidogenic enzyme genes, in gonads of male and female fish. Once constrained, the optimization framework of flux balance analysis (FBA) was used to calculate an optimal flux through the biomass reaction (analogous to gonad growth) and associated steroidogenic flux distributions required to generate biomass. FBA successfully predicted effects of EE2 exposure on fathead minnow gonad growth (%gonadosomatic index or %GSI) and perturbed production of steroid hormones. Specifically, FBA accurately predicted no effects of exposure on male %GSI and a significant reduction for female %GSI. Furthermore, in silico simulations accurately identified disrupted reaction fluxes catalyzing productions of androgens (in male fish) and progestogens (in female fish), an observation which agreed with in vivo experimentation. The analyses presented is the first-ever to successfully associate underlying flux properties of the steroidogenic network with gonad growth in fish, an approach which can incorporate in silico predictions with toxicological risk assessments.


Allergy to kiwi in patients with baker's asthma: identification of potential cross-reactive allergens.
Baker's asthma is a frequent IgE-mediated occupational disorder mainly provoked by inhalation of cereal flour. Allergy to kiwifruit has being increasingly reported in the past few years. No association between both allergic disorders has been described so far. Twenty patients with occupational asthma caused by wheat flour inhalation were studied. Kiwi allergens Act d 1 and Act d 2 were purified by cation-exchange chromatography. Wheat, rye, and kiwi extracts, purified kiwi allergens, and model plant glycoproteins were analyzed by IgE immunodetection, enzyme-linked immunosorbent assay (ELISA), and inhibition ELISAs. Kiwifruit ingestion elicited oral allergy syndrome in 7 of the 20 patients (35%) with baker's asthma. Positive specific IgE and skin prick test responses to this fruit were found in all these kiwi allergic patients, and IgE to Act d 1 and Act d 2 was detected in 57% and 43%, respectively, of the corresponding sera. Actinidin Act d 1 and bromelain (harboring cross-reactive carbohydrate determinants) reached above 50% inhibition of the IgE binding to wheat and/or kiwi extracts. A potential association between respiratory allergy to cereal flour and allergy to kiwifruit has been disclosed. Cross-reactive carbohydrate determinants and thiol-proteaseshomologous to Act d 1 are responsible for wheat-kiwi crossreactivity in some patients.


Prevalence of covid-19 and long covid in collegiate student athletes from spring 2020 to fall 2021: a retrospective survey.
Symptomatic COVID-19 and Long COVID, also referred to as post-acute sequelae of SARS-CoV-2 (PASC) or post-COVID conditions, have been widely reported in young, healthy people, but their prevalence has not yet been determined in student athletes. We sought to estimate the prevalence of reported COVID-19, symptomatic COVID-19, and Long COVID in college athletes in the United States attending 18 schools from spring 2020 to fall 2021. We developed an online survey to measure the prevalence of student athletes who tested positive for COVID-19, developed Long COVID, and did not return to their sport during the relevant time period. We surveyed a convenience sample of 18 collegiate school administrators, representing about 7,000 student athletes. Of those schools surveyed, 16 responded regarding the spring 2020 semester, and 18 responded regarding the full academic year of fall 2020 to spring 2021 (both semesters). According to the survey responses, there were 9.8% of student athletes who tested positive for COVID-19 in spring 2020 and 25.4% who tested positive in the academic year of fall 2020 to spring 2021. About 4% of student athletes who tested positive from spring 2020 to spring 2021 developed Long COVID, defined as new, recurring, or ongoing physical or mental health consequences occurring 4 or more weeks after SARS-CoV-2 infection. This study highlights that Long COVID occurs among young, healthy athletes and is a real consequence of COVID-19. Understanding the prevalence of Long COVID in this population requires longer follow-up and further study.


A Diffusion and Clustering-Based Approach for Finding Coherent Motions and Understanding Crowd Scenes.
This paper addresses the problem of detecting coherent motions in crowd scenes and presents its two applications in crowd scene understanding: semantic region detection and recurrent activity mining. It processes input motion fields (e.g., optical flow fields) and produces a coherent motion field named thermal energy field. The thermal energy field is able to capture both motion correlation among particles and the motion trends of individual particles, which are helpful to discover coherency among them. We further introduce a two-step clustering process to construct stable semantic regions from the extracted time-varying coherent motions. These semantic regions can be used to recognize pre-defined activities in crowd scenes. Finally, we introduce a cluster-and-merge process, which automatically discovers recurrent activities in crowd scenes by clustering and merging the extracted coherent motions. Experiments on various videos demonstrate the effectiveness of our approach.


During early and mid-adolescence, greater mental toughness is related to increased sleep quality and quality of life.
The aim of this study was to explore the association between mental toughness, subjective sleep, physical activity, and quality of life during early and mid-adolescence. A total of 1475 participants (mean age = 13.4 years; range: 11-16 years) took part in the study. They completed questionnaires related to mental toughness, physical activity, subjective sleep, and quality of life. Greater mental toughness was related to more favorable quality of life and increased subjective sleep. Mental toughness was not related to physical activity. Increased mental toughness, favorable quality of life, and sleep are related during early and mid-adolescence. Against our expectations, mental toughness was not related to physical activity.


Economic evaluations in community aged care: a systematic review.
This paper reports the methods and findings from a systematic review of economic evaluations conducted in the community aged care sector between 2000 and 2016. Online databases searched were PubMed, Medline, Scopus, and web of science, CINAHL and informit. Studies were included if they 1) were full economic evaluations that compared both the costs and outcomes of two or more interventions 2) in study population of people aged 65 years and over 3) dependent older people living in the community 4) alternatives being compared were care models or service delivery interventions in the community aged care sector (a group of programs that have been established as a support system to allow older people to remain living in their own homes for as long as possible, as an alternative to institutional or residential care) and 5) published in the English language between 2000 and November 2016. Eleven studies reporting upon economic evaluations of service delivery interventions in community aged care were identified; the majority of which were undertaken in Europe. Critical appraisal of the identified studies highlighted the methodological rigour in these evaluations. This systematic review highlights the paucity of economic evaluation studies conducted to date in the community aged care sector. The findings highlight the importance of cost utility analysis methodology as it allows for a uniform outcome measure, that facilitates the comparison of different interventions. In addition, multi-attribute utility measures that represent those quality of life domains that are most important to older people should be used and attention must be paid to the inclusion of informal care costs and outcomes as this is a key resource in community aged care service delivery.


Age as a critical factor in the success of surgical correction of craniosynostosis.
The effect of timing of the surgical release of prematurely immobilized coronal sutures was studied in rabbits. At 9 days of age, the coronal suture was mechanically immobilized by the application of methyl cyanoacrylate adhesive. These animals and a control group then received metallic implants on each side of the suture to monitor growth. At 30, 60, or 90 days after suture immobilization, separate groups of animals underwent a linear suturectomy to release the restriction. In animals in which the suture was not released, growth at the coronal suture was significantly restricted and resulted in severe deformities in the neurocranium. The benefits derived from surgical release were time-dependent. Suturectomy at 30 days of age resulted within 60 days in achievement of 100% of the growth in sham-treated controls. In contrast, delayed surgery at 60 or 90 days of age resulted in achievement of only 38% and 17% of normal growth, respectively. Angular measurements of the vault and base of the cranium showed a similar graded response toward normality, with the greatest correction occurring with the earliest operation. These results support the clinical impression that early surgical correction of craniosynostosis results in superior cosmetic appearance. A further implication of this work is that abnormality at a single suture strongly influences the development of other areas in the craniofacial complex.


Update to 'A Contemporary Systematic Review on Liver Transplantation for Unresectable Liver Metastasis of Colorectal Cancer'.
Colorectal cancer is the second most common cause of cancer-related death worldwide, and half of patients present with colorectal liver metastasis (CRLM). Liver transplant (LT) has emerged as a treatment modality for otherwise unresectable CRLM. Since the publication of the Lebeck-Lee systematic review in 2022, additional evidence has come to light supporting LT for CRLM in highly selected patients. This includes reports of >10-year follow-up with over 80% survival rates in low-risk patients. As these updated reports have significantly changed our collective knowledge, this article is intended to serve as an update to the 2022 systematic review to include the most up-to-date evidence on the subject.


Cloning and nucleotide sequences of NADH-putidaredoxin reductase gene (camA) and putidaredoxin gene (camB) involved in cytochrome P-450cam hydroxylase of Pseudomonas putida.
Pseudomonas putida PpGl, which carries the CAM plasmid encoding enzymes involved in the degradation pathway of D-camphor, can utilize D-camphor as a sole carbon source. Cytochrome P-450cam and related enzymes participate in the early oxidation steps of D-camphor degradation metabolism. We cloned from a HindIII DNA library of PpGl a 2.9 kbp CAM segment which carries the major part of camA gene encoding NADH-putidaredoxin reductase and the entire camB gene encoding putidaredoxin. The 2.9 kbp CAM segment was adjacent to the 4.27 kbp HindIII CAM segment which has been previously cloned (Koga et al. (1986) J. Bacteriol. 166, 1089-1095). Thus, the total 7.17 kbp HindIII CAM directed all the genes responsible for early steps of D-camphor degradation, i.e. 5-exo-hydroxycamphor dehydrogenase (camD gene), cytochrome P-450cam (camC), NADH-putidaredoxin reductase (camA), and putidaredoxin (camB). These cam genes form an operon, camDCAB, and are under negative control by the gene camR located immediately upstream from the camD gene. The total number of amino acids deduced from the nucleotide sequence is 422 for putidaredoxin reductase, and 106 for putidaredoxin.


Clinical outcome, PDGFRβ and KIT expression in feline histiocytic disorders: a multicentre study.
Information about histiocytic disease in cats is limited. The aim of this study was to document clinical findings and outcome in feline histiocytic disorders, and characterize the expression of PDGFRβ and KIT in order to identify potential treatment targets. Morphologically diagnosed feline histiocytic tumours were reviewed and characterized by immunohistochemistry (IHC). Five cases of feline progressive histiocytosis (FPH), eight histiocytic sarcomas (HS) and two haemophagocytic histiocytic sarcomas (HaeHS) were confirmed. PDGFRβ was variably positive in most histiocytic cases, while KIT was negative in all. Clinical presentation, treatment and outcome were also evaluated. Partial responses were recorded in measurable disease with tyrosine kinase inhibitors and lomustine, and radiotherapy achieved long-term control in some cases. Survival times were shortest in HaeHS and disseminated disease. PDGFRβ, but not KIT, may represent a therapeutic target in feline histiocytic disorders but more studies are needed to investigate other potential treatment targets.


Maternal Vaccination and Infant Influenza and Pertussis.
Infant influenza and pertussis disease causes considerable morbidity and mortality worldwide. We examined the effectiveness of maternal influenza and pertussis vaccines in preventing these diseases in infants. This inception cohort study comprised women whose pregnancies ended between September 1, 2015, and December 31, 2017, in Victoria, Australia. Maternal vaccination status was sourced from the Victorian Perinatal Data Collection and linked to 5 data sets to ascertain infant outcomes and vaccination. The primary outcome of interest was laboratory-confirmed influenza or pertussis disease in infants aged <2 months, 2 to <6 months, and <6 months combined. Secondary outcomes included infant hospitalization (emergency presentation or admission) and death. Risk ratios and 95% confidence intervals (CIs) were estimated by Poisson regression. Vaccine effectiveness (VE) was estimated as (1 minus the risk ratio) x 100%. Among 186 962 pregnant women, 85 830 (45.9%) and 128 060 (68.5%) were vaccinated against influenza and pertussis, respectively. There were 175 and 51 infants with laboratory-confirmed influenza and pertussis disease, respectively. Influenza VE was 56.1% (95% CI, 23.3% to 74.9%) for infants aged <2 months and 35.7% (2.2% to 57.7%) for infants aged 2 to <6 months. Pertussis VE was 80.1% (95% CI, 37.1% to 93.7%) for infants aged <2 months and 31.8% (95% CI, -39.1% to 66.6%) for infants aged 2 to <6 months. Our study provides evidence of the direct effectiveness of maternal influenza and pertussis vaccination in preventing these diseases in infants aged <2 months. The findings strengthen the importance of maternal vaccination to prevent these diseases in infants.


Noninvasive vascular elastography using plane-wave and sparse-array imaging.
Stroke may occur when an atherosclerotic plaque ruptures in the carotid artery. Noninvasive vascular elastography (NIVE) visualizes the strain distribution within the carotid artery, which is related to its mechanical properties that govern plaque rupture. Strain elastograms obtained from the transverse plane of the carotid artery are difficult to interpret, because strain is estimated in Cartesian coordinates. Sparsearray (SA) elastography overcomes this problem by transforming shear and normal strain to polar coordinates. However, the SA's transmit power may be too weak to produce useful elastograms in the clinical setting. Consequently, we are exploring other imaging methods to solve this potential problem. This study evaluated the quality of elastograms produced with SA imaging, plane-wave (PW) imaging, and compounded-plane-wave (CPW) imaging. We performed studies on simulated and physical vessel phantoms, and the carotid artery of a healthy volunteer. All echo imaging was performed with a linear transducer array that contained 128 elements, operating at 5 MHz. In SA imaging, 7 elements were fired during transmission, but all 128 elements were active during reception. In PW imaging, all 128 elements were active during both transmission and reception. We created CPW images by steering the acoustic beam within the range of -15° to 15° in increments of 5°. SA radial and circumferential strain elastograms were comparable to those produced using PW and CPW imaging. Additionally, side-lobe levels incurred during SA imaging were 20 dB lower than those produced during PW imaging, and 10 dB lower than those computed using CPW imaging. Overall, SA imaging performs well in vivo; therefore, we plan to improve the technique and perform preclinical studies.


Using prevention cascades to investigate coverage of contraception services among young women enrolled in a large-scale combination HIV prevention program in South Africa.
We investigated the coverage of contraception services (excluding condoms) to prevent unintended pregnancy among young women and girls aged 15 to 24 years who were beneficiaries of one of the two largest combination HIV and pregnancy prevention program in South Africa. We invited 2160 randomly sampled beneficiaries who were living in six of the 12 program districts across six provinces to participate in a telephone survey. We created pregnancy prevention coverage cascades and conducted univariate and multivariable analyses to identify key barriers and facilitators associated with each step of the cascade. We achieved a response rate of 23.8%, resulting in 515 respondents, of whom 303 had sex in the 6 months before the survey. Of this subsample, 80.4% had access to contraception services, 60.6% had access and motivation to use contraceptives, and 21.9% had access to, motivation to use, and effectively used contraceptives. Distance to travel to services and not ever being offered contraceptives by health workers were access barriers, while low pregnancy risk perception was a barrier to motivation. Most respondents had access to and were motivated to use contraceptives other than condoms but were not effectively using them. Having been offered contraceptives facilitated better access, while distance to the services was a barrier, suggesting the importance of improving supply-side interventions, such as increasing the number and accessibility of spaces where Sexual and Reproductive Health (SRH) services are offered. We recommend longitudinal behavioral counseling for young people, especially adolescents, as well as risk reduction and information-tailored interventions. Pregnancy prevention cascades are a promising tool to monitor progress toward universal access to contraception services and to identify barriers that need to be addressed to achieve the effective use of contraceptives.


Clinical validation and guidelines for the SCORAD index: consensus report of the European Task Force on Atopic Dermatitis.
We have previously reported how the SCORAD index was designed. This cumulative index combines objective (extent and intensity of lesions) and subjective (daytime pruritus and sleep loss) criteria. To study interobserver variability in scoring for objective SCORAD criteria and to optimize the scoring guidelines. Three scoring sessions were organized in 1993-1994 in Hamburg, Bordeaux and Rotterdam totalizing 19 patients (14 children and 5 adults) and 23 physicians, among whom 12 participated in at least 2 scoring sessions; 169 evaluation sheets have been processed using the SCORAD File Marker Pro software. At each session, total body photographs and close-up views were taken of each patient, and this material was reviewed at the final evaluation. The extent of lesions according to the rule of nines showed interobserver variability mostly for patients with lesions of moderate intensity involving 20-60% of body surface. Intensity items were scored with more consistency overall, but variations subsided especially for oozing/crusts and lichenifications. Low and high scorer profiles and the benefit of training were noted. This study has allowed to optimize clinical scoring using the SCORAD system. A proposal has been made to grade the severity of atopic dermatitis according to objective criteria in three groups for inclusion in clinical trials. The SCORAD index remains the major criterion for follow-up in trials.


Dietary carbohydrate, a Big Mac, and insulin requirements in type I diabetes.
Using the artificial beta-cell (Biostator), we determined the insulin requirements in five nonobese type I (insulin-dependent) diabetic subjects who received isocaloric 40 and 60% mixed-carbohydrate diets in a crossover randomized fashion for 4 days, each day consisting of four equal meals. This was followed on day 5 by a "Big Mac Attack" lunch consisting of a Big Mac, french fries, and milk shake. Insulin requirements to maintain normoglycemia were calculated for each 24-h period and for the 2 h after each meal. The mean 24-h insulin requirements to maintain normoglycemia was greater for the 60% carbohydrate diet than the 40% diet. Although the four meals were of equal size, in all patients the insulin required to cover breakfast greater than lunch greater than dinner greater than or equal to snack. Expressed as milliunits per kilocalorie, the amount of insulin to cover breakfast was greater for the 60% (P less than .05) than the 40% carbohydrate diet and greater for breakfast than the other meals (P less than .01). Insulin requirements for the Big Mac (43% carbohydrate) were 58% greater than for the 40% carbohydrate diet, even after correction for caloric differences. In summary, 1) increasing dietary carbohydrate from 40 to 60% results in an increased insulin requirement for meals only; 2) insulin requirements are greater in the morning than in the evening, even when meal size is constant; and 3) very large meals with high fat and carbohydrate content result in a major increase in insulin requirement. These data indicate that diet has an important impact on insulin requirements in diabetes.


Trust and reciprocity: are effort and money equivalent?
Trust and reciprocity facilitate cooperation and are relevant to virtually all human interactions. They are typically studied using trust games: one subject gives (entrusts) money to another subject, which may return some of the proceeds (reciprocate). Currently, however, it is unclear whether trust and reciprocity in monetary transactions are similar in other settings, such as physical effort. Trust and reciprocity of physical effort are important as many everyday decisions imply an exchange of physical effort, and such exchange is central to labor relations. Here we studied a trust game based on physical effort and compared the results with those of a computationally equivalent monetary trust game. We found no significant difference between effort and money conditions in both the amount trusted and the quantity reciprocated. Moreover, there is a high positive correlation in subjects' behavior across conditions. This suggests that trust and reciprocity may be character traits: subjects that are trustful/trustworthy in monetary settings behave similarly during exchanges of physical effort. Our results validate the use of trust games to study exchanges in physical effort and to characterize inter-subject differences in trust and reciprocity, and also suggest a new behavioral paradigm to study these differences.


Distribution and occurrence of the insect pathogenic alga Helicosporidium sp. (Chlorophyta: Trebouxiophyceae) in the predator beetle Rhizophagus grandis G: yll. (Coleoptera: Rhizophagidae)-rearing laboratories.
The distribution and occurrence of the insect pathogenic algae Helicosporidium sp. (Chlorophyta: Trebouxiophyceae) in the predator beetle Rhizophagus grandis (Coleoptera: Rhizophagidae)-rearing laboratories were studied and reported here for the first time. The insect pathogenic alga Helicosporidium sp. infection was observed in all R. grandis-rearing laboratories. The infection rate reached more than 20% which is significant among the samples in some R. grandis-rearing laboratories. The infection rates of the examined beetles showed noticeable differences between localities and years. There was no significant difference in the infection levels of male and female beetles. These results showed that Helicosporidium sp. is one of the factors that decrease efficiency of the R. grandis-rearing laboratories.


Formulation and Shelf-life of Fish Burgers Served to Preschool Children.
Consumer is very careful about healthiness; in this context nutritionists often highlight the importance of fish for human nutrition because of their protein and fatty acid composition. In order to stimulate utilisation and consumption of fish species by unusual target groups such as children, the aim of this research was to formulate and to evaluate shelf-life and nutritional values of fish preparations stored in modified atmosphere packaging (MAP). Fish species used for trail were Trachurus trachurus and Oncorhynchus mykiss fished and farmed in Basilicata region respectively. Fish burgers were made with different ingredients of plant and animal origin and packed in air (control) and in MAP and stored at refrigeration atemperature. Sensory, physical-chemical analysis as pH, aw, total volatile nitrogen (TVN), trimetilammine (TMA), thiobarbituric acid (TBA), free fatty acids (FFA) and microbiological analysis like aerobic plate count, Enterobacteriaceae, Escherichia coli, Pseudomonas spp., sulphite-reducing clostridia, Staphylococci, Salmonella spp. and Listeria monocytogenes were performed at intervals of 0°, 1°, 2°, 5°, 8°, 15°, 22°, day from production. Results showed that fish burgers stored in MAP had a longer shelf-life; protein degradation indexes and spoilage bacterial species showed lower values in the samples packaged in MAP compared with the control. The formulation of the fish burger meets the approval of the target consumers. The mixing of natural ingredients has made possible both the enhancement of the organoleptic characteristics with an excellent balance of nutritional values. The diversification of fish preparations, besides enhancing the fish production of marginal areas would add value to a product with potential and remarkable profit margins.


Androgen deficiency in long-term intrathecal opioid administration.
Intrathecal drug delivery of opioids is an efficient and effective treatment option for pain management in the chronic nonmalignant pain population. As with all treatments, in addition to the benefits, risks and side effects exist. One such risk in intrathecal opioids is opioid-induced androgen deficiency. This study evaluates opioid-induced androgen deficiency in long-term intrathecal opioid administration in chronic nonmalignant pain. Case series. Sixteen consecutive patients with intrathecal drug delivery with opioids were screened for androgen deficiency. Academic university-based pain management center. All the subjects were seen in a 2 month period, during a scheduled maintenance refill visit. Eight consecutive men and eight consecutive women receiving intrathecal drug delivery therapy for non-malignant chronic pain were ordered blood work and asked to complete a questionnaire. Patient and patient-related data were also collected. Ten of the 16 (62.5%) patients were found to have androgen deficiency, 4 of 8 men based on free testosterone levels and 6 of 8 women based on DHEA levels. In men, erectile dysfunction correlated with endocrine dysfunction (P = 0.02) while depressive symptoms correlated in women (P = .03). Overall, 2 of the 16 patients had hydromorphone as the opioid in the intrathecal system. Both patients had normal endocrine functions. Both patients with hydromorphone were men and the use of hydromorphone showed an insignificant trend (P = 0.06). Three of the 4 men with normal endocrine functions had in addition to an opioid, bupivacaine, in the intrathecal system. The presence of bupivicaine in men was significant (P = 0.02). No women had bupivicaine while one of the 8 women had clonidine in addition to the opioid. Presence of another substance in addition to the opioid showed an insignificant trend (P = 0.08). Study limitations include the small sample size and case series nature. Additionally the symptoms data was solely based on subjective patient reports. Androgen deficiency is common in patients treated with intrathecal opioids for chronic nonmalignant pain. Patients experience numerous and wide ranging symptoms. Erectile dysfunction may be more suggestive for androgen deficiency in men while complaints of depressed mood may be correlative in women. Additionally, combining bupivicaine with the intrathecal opioid may provide a protective role.


Canadian Asthma Consensus Report, 1999. Canadian Asthma Consensus Group.
To provide physicians with current guidelines for the diagnosis and optimal management of asthma in children and adults, including pregnant women and the elderly, in office, emergency department, hospital and clinic settings. The consensus group considered the roles of education, avoidance of provocative environmental and other factors, diverse pharmacotherapies, delivery devices and emergency and in-hospital management of asthma. Provision of the best control of asthma by confirmation of the diagnosis using objective measures, rapid achievement and maintenance of control and regular follow-up. The key diagnostic and therapeutic recommendations are based on the 1995 Canadian guidelines and a critical review of the literature by small groups before a full meeting of the consensus group. Recommendations are graded according to 5 levels of evidence. Differences of opinion were resolved by consensus following discussion. Respirologists, immunoallergists, pediatricians and emergency and family physicians gave prime consideration to the achievement and maintenance of optimal control of asthma through avoidance of environmental inciters, education of patients and the lowest effective regime of pharmacotherapy to reduce morbidity and mortality. Adherence to the guidelines should be accompanied by significant reduction in patients' symptoms, reduced morbidity and mortality, fewer emergency and hospital admissions, fewer adverse side-effects from medications, better quality of life for patients and reduced costs. Recommendations are included in each section of the report. In summary, after a diagnosis of asthma is made based on clinical evaluation, including demonstration of variable airflow obstruction, and contributing factors are identified, a treatment plan is established to obtain and maintain optimal asthma control. The main components of treatment are patient education, environmental control, pharmacotherapy tailored to the individual and regular follow-up. The recommendations were distributed to the members of the Canadian Thoracic Society Asthma and Standards Committees, as well as members of the board of the Canadian Thoracic Society. In addition, collaborating groups representing the Canadian Association of Emergency Physicians, the Canadian College of Family Physicians, the Canadian Paediatric Society and the Canadian Society of Allergy and Immunology were asked to validate the recommendations. The recommendations were discussed at regional meetings throughout Canada. They were also compared with the recommendations of other similar groups in other countries. DISSEMINATION AND IMPLEMENTATION: An implementation committee has established a strategy for disseminating these guidelines to physicians, other health professionals and patients and for developing tools and means that will help integrate the recommendations into current asthma care. The plan is outlined in this report.


A survey of recently emerged genome-wide computational enhancer predictor tools.
The race for the discovery of enhancers at a genome-wide scale has been on since the commencement of next generation sequencing decades after the discovery of the first enhancer, SV40. A few enhancer-predicting features such as chromatin feature, histone modifications and sequence feature had been implemented with varying success rates. However, to date, there is no consensus yet on the single enhancer marker that can be employed to ultimately distinguish and uncover enhancers from the enormous genomic regions. Many supervised, unsupervised and semi-supervised computational approaches had emerged to complement and facilitate experimental approaches in enhancer discovery. In this review, we placed our focus on the recently emerged enhancer predictor tools that work on general enhancer features such as sequences, chromatin states and histone modifications, eRNA and of multiple feature approach. Comparisons of their prediction methods and outcomes were done across their functionally similar counterparts. We provide some recommendations and insights for future development of more comprehensive and robust tools.


Clinical profile, genetic spectrum and therapy evaluation of 19 Chinese pediatric patients with lipoprotein lipase deficiency.
Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization. To describe the manifestations and management of 19 pediatric patients with LPL-FCS. LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed. Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed. This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy.


Role of virtual reality simulation in teaching and assessing technical skills in endovascular intervention.
Training in endovascular intervention ultimately aims to produce interventionalists who demonstrate competence in technical skills. Herein, the authors investigate the rationale for simulation-based training by providing an overview of the psychological theories underpinning acquisition of technical skills, training and assessment history, recent advances in simulation technology, and a critical appraisal of their role in training and assessment in endovascular intervention. Simulators have potential for training and assessment and promise solution to many shortcomings of traditional 'apprenticeship' training models. Before inclusion into the curriculum, further work is needed regarding fidelity, validity, reliability, and design of simulators to ensure accurate transfer of acquired endovascular skills from simulator to patient.


Control of root hair development in Arabidopsis thaliana by an endoplasmic reticulum anchored member of the R2R3-MYB transcription factor family.
The evolution of roots and root hairs was a crucial innovation that contributed to the adaptation of plants to a terrestrial environment. Initiation of root hairs involves transcriptional cues that in part determine cell patterning of the root epidermis. Once root hair initiation has occurred, elongation of the root hair takes place. Although many genes have been identified as being involved in root hair development, many contributors remain uncharacterized. In this study we report on the involvement of a member (here dubbed maMYB) of the plant-specific R2R3-MYB family of transcription factors in root hair elongation in Arabidopsis. We show that maMYB is associated with the endoplasmic reticulum membrane with the transcription factor domain exposed to the cytosol, suggesting that it may function as a membrane-tethered transcription factor. We demonstrate that a truncated form of maMYB (maMYB⁸⁴⁻³⁰⁹), which contains the R2R3-MYB transcription factor domain, is localized and retained in the nucleus, where it regulates gene expression. Silencing of maMyb resulted in plants with significantly shorter root hairs but similar root hair density compared with wild type, implying a role of the protein in root hair elongation. 2,4-D (2,4-dichlorophenoxyacetic acid), an exogenous auxin analog that promotes root hair elongation, rescued the short root hair phenotype and maMyb mRNA was induced in the presence of 2,4-D and IAA (indole-3-acetic acid). These results indicate a functional role of maMYB, which is integrated with auxin, in root hair elongation in Arabidopsis.


Association between genetic variants in the 8q24 cancer risk regions and circulating levels of androgens and sex hormone-binding globulin.
Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder. To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3alphadiol G, and bioavailable testosterone), and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels. Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 x 10(-3)) and bioavailable testosterone (P < 6.3 x 10(-4)). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05). These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels. These results might provide some clues for the strong link between 8q24 and prostate cancer risk.


Professionally responsible intrapartum management of patients with major mental disorders.
Pregnant women with major mental disorders present obstetricians with a range of clinical challenges, which are magnified when a psychotic or agitated patient presents in labor and there is limited time for decision making. This article provides the obstetrician with an algorithm to guide professionally responsible decision making with these patients. We searched for articles related to the intrapartum management of pregnant patients with major mental disorders, using 3 main search components: pregnancy, chronic mental illness, and ethics. No articles were found that addressed the clinical ethical challenges of decision making during the intrapartum period with these patients. We therefore developed an ethical framework with 4 components: the concept of the fetus as a patient; the presumption of decision-making capacity; the concept of assent; and beneficence-based clinical judgment. On the basis of this framework we propose an algorithm to guide professionally responsible decision making that asks 5 questions: (1) Does the patient have the capacity to consent to treatment?; (2) Is there time to attempt restoration of capacity?; (3) Is there an opportunity for substituted judgment?; (4) Is the patient accepting treatment?; (5) Is there an opportunity for active assent?; and (6) coerced clinical management as the least worst alternative. The algorithm is designed to support a deliberative, clinically comprehensive, preventive-ethics approach to guide obstetricians in decision making with this challenging population of patients.


Gain of function in FHM-1 Cav2.1 knock-in mice is related to the shape of the action potential.
Familial hemiplegic migraine type-1 FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the alpha(1A) pore-forming subunit of Ca(V)2.1 Ca(2+) channels. We used knock-in (KI) transgenic mice harboring the pathogenic FHM-1 mutation R192Q to study neurotransmission at the calyx of Held synapse and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch-clamp recordings in brain stem slices, we confirmed that KI Ca(V)2.1 Ca(2+) channels activated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents (I(pCa)) evoked by presynaptic action potentials (APs) were similar in amplitude, kinetic parameters, and neurotransmitter release. Ca(V)2.1 Ca(2+) channels in cortical layer 2/3 PCs from KI mice also showed a negative shift in their activation voltage. PCs had APs with longer durations and smaller amplitudes than the calyx of Held. AP-evoked Ca(2+) currents (I(Ca)) from PCs were larger in KI compared with wild-type (WT) mice. In contrast, when I(Ca)was evoked in PCs by calyx of Held AP waveforms, we observed no amplitude differences between WT and KI mice. In the same way, Ca(2+) currents evoked at the presynaptic terminals (I(pCa))of the calyx of Held by the AP waveforms of the PCs had larger amplitudes in R192Q KI mice that in WT. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice. In addition, our results indicate that consequences of FHM-1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission (neurons in the calyx of Held vs. excitatory/inhibitory neurons in the cortex), adding to the complexity of the pathophysiology of migraine.


Relaxation matrix for symmetric tops with inversion symmetry: Line coupling and line mixing effects on NH3 lines in the 𝝂4 band.
Line shape parameters including the half-widths and the off-diagonal elements of the relaxation matrix have been calculated for self-broadened NH3 lines in the perpendicular ν4 band. As in the pure rotational and the parallel ν1 bands, the small inversion splitting in this band causes a complete failure of the isolated line approximation. As a result, one has to use formalisms not relying on this approximation. However, due to differences between parallel and perpendicular bands of NH3, the applicability of the formalism used in our previous studies of the ν1 band and other parallel bands must be carefully verified. We have found that, as long as potential models only contain components with K1 = K2 = 0, whose matrix elements require the selection rule Δk = 0, the formalism is applicable for the ν4 band with some minor adjustments. Based on both theoretical considerations and results from numerical calculations, the non-diagonality of the relaxation matrices in all the PP, RP, PQ, RQ, PR, and RR branches is discussed. Theoretically calculated self-broadened half-widths are compared with measurements and the values listed in HITRAN 2012. With respect to line coupling effects, we have compared our calculated intra-doublet off-diagonal elements of the relaxation matrix with reliable measurements carried out in the PP branch where the spectral environment is favorable. The agreement is rather good since our results do well reproduce the observed k and j dependences of these elements, thus validating our formalism.


Intracranial area: a validated method for estimating intracranial volume.
Controlling for intracranial volume is crucial in magnetic resonance studies of changes in brain volumes. However, full intracranial volume measurement requires prolonged scanning and analysis, and simple, validated methods for intracranial volume estimation are lacking. The authors developed and evaluated a method of estimating intracranial volume using a single mid-sagittal slice, the intracranial cross-sectional area. Forty men aged 65-70 had whole skull magnetic resonance scans at 1.9 T, with slice thickness of 1.5 mm (no interslice gap). Intracranial cross-sectional area was traced in the midline sagittal slice of the 3-view localizer. Intracranial volume was measured using every slice. Ten intracranial cross-sectional area measurements were tested for interrater reliability. Intracranial cross-sectional area and intracranial volume correlated highly (r = .88, P < .0001). A modified Bland-Altman plot showed good agreement between intracranial cross-sectional area and intracranial volume. The intraclass correlation (an indicator of reliability) for intracranial cross-sectional area was r = .976 (P < .005). The rapid and simple technique of intracranial cross-sectional area measurement provides a valid and reliable estimate of intracranial volume.


Primary pleomorphic rhabdomyosarcoma of breast: Report of a rare neoplasm.
Primary sarcoma of the breast is very rare and constitutes less than 1% of all breast cancers. Herein, we report a case of pleomorphic rhabdomyosarcoma (PRMS) of the right breast in a 49-year-old female patient presented with a mass (7 cm × 6.5 cm). Mammography and ultrasonography suspected a malignant lesion and a diagnosis of poorly differentiated carcinoma was made on fine needle aspiration cytology. Modified radical mastectomy was carried out. Histopathological examination revealed a high grade stromal sarcoma with rhabdoid morphology and multinucleated tumor giant cells. The tumor cells were strongly positive for desmin, vimentin and Myo D1 focally. The tumor cells were immunonegative for cytokeratin, epithelial membrane antigen (EMA), CD34, CD45, SMA, S100, CD68 and HMB45. A final diagnosis of PRMS was rendered. Surgical margins were free and no metastasis was seen in axillary lymph nodes. Neither post-operative radiotherapy nor adjuvant chemotherapy was given and the patient has remained disease free 12 months post-operatively.


Drosophila TGIF proteins are transcriptional activators.
The information carried by transforming growth factor beta (TGF-beta) signaling molecules induces profound responses in target cells. To restrict this information to appropriate cells, TGF-beta signaling pathways are tightly regulated by dynamic interactions with transcriptional activators and repressors. Numerous cross-species experiments have shown that TGF-beta family members and their signal transduction machinery (receptors and Smad signal transducers) are functionally conserved between vertebrates and invertebrates. TG-interacting factor (TGIF) is a homeodomain-containing transcriptional corepressor of TGF-beta-dependent gene expression in mammals that is associated with holoprosencephaly in humans. Here we report a biochemical analysis of TGIF from zebra fish and Drosophila. Our study reveals an unprecedented role reversal between vertebrate and invertebrate TGIF proteins. Zebra fish TGIF, like its mammalian relative, interacts with general corepressors and represses TGF-beta-responsive gene expression. We identified a tandem duplication of TGIF genes in Drosophila. In contrast to vertebrate TGIFs, both Drosophila TGIFs strongly activate transcription. We also demonstrate that Drosophila TGIF proteins physically interact with both Mad and dSmad2, suggesting a role in Dpp and activin signaling. Thus, dTGIF may be the first transcription factor in the Drosophila activin pathway. Overall, our study suggests that assumptions about the functional equivalence of conserved proteins must be validated experimentally.


Effects of physical activity on bone mineral density in older adults: Korea National Health and Nutrition Examination Survey, 2008-2011.
We compared the relationship between physical activity (PA) and bone mineral density (BMD) in men and women aged over 50 years. Only moderate-to-vigorous PA was positively associated with hip BMD in men. There was no association between PA and BMD at any site in women. Physical activity (PA) is widely recommended for osteoporosis. However, epidemiological data regarding the intensity or volume of PA required for bone health are lacking. We aimed to investigate and compare the relationship between PA and bone mineral density (BMD) in men and women. This population-based cross-sectional study used data from the 4th and 5th Korea National Health and Nutrition Examination Surveys and included 2767 men and 2753 women aged > 50 years. The intensity, frequency, and duration of PA were assessed using a questionnaire, and the participants were divided into the no activity, walking-only, moderate PA, and vigorous PA groups. BMD was measured at the lumbar spine (LS), femur neck (FN), and total hip (TH) using dual-energy X-ray absorptiometry. Adjusted-BMDs of the hip were higher in men and women in the moderate and vigorous PA groups than those in men and women in the walking-only and no activity groups, while frequency and duration of PA were not associated with BMD at any site. The odds ratios for osteoporosis were the lowest at the FN and TH in men in the vigorous PA group (0.354, 95% confidence interval (CI) 0.139-0.901, P < 0.002, and 0.072, 95% CI 0.007-0.766, P < 0.003, respectively), while it was not significant in women. Only moderate-to-vigorous PA was positively associated with the hip BMD in men. There was no association between PA and BMD at any site in women. It is necessary to assess the PA intensity for bone health based on the site and sex.


Update on the natural history of intracranial atherosclerotic disease: A critical review.
Intracranial atherosclerotic disease (ICAD) contributes to a significant number of ischemic strokes. There is debate in the recent literature concerning the impact of the location of stenosis in ICAD on outcome. Some reports have suggested that disease processes and outcomes vary by vessel location, potentially altering the natural history and indications for intervention. Here we have performed a comprehensive, critical review of the natural history of ICAD by vessel in an attempt to assess the differences in disease specific to each of the vascular territories. Our assessment concludes that only minor differences exist between patients with different vessels affected in vessel-specific ICAD. We have found that middle cerebral artery disease confers a lower mortality than vessel-specific ICAD in other intracranial vessels, asymptomatic disease follows a more benign course than symptomatic disease, and that plaque progression or the detection of microemboli on transcranial Doppler may predict poor outcome. Given the expanding indications for treatment of ICAD and rapidly developing endovascular techniques to confront this disease, a thorough understanding of the natural history of ICAD aids the interventional neuroradiologist in determining when to treat and how to predict outcome in this patient population.


STEAK: A specific tool for transposable elements and retrovirus detection in high-throughput sequencing data.
The advancements of high-throughput genomics have unveiled much about the human genome highlighting the importance of variations between individuals and their contribution to disease. Even though numerous software have been developed to make sense of large genomics datasets, a major short falling of these has been the inability to cope with repetitive regions, specifically to validate structural variants and accordingly assess their role in disease. Here we describe our program STEAK, a massively parallel software designed to detect chimeric reads in high-throughput sequencing data for a broad number of applications such as identifying presence/absence, as well as discovery of transposable elements (TEs), and retroviral integrations. We highlight the capabilities of STEAK by comparing its efficacy in locating HERV-K HML-2 in clinical whole genome projects, target enrichment sequences, and in the 1000 Genomes CEU Trio to the performance of other TE and virus detecting tools. We show that STEAK outperforms other software in terms of computational efficiency, sensitivity, and specificity. We demonstrate that STEAK is a robust tool, which allows analysts to flexibly detect and evaluate TE and retroviral integrations in a diverse range of sequencing projects for both research and clinical purposes.


Interference and memory capacity limitations.
Working memory (WM) is thought to have a fixed and limited capacity. However, the origins of these capacity limitations are debated, and generally attributed to active, attentional processes. Here, we show that the existence of interference among items in memory mathematically guarantees fixed and limited capacity limits under very general conditions, irrespective of any processing assumptions. Assuming that interference (a) increases with the number of interfering items and (b) brings memory performance to chance levels for large numbers of interfering items, capacity limits are a simple function of the relative influence of memorization and interference. In contrast, we show that time-based memory limitations do not lead to fixed memory capacity limitations that are independent of the timing properties of an experiment. We show that interference can mimic both slot-like and continuous resource-like memory limitations, suggesting that these types of memory performance might not be as different as commonly believed. We speculate that slot-like WM limitations might arise from crowding-like phenomena in memory when participants have to retrieve items. Further, based on earlier research on parallel attention and enumeration, we suggest that crowding-like phenomena might be a common reason for the 3 major cognitive capacity limitations. As suggested by Miller (1956) and Cowan (2001), these capacity limitations might arise because of a common reason, even though they likely rely on distinct processes. (PsycINFO Database Record


Nucleic acid degradation as barrier to gene delivery: a guide to understand and overcome nuclease activity.
Gene therapy is on its way to revolutionize the treatment of both inherited and acquired diseases, by transferring nucleic acids to correct a disease-causing gene in the target cells of patients. In the fight against infectious diseases, mRNA-based therapeutics have proven to be a viable strategy in the recent Covid-19 pandemic. Although a growing number of gene therapies have been approved, the success rate is limited when compared to the large number of preclinical and clinical trials that have been/are being performed. In this review, we highlight some of the hurdles which gene therapies encounter after administration into the human body, with a focus on nucleic acid degradation by nucleases that are extremely abundant in mammalian organs, biological fluids as well as in subcellular compartments. We overview the available strategies to reduce the biodegradation of gene therapeutics after administration, including chemical modifications of the nucleic acids, encapsulation into vectors and co-administration with nuclease inhibitors and discuss which strategies are applied for clinically approved nucleic acid therapeutics. In the final part, we discuss the currently available methods and techniques to qualify and quantify the integrity of nucleic acids, with their own strengths and limitations.


[Oxidation of lipids contained in total parental nutrition].
The components used in parenteral nutrition mixtures are subject to oxidation. The oxidation of polyunsaturated lipids leads to the formation of toxic lipoperoxides. This toxicity is of particular significance in new-born children, because of the lack of maturity of their defensive systems against oxidative processes, and also in critically-ill patients, whose oxidative metabolism is increased. A review of the literature is effected to assess the following: toxicity of lipoperoxides, factors involved in the oxidation of parenteral nutrition mixtures and the analytical methods used to determine the peroxides present in parenteral nutrition mixtures. The factors influencing the oxidation of parenteral nutrition mixtures include: the amount of polyunsaturated fatty acids, the presence of bisulphite, vitamin complexes and their polysorbate content, temperature, type of bag and exposure to light. The analytical methods found for the analysis of peroxides in TPN mixtures are: iodine measurement analysis, high resolution liquid chromatography, the thiobarbituric acid test, and oxidation of the ferrous cation in the presence of xylenol orange. Depending on the method, it is possible to determine total peroxides or only lipoperoxides. The literature reviewed does not establish a threshold level of peroxide concentration below which a parenteral nutrition mixture can be considered safe.


Improved cerebral oxygen saturation and blood flow pulsatility with pulsatile perfusion during pediatric cardiopulmonary bypass.
Brain monitoring techniques near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) ultrasound were used in pediatric patients undergoing cardiopulmonary bypass for congenital heart defect (CHD) repair to analyze the effect of pulsatile or nonpulsatile flow on brain protection. Regional cerebral oxygen saturation (rSO2) and cerebrovascular pulsatility index (PI) were measured by NIRS and TCD, respectively, in 111 pediatric patients undergoing bypass for CHD repair randomized to pulsatile (n = 77) or nonpulsatile (n = 34) perfusion. No significant differences in demographic and intraoperative data, including surgical risk stratification, existed between groups. Patients undergoing pulsatile perfusion had numerically lower decreases in rSO2 from baseline for all time points analyzed compared with the nonpulsatile group, with significant ∼12% lower decreases at 40 and 60 min after crossclamp. Patients undergoing pulsatile perfusion had numerically lower decreases in PI from baseline for the majority of time points compared with the nonpulsatile group, with significant ∼30% lower decreases between 5 and 40 min after crossclamp. Pulsatile flow has advantages over nonpulsatile flow as measured by NIRS and TCD, especially at advanced time points, which may improve postoperative neurodevelopmental outcomes.


Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration.
There is a growing realisation that the gut-brain axis and its regulation by the microbiota may play a key role in the biological and physiological basis of neurodevelopmental, age-related and neurodegenerative disorders. The routes of communication between the microbiota and brain are being unravelled and include the vagus nerve, gut hormone signalling, the immune system, tryptophan metabolism or by way of microbial metabolites such as short chain fatty acids. The importance of early life gut microbiota in shaping future health outcomes is also emerging. Disturbances of this composition by way of antibiotic exposure, lack of breastfeeding, infection, stress and the environmental influences coupled with the influence of host genetics can result in long-term effects on physiology and behaviour, at least in animal models. It is also worth noting that mode of delivery at birth influences microbiota composition with those born by Caesarean section having a distinctly different microbiota in early life to those born per vaginum. At the other extreme of life, ageing is associated with a narrowing in microbial diversity and healthy ageing correlates with a diverse microbiome. Recently, the gut microbiota has been implicated in a variety of conditions including depression, autism, schizophrenia and Parkinson's disease. There is still considerable debate as to whether or not the gut microbiota changes are core to the pathophysiology of such conditions or are merely epiphenomenal. It is plausible that such neuropsychiatric disorders might be treated in the future by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics.


Exploring the Potential for Multivariate Fragility Representations to Alter Flood Risk Estimates.
In flood risk analysis, limitations in the multivariate statistical models adopted to model the hydraulic load have restricted the probability of a defense suffering structural failure to be expressed conditionally on a single hydraulic loading variable. This is an issue at the coastal level where multiple loadings act on defenses with the exact combination of loadings dictating their failure probabilities. Recently, a methodology containing a multivariate statistical model with the flexibility to robustly capture the dependence structure between the individual loadings was used to derive extreme nearshore loading conditions. Its adoption will permit the incorporation of more precise representations of a structure's vulnerability in future analyses. In this article, a fragility representation of a shingle beach, where the failure probability is expressed over a three-dimensional loading parameter space-water level, wave height, and period-is derived at two localities. Within the approach, a Gaussian copula is used to capture any dependencies between the simplified geometric parameters of a beach's shape. Beach profiles are simulated from the copula and the failure probability, given the hydraulic load, determined by the reformulated Bradbury barrier inertia parameter model. At one site, substantial differences in the annual failure probability distribution are observed between the new and existing approaches. At the other, the beach only becomes vulnerable after a significant reduction of the crest height with its mean annual failure probability close to that presently predicted. It is concluded that further application of multivariate approaches is likely to yield more effective flood risk management.


Processes of adjustment to end-of-life losses: a reintegration model.
The processes surrounding psychological adjustment to losses due to advancing and end-stage illness have not been well delineated. While adjustment to losses due to death are often thought of as the bereaved's lot, dying persons experience multiple, accumulating, and profound losses of functions, abilities, roles, and relationships and therefore have to adjust as well. Many people who are facing death in the near future negotiate these losses, still achieving quality of life in all dimensions. Others fare less well. It is hard to intervene helpfully without a clear understanding of how either trajectory occurs. Building from current literature on loss and adjustment, we describe a conceptual framework of key adjustment processes that allow for quality of life during terminal illness. We term this the reintegration model. It has comprehension, creative adaptation and reintegration components, each involving the physical, psychological, social, and existential domains in ways that are characteristic of the needs, tasks and options available to a seriously ill and dying person. In this paper, we discuss the model, focusing on normal adjustment processes, and describe the implications of the framework for the dying person, caregivers, and the palliative care team.


Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase.
The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.


The gut microbiome of the healthy population in Kolkata, India, is a reservoir of antimicrobial resistance genes emphasizing the need of enforcing antimicrobial stewardship.
Antimicrobial resistance (AMR) alleviation warrants antimicrobial stewardship (AS) entailing the indispensability of epidemiological surveillance. We undertook a small-scale surveillance in Kolkata to detect the presence of antimicrobial resistance genes (ARGs) in the healthy gut microbiome. We found that it was a reservoir of ARGs against common antibiotics. A targeted Polymerase Chain Reaction (PCR) and sequencing-based ARGs detection against tetracyclines, macrolides, trimethoprim, sulfamethoxazole, aminoglycosides, amphenicol, and mobile genetic element (MGE) markers were deployed in 25 fecal samples. Relative abundance and frequency of ARGs were calculated. We detected markers against all these classes of antibiotics. 100% samples carried aminoglycoside resistance marker and int1U. A comparison with our previously published diarrheal resistome from the same spatial and temporal frame revealed that a higher diversity of ARGs were detected in the community and a higher rate of isolation of tetC, msrA, tmp, and sul-2 was found. The presence of common markers in the two cohorts proves that the gut microbiome has been contaminated with ARGs and which are being disseminated among different ecosystems. This is an issue of discerning concern for public health. The study raises an alarming picture of the AMR crisis in low-middle and emergent economies. It emphasizes the strict enforcement of AS in the community.


Stereotactic body radiotherapy with CyberKnife for cardiac malignancies.
Radiobiological and technical considerations have traditionally limited the role of radiation therapy in the context of primary and secondary cardiac malignancies. Stereotactic body radiotherapy (SBRT) is a promising modality for the delivery of focused high-dose radiation with ablative potential to complex targets such as small, deep-seated, moving lesions, allowing also for re-irradiation. Between January 2013 and October 2013, 3 patients underwent SBRT for cardiac lesions: 2 patients had recurrent, previously irradiated cardiac angiosarcomas (PCA) and 1 patient had a cardiac metastasis from melanoma. They were treated with fiducial-guided robotic radiotherapy with CyberKnife. As for dose prescription, 24 Gy in 3 fractions (80% isodose) and 30 Gy in 5 fractions (80% isodose) were administered to the recurrent PCAs and cardiac metastasis, respectively. At 2 months after SBRT, cardiac MRI showed a partial response in the patients treated for recurrent PCA while the cardiac metastasis remained stable. In all cases, absence of local progression was subsequently confirmed by contrast-enhanced cardiac MRI after 6 months, without any evidence of treatment-related side effects. Fiducial-guided SBRT proved to be feasible and effective in preventing local disease progression in selected patients with cardiac malignancies.


Role of galanin receptor 1 in gastric motility in rat.
Galanin actions are mediated by distinct galanin receptors (GAL-R), GAL-R1, -R2 and -R3. We investigated the role of GAL-R1 in gastric motility and the expression of GAL-R1 in the rat stomach. In vivo, in urethane-anaesthetized rats, galanin (equipotent for all GAL-Rs) induced a short inhibition of gastric motility, followed by increase in tonic and phasic gastric motility; the latter was significantly reduced by the GAL-R1 antagonist, RWJ-57408. Galanin 1-16 (high affinity for GAL-R1 and -R2) induced a long-lasting decrease of intragastric pressure, which was not modified by RWJ-57408. In vitro, galanin and galanin 1-16 induced increase of intragastric pressure that was not affected by RWJ-57408. Tetrodotoxin (TTX) did not suppress the galanin excitatory effect, whereas the effect of galanin 1-16 on gastric contraction was increased by TTX- or N-nitro-L-arginine, an inhibitor of nitric oxide synthase. GAL-R1 immunoreactivity was localized to cholinergic and tachykinergic neurons and to neurons immunoreactive for nitric oxide synthase or vasoactive intestinal polypeptide. This study suggests that an extrinsic GAL-R1 pathway mediates the galanin excitatory action, whereas an extrinsic, non GAL-R1 pathway is likely to mediate the galanin inhibitory effect in vivo. GAL-R1 intrinsic neurons do not appear to play a major role in the control of gastric motility.


Synthesis of nanosheet crystallites of ruthenate with an alpha-NaFeO2-related structure and its electrochemical supercapacitor property.
Unilamellar crystallites of conductive ruthenium oxide having a thickness of about 1 nm were obtained via elemental exfoliation of a protonic layered ruthenate, H(0.2)RuO(2).0.5H(2)O, with an alpha-NaFeO(2)-related crystal structure. The obtained RuO(2) nanosheets possessed a well-defined crystalline structure with a hexagonal symmetry, reflecting the crystal structure of the parent material. The restacked RuO(2) nanosheets exhibited a high pseudocapacitance of approximately 700 F g(-1) in an acidic electrolyte, which is almost double the value of the nonexfoliated layered protonated ruthenate.


The effect of high-sugar grass on predicted nitrogen excretion and milk yield simulated using a dynamic model.
High-sugar grass varieties have received considerable attention for their potential to reduce nitrogen (N) excretion and increase milk yield in cattle. However, considerable variation exists in the magnitude of response in published results. The purpose of this study is to explain the variation in response using a dynamic mechanistic model to predict observed N and milk yield results from the literature, and from simulated data. Examined effects were (1) water-soluble carbohydrate [WSC; g/kg of dry matter (DM)] increase; (2) change in crude protein (CP) and neutral detergent fiber (NDF) content of the plant with WSC increase; and (3) the level of N fertilization. The database for evaluation of model N and milk yield predictions consisted of 4 published studies with 28 treatment means for which high-sugar grasses were being evaluated. Water-soluble carbohydrate content of the diets ranged from 95 to 248 g/kg of DM, CP content ranged from 115 to 263 g/kg of DM, and the NDF content ranged from 400 to 568 g/kg of DM. Urine N, milk N, and total N excretion were predicted well by the model and followed the directional pattern of observed values within each study. Simulation results showed that the N utilization ratio increased as the WSC content of the diet increased, but to varying degrees depending on the grass scenario examined. The greatest benefit in terms of N utilization ratio and urine N levels were seen when the WSC content of grass increased at the expense of CP, followed by a 50:50 CP and NDF mix, followed by a trade for NDF. Simulated milk yield decreased slightly when WSC increased at the expense of CP, increased slightly when it increased at the expense of a CP and NDF mix, and increased most when WSC increased at the expense of NDF. Results were amplified slightly under conditions of low-N fertilization and in the absence of grain feeding. Overall, modeling is useful as an explanatory tool. The variation from results in the literature with high-WSC grass feeding may be, at least in part, the result of the level of WSC (g/kg of DM) increase, concurrent changes occurring within the CP and NDF fractions of the plant, and the plane of nutrition of the diet (grain feeding and N fertilization levels).


Phase 1, placebo-controlled, dose escalation trial of chicory root extract in patients with osteoarthritis of the hip or knee.
Extracts of chicory root have anti-inflammatory properties in vitro and in animal models of arthritis. The primary objective of this investigator-initiated, Phase 1, placebo-controlled, double blind, dose-escalating trial was to determine the safety and tolerability of a proprietary bioactive extract of chicory root in patients with osteoarthritis (OA). Secondary objectives were to assess effects on the signs and symptoms of this disorder. Individuals greater than 50 years of age with OA of the hip or knee were eligible for trial entry. A total of 40 patients were enrolled in 3 cohorts and were treated with escalating chicory doses of 600 mg/day, 1200 mg/day and 1800 mg/day for 1 month. The ratio of active treatment to placebo was 5:3 in cohorts 1 and 2 (8 patients) each and 16:8 in cohort 3 (24 patients). Safety evaluations included measurement of vital signs and routine lab tests at baseline and the end of the treatment period. Efficacy evaluations at baseline and final visits included self-assessment questionnaires and measurement of the 25-foot walking time. In the highest dose cohort, 18 patients who completed treatment per protocol were analyzed for efficacy. In this group, 13 patients showed at least 20% improvement in the defined response domains of pain, stiffness and global assessment: 9 of 10 (90%) patients randomized to active treatment with chicory and 4 of 8 (50%) patients randomized to placebo (P = 0.06). In general, the treatment was well-tolerated. Only one patient who was treated with the highest dose of chicory had to discontinue treatment due to an adverse event. The results of this pilot study suggest that a proprietary bioactive extract of chicory root has a potential role in the management of OA and merits further investigation. Clinicaltrials.gov identifier: NCT 01010919.


Cardiovascular fitness modifies the associations between physical activity and abdominal adiposity in children and adolescents: the European Youth Heart Study.
To examine the associations between physical activity (PA) and abdominal adiposity, as measured by waist circumference, in children and adolescents, and to test whether cardiovascular fitness (CVF) modifies these associations. PA components were measured by accelerometry in 1075 individuals aged 9 or 15 years old. CVF was measured by a maximal cycling test. Self-reported maternal educational level, body mass index, children's birth weight and television viewing were used as confounders. Linear regression did not show any association between the PA variables and waist circumference, after controlling for sex, age and height. When stratifying by CVF level (low/high), time spent at vigorous PA was inversely associated with waist circumference (p < or = 0.05) in the low CVF group. Unexpectedly, in the high CVF group, the PA variables were positively associated with waist circumference (p < or = 0.05). In both groups, the results were unchanged after controlling for the confounders. CVF was inversely associated with waist circumference, after controlling for all PA variables (p < or = 0.01) and confounders (p < or = 0.01). CVF is inversely associated with abdominal adiposity and seems to modify the associations between PA and abdominal adiposity. In low-fit children and adolescents, time spent in vigorous PA seems to be the key component linked to abdominal adiposity. This finding should be considered in further development of lifestyle intervention strategies. The results found in the high-fit group need to be confirmed.


Pharmacogenetics in neuropsychiatric diseases: epilepsy as a model.
Individual drug responses are the result of interactions of multiple environmental and genetic factors. Pharmacogenetics studies the influence of genetic variation on interindividual differences in drug efficacy, adverse events and dosing. This article discusses general strategies for candidate gene selection and pharmacogenetic association studies. A summary of the major pharmacogenetic associations reported in neuropsychiatric disease is presented. The example of epilepsy pharmacogenetics will be covered in more detail, including an overview of epilepsy pharmacogenetic candidate genes and results of association studies reported so far. With the advent of large-scale, rigorously designed association studies, it is hoped that genetic factors will be identified that will lead to a targeted, more efficacious and safer treatment, and perhaps to the development of new and more efficacious drugs for neuropsychiatric diseases.


Octree rasterization: accelerating high-quality out-of-core GPU volume rendering.
We present a novel approach for GPU-based high-quality volume rendering of large out-of-core volume data. By focusing on the locations and costs of ray traversal, we are able to significantly reduce the rendering time over traditional algorithms. We store a volume in an octree (of bricks); in addition, every brick is further split into regular macrocells. Our solutions move the branch-intensive accelerating structure traversal out of the GPU raycasting loop and introduce an efficient empty-space culling method by rasterizing the proxy geometry of a view-dependent cut of the octree nodes. This rasterization pass can capture all of the bricks that the ray penetrates in a per-pixel list. Since the per-pixel list is captured in a front-to-back order, our raycasting pass needs only to cast rays inside the tighter ray segments. As a result, we achieve two levels of empty space skipping: the brick level and the macrocell level. During evaluation and testing, this technique achieved 2 to 4 times faster rendering speed than a current state-of-the-art algorithm across a variety of data sets.


Glaucoma Mini-Shunt Implantation After Keratoplasty.
To report the outcomes of patients who underwent miniature glaucoma shunt implantation after secondary glaucoma due to keratoplasty. Prospective study of consecutive clinical cases who underwent mini-glaucoma shunt implantation following keratoplasty. In brief, a fornix-based conjunctival flap was performed, approximately 50% thickness scleral flap. Mitomycin C 0.025% placed under Tenon's capsule. A 25-G needle created entry for mini-shunt. Ex-PRESS model P-50 was inserted. Scleral flap and conjunctiva were closed with 10-0 Nylon. STATA 8.0 and SPSS software were used for statistical analysis. Seventeen eyes of 17 patients with a mean age of 39.70 years (SD=18.33, range: 18 to 76). A total of 64.70% were male and 35.30% female. Eleven cases after penetrating keratoplasty, 3 cases after triple procedure, 2 after deep anterior lamellar keratoplasty, and 1 following endothelial keratoplasty. Most of the indications for keratoplasty were keratoconus in 9 cases (52.94%), 4 due to endothelial failure (23.52%), 3 cases of herpetic keratitis (17.64%), and 1 case of post-LASIK ectasia (5.88%). Mean preoperative intraocular pressure was 35.94 mm Hg with maximal medical therapy (SD=9.65, range: 18 to 55). Decreasing intraocular pressure to 12.76 mm Hg postoperatively (SD=2.51, range 10 to 18) (P=0.001). Mean follow-up after mini-glaucoma shunt implantation was 23.76 months (SD=8.73, range: 10 to 35 mo). Preoperative mean uncorrected distance visual acuity (UDVA) was 1.31±0.63 (20/408 Snellen) and postoperative mean UDVA was 0.85±0.40 (20/141 Snellen) (P=0.001). Preoperative mean corrected distance visual acuity (CDVA) was 0.83±0.76 (20/135 Snellen) and postoperative mean CDVA was 0.56±0.44 (20/72 Snellen) (P=0.032). Ex-PRESS miniature glaucoma shunt could be an alternative treatment in postkeratoplasty glaucoma resistant to medical treatment. This technique may be helpful, in trying to avoid corneal damage produced by conventional glaucoma procedures.


Exploring potential mechanisms responsible for observed changes of ultrasonic backscattered energy with temperature variations.
Previous studies have provided the observation that the ultrasonic backscattered energy from a tissue region will change due to a change of temperature. The mechanism responsible for the changes in backscattered energy (CBE) with temperature has been hypothesized to be from the changes in scattering properties of local aqueous and lipid scatterers. An alternative mechanism is hypothesized here to be capable of producing similar CBE curves, i.e., changes in speckle resulting from changes in summation of scattered wavelets. Both simulations and experiments were conducted with a 5.5 MHz, 128-element linear array and synthetic and physical phantoms containing randomly spaced scatterers. The speckle pattern resulting from summation of scattered wavelets was changed in simulations and experiments by directly increasing the background sound speed from 1520 to 1540 m/s, and changing the temperature from 37 °C to 48 °C, respectively. Shifts in the backscattered signal were compensated using 2D cross-correlation techniques. Excellent agreement between simulations and experiments was observed, with each pixel in the CBE images on average undergoing either a monotonic increase (up to 3.2 dB) or a monotonic decrease (down to -1.9 dB) with increasing sound speed or temperature. Similar CBE curves were also produced by shifting the image plane in the elevational and axial directions even after correcting for apparent motion. CBE curves were produced by changing the sound speed or temperature in tissue mimicking phantoms or by shifting the image plane in the elevational and axial directions and the production of these CBE curves did not require the presence of lipid and aqueous scatterers.


Glucose-related dissociation between icaADBC transcription and biofilm expression by Staphylococcus epidermidis: evidence for an additional factor required for polysaccharide intercellular adhesin synthesis.
Biofilm formation in Staphylococcus epidermidis depends, in the majority of the strains, on the activity of the icaADBC locus. The expression of the operon that encodes the synthetic enzymes of the intercellular polysaccharide adhesin (PIA) depends on a variety of exogenic environmental conditions and is, at least in part, regulated by the alternative sigma factor sigma(B). We investigated the transcriptional regulation of the ica operon and the respective phenotypes expressed under growth conditions differing in the content of glucose in the growth medium. In the presence of glucose, S. epidermidis exhibited a PIA- and biofilm-positive phenotype whereas ica transcription was down-regulated in the postexponential and stationary phases of growth. Surprisingly, maximum transcription of ica was detectable in the stationary phase of growth in the absence of glucose despite the expression of a PIA- and biofilm-negative phenotype. In vitro enzymatic assays and phenotypic characterization showed that the abundant amount of ica mRNA was functionally active because induction of stationary-phase cells with glucose led to immediate PIA synthesis. Induction of biofilm formation could be completely inhibited by chloramphenicol, which, given at a later stage of biofilm accumulation, also inhibited further development of preformed biofilm, indicating that continuous translation of an additional, icaADBC-independent factor is required for the expression of a biofilm-positive phenotype.


A patienthood that transcends the patient: An analysis of patient research partners' narratives of involvement in a Canadian arthritis patient advisory board.
Incorporating the perspectives of patients and public into the conduct of research has the potential to make scientific research more democratic. This paper explores how being a patient partner on an arthritis patient advisory board shapes the patienthood of a person living with arthritis. An analysis was undertaken of the narratives of 22 patient research partners interviewed about their experiences on the Arthritis Patient Advisory Board (APAB), based in Vancouver, Canada. Participants' motivations to become involved in APAB stemmed largely from their desire to change their relationship with their condition. APAB was a living collective project in which participants invested their hope, both for their own lives as patients and for others with the disease. Our findings highlight how the journeys of patient partners connect and integrate seemingly disparate conceptions of what it means to be a patient. One's experience as a clinical 'patient' transforms into the broader notion of civic patienthood.


Does influenza vaccination status change physician ordering patterns for respiratory viral panels? Inspection for selection bias.
Hospitalized patients with an acute respiratory illness (ARI) were compared to determine if demographic characteristics, timing or influenza vaccination biased who received clinical respiratory viral panel (RVP) testing. 171 enrollees in an influenza vaccine effectiveness study and a sample of non-enrollees (N = 1029) admitted to a community hospital with ARI during December 2015 through April 2016 comprised the study sample. Those who received clinical RVP testing (n = 292) were compared to those who did not by age, sex, influenza vaccination status, and period (pre-peak influenza season vs. peak/post peak influenza season), using Chi square- and t-tests, and logistic regression. Mean age of participants was 70 years, 58% was female and 45% had been vaccinated against influenza in the 2015-2016 season. Those with clinical RVP testing were significantly younger (67 years) than those without RVP (71 years; P < 0.001), but did not differ with respect to sex or vaccination status. The odds of clinical RVP testing were significantly (P = 0.004) related to younger age (< 65 years) (Odds ratio (OR) = 1.51; 95% CI = 1.14-2.00) and to later period (peak/post peak influenza season; OR = 2.64; 95% CI = 1.84-3.79) but were unrelated to influenza vaccination status or the interaction of time and vaccination status. RVP testing was significantly higher among younger hospitalized patients with an ARI and during the peak and post peak influenza periods than earlier in the season, but influenza vaccination status was not a significant factor. Studies that enroll based on clinical RVP testing should account for potential differences by age.


[Alzheimer's disease and informed consent of incapacitated people: propositions aimed at improving the procedure].
Ethical considerations must be given priority when deciding whether or not to include an Alzheimer's Disease patient in a study leading to direct individual benefits. Although the law applies to ethics, the Huriet-Serusclat law was nevertheless written in the spirit of the major ethical declarations of the last 50 years (Nurenberg, Helsinki, Tokyo...) in order to protect patients from abusive decisions, whether these decisions were for or against the patient receiving treatment. This paper describes an incident during a phase II trial involving patients with Alzheimer's Disease. Four incapacitated patients protected by guardianship had given their informed consent to take part in the study. Their participation required that the informed consent be signed by the guardian as well. By misunderstanding of the law, the guardian transmitted the decision to the guardianship judge. Surprisingly, the guardianship judge refused permission for all patients to take part in this therapeutic trial against the wishes of the patients. Even more surprisingly, it appeared clearly that this judge was not thoroughly informed of each detail of the law. Prevention of this kind of situation might require modifications of the responsibilities of the CCPPRB. It is suggested that before the start of a study the CCPPRB should give a precise definition of the way in which incapacitated persons should be treated.


Pediatric Rehabilitation Services for Children With Cerebral Palsy: What Can Existing Data Sources Tell Us?
Knowledge about associated service utilization patterns and positive outcomes in children with cerebral palsy (CP) of varying levels of severity is a national priority. Families, clinicians, program directors, and policy makers need this information for clinical decision-making and service planning. Existing data sources in the United States that contain information about children with CP, their health, function, well being, and utilization of health services may add to our existing knowledge. We provide a summary of fourteen national, state, and local sources' data: where the data come from, challenges and/or specific considerations when using or accessing information, and specific data elements included. Currently available sources of data can provide meaningful information for policy, practice, and program development. We propose questions for future inquiry and suggest elements that may be useful for when developing data sources specific to physical therapy and individuals with CP. A physical therapy specific registry is warranted.


Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer.
Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to epidermal growth factor receptor (EGFR)-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual. Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial. As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.


Human T-cell antigens defined by monoclonal antibodies. Absence of T65 on committed myeloid and erythroid progenitors.
The complement-dependent cytotoxicity of monoclonal T-cell antibody (T101) for normal and abnormal hemopoietic progenitors was assessed. T101 demonstrated toxicity for normal T-colony-forming cells from peripheral blood and bone marrow. Cytotoxicity was absent for normal peripheral blood and bone marrow granulocytes/macrophage (CFU-C) and erythroid (BFU-E) progenitors. The antibody was also not toxic for peripheral blood blast progenitors from patients with acute myelogenous leukemia (AML). These studies indicate the absence of the antigen defined by T101 (T65) from normal progenitor cells and from blast progenitors in patients with AML. T101 may be used in the treatment of T-cell malignancies and in the prevention of graft-versus-host disease (GVHD) without damage to normal progenitor cells.


Mupirocin treatment of nasal staphylococcal colonization.
The effectiveness and safety of mupirocin calcium ointment applied to the anterior part of the nares for 5 days in the eradication of nasal carriage of Staphylococcus aureus was investigated in a placebo-controlled, double-blind study. Subjects were healthy medical center staff who had two positive cultures of the anterior nares for S aureus. Antimicrobial susceptibility, phage typing, and restriction endonuclease analysis of plasmid DNA were used to monitor the identity of relapsing and persisting strains. Mupirocin eliminated 74% of S aureus at early follow-up and 91% of original strains. At 4 weeks, 78% of the original strains were eradicated, whereas all of the placebo group remained colonized. Recolonization with mupirocin-resistant strains occurred in six patients, but these were of different phage and plasmid types from the original isolates. None of the subjects had serious adverse effects. Applied intranasally for 5 days, a calcium preparation of mupirocin in a paraffin base is effective in eliminating S aureus nasal carriage and is well tolerated.