First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.


Physicians' perspectives on communication and decision making in clinical encounters for treatment of latent tuberculosis infection.
The aim of the study was to explore the views of tuberculosis (TB) physicians on treatment of latent TB infection (LTBI), focusing on decision making and communication in clinical practice. 20 Australian TB physicians participated in a semistructured interview in person or over the telephone. Interviews were recorded, transcribed and analysed thematically. The study identified challenges that physicians face when discussing treatment for LTBI with patients. These included difficulties explaining the concept of latency (in particular to patients from culturally and linguistically diverse backgrounds) and providing guidance to patients while still framing treatment decisions as a choice. Tailored estimates of the risk of developing TB and the risk of developing an adverse effect from LTBI treatment were considered the most important information for decision making and discussion with patients. Physicians acknowledged that there is a significant amount of unwarranted treatment variation, which they attributed to the lack of evidence about the risk-benefit balance of LTBI treatment in certain scenarios and guidelines that refer to the need for case-by-case decision making in many instances. In order to successfully implement LTBI treatment at a clinical level, consideration should be given to research on how to best address communication challenges arising in clinical encounters.


Frequency and evaluation of the perceptions towards caesarean section among pregnant women attending public hospitals in Pakistan and the implications.
There is increasing prevalence of caesarean sections (CS) worldwide; however, there are concerns about their rates in some countries, including potential fears among mothers. Consequently, we aimed to determine the frequency of CS, and explore patient's perception towards CS attending public hospitals in Pakistan, to provide future guidance. A two-phased study design (retrospective and cross sectional) was adopted. A retrospective study was conducted to assess the frequency of CS over one year among four public hospitals. A cross sectional study was subsequently conducted to determine patients' perception towards CS attending the four tertiary care public hospitals in Quetta city, Pakistan, which is where most births take place. Overall prevalence of CS was 13.1% across the four hospitals. 728 patients were approached and 717 responded to the survey. Although 78.8% perceived CS as dangerous, influenced by education (p = 0.004), locality (p = 0.001) and employment status (p = 0.001), 74.5% of patients were in agreement that this is the best approach to save mother's and baby's lives if needed. 62% of respondents reported they would like to avoid CS if they could due to post-operative pain, and 58.9% preferred a normal delivery. There was also a significant association with education (p = 0.001) and locality (p = 0.001) where respondents considered normal vaginal delivery as painful. The overall frequency of CS approximates to WHO recommendations, although there is appreciable variation among the four hospitals. When it comes to perception towards CS, women had limited information. There is a need to provide mothers with education during the antenatal period, especially those with limited education, to accept CS where needed.


The changes in airways structure associated with reduced forced expiratory volume in one second.
We compared the structure of the membranous and respiratory bronchioles of resected lungs from 111 patients with a normal predicted forced expiratory volume in one second (FEV1) to the structure of these airways from 45 patients with an FEV1 reduced below the 95% confidence limits for height and age. Membranous and respiratory bronchioles of less than 2 mm in internal diameter were counted and their diameter and wall thickness were measured. The data show that there were more membranous bronchioles of internal diameter less than 0.4 mm in patients with reduced FEV1. The wall thickness of respiratory bronchioles was increased in the obstructed group and there was also an increase in the ratio of wall thickness to lumen diameter in these airways. The walls of membranous bronchioles were not increased in thickness but there was an increase in the ratio of wall thickness to lumen diameter. Although the data is consistent with the hypothesis that airways obstruction in patients with chronic obstructive pulmonary disease is due to thickening of the airway wall and narrowing of the airway lumen, we cannot rule out distortion of the membranous bronchioles by loss of elastic recoil.


Prediction of cerebral hyperperfusion syndrome after carotid stenting: a cerebral perfusion computed tomography study.
The objective of this study was to evaluate the role of cerebral perfusion computed tomography (CT) in predicting cerebral hyperperfusion syndrome (CHS) after carotid stenting. This study was approved by the institutional review board, and written informed consent was obtained from all patients. Fifty-five consecutive symptomatic patients with greater than or equal to 70% of cervical carotid artery stenosis who underwent carotid stenting from March 2001 to December 2003 were recruited. Age, sex, stenting side, and degree of cervical carotid stenosis at the stenting and contralateral sides were recorded. Cerebral perfusion CT was performed 1 day before stenting. Absolute values of the cerebral blood volume, mean transit time, and cerebral blood flow were calculated. Relative values based on the comparison between ipsilateral and contralateral hemispheres, that is, relative cerebral blood volume (ipsilateral-to-contralateral ratio), relative cerebral blood flow (ipsilateral-to-contralateral ratio), and absolute difference in mean transit time (dMTT), were derived. The association between occurrence of CHS and parameters of cerebral perfusion CT was investigated by the Mann-Whitney U test. Three (5%) of 55 patients had CHS after carotid stenting. The only significant factor related to the occurrence of CHS was dMTT (P = 0.003). A dMTT value of 3 seconds was considered as a cutoff value to distinguish between the occurrence and absence of CHS. The other clinical or cerebral perfusion CT parameters had no significant correlation with the occurrence of CHS. Our findings suggest that patients with a prolonged dMTT of more than 3 seconds should be closely monitored for evidence of hyperperfusion after undergoing carotid stenting.


Expression of truncated PrP targeted to Purkinje cells of PrP knockout mice causes Purkinje cell death and ataxia.
PrP knockout mice with disruption of only the PrP-encoding region (Zürich I-type) remain healthy, whereas mice with deletions extending upstream of the PrP-encoding exon (Nagasaki-type) suffer Purkinje cell loss and ataxia, associated with ectopic expression of Doppel in brain, particularly in Purkinje cells. The phenotype is abrogated by co-expression of full-length PrP. Doppel is 25% similar to PrP, has the same globular fold, but lacks the flexible N-terminal tail. We now show that in Zürich I-type PrP-null mice, expression of N-terminally truncated PrP targeted to Purkinje cells also leads to Purkinje cell loss and ataxia, which are reversed by PrP. Doppel and truncated PrP probably cause Purkinje cell degeneration by the same mechanism.


Artificial intelligence in the diagnosis and management of arrhythmias.
The field of cardiac electrophysiology (EP) had adopted simple artificial intelligence (AI) methodologies for decades. Recent renewed interest in deep learning techniques has opened new frontiers in electrocardiography analysis including signature identification of diseased states. Artificial intelligence advances coupled with simultaneous rapid growth in computational power, sensor technology, and availability of web-based platforms have seen the rapid growth of AI-aided applications and big data research. Changing lifestyles with an expansion of the concept of internet of things and advancements in telecommunication technology have opened doors to population-based detection of atrial fibrillation in ways, which were previously unimaginable. Artificial intelligence-aided advances in 3D cardiac imaging heralded the concept of virtual hearts and the simulation of cardiac arrhythmias. Robotics, completely non-invasive ablation therapy, and the concept of extended realities show promise to revolutionize the future of EP. In this review, we discuss the impact of AI and recent technological advances in all aspects of arrhythmia care.


Engineering a stable and selective peptide blocker of the Kv1.3 channel in T lymphocytes.
Kv1.3 potassium channels maintain the membrane potential of effector memory (T(EM)) T cells that are important mediators of multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. The polypeptide ShK-170 (ShK-L5), containing an N-terminal phosphotyrosine extension of the Stichodactyla helianthus ShK toxin, is a potent and selective blocker of these channels. However, a stability study of ShK-170 showed minor pH-related hydrolysis and oxidation byproducts that were exacerbated by increasing temperatures. We therefore engineered a series of analogs to minimize the formation of these byproducts. The analog with the greatest stability, ShK-192, contains a nonhydrolyzable phosphotyrosine surrogate, a methionine isostere, and a C-terminal amide. ShK-192 shows the same overall fold as ShK, and there is no evidence of any interaction between the N-terminal adduct and the rest of the peptide. The docking configuration of ShK-192 in Kv1.3 shows the N-terminal para-phosphonophenylalanine group lying at the junction of two channel monomers to form a salt bridge with Lys(411) of the channel. ShK-192 blocks Kv1.3 with an IC(50) of 140 pM and exhibits greater than 100-fold selectivity over closely related channels. After a single subcutaneous injection of 100 microg/kg, approximately 100 to 200 pM concentrations of active peptide is detectable in the blood of Lewis rats 24, 48, and 72 h after the injection. ShK-192 effectively inhibits the proliferation of T(EM) cells and suppresses delayed type hypersensitivity when administered at 10 or 100 microg/kg by subcutaneous injection once daily. ShK-192 has potential as a therapeutic for autoimmune diseases mediated by T(EM) cells.


Percentage of total body fat as estimated by three automatic bioelectrical impedance analyzers.
The present study aimed to compare the accuracy of estimating the percentage of total body fat (%TBF) among three bioelectrical impedance analysis (BIA) devices: a single-frequency BIA with four tactile electrodes (SF-BIA4), a single-frequency BIA with eight tactile electrodes (SF-BIA8) and a multi-frequency BIA with eight tactile electrodes (MF-BIA8). Dual-energy x-ray absorptiometry (DXA) and hydrostatic weighing (HW) were used as references for the measured values. Forty-five healthy college student volunteers (21 males: 172.9 +/- 5.5 cm and 65.8 +/- 9.1 kg and 24 females: 160.7 +/- 6.6 cm, 52.6 +/- 6.2 kg) were the subjects. Correlation coefficients between the BIA measurements and the references were calculated. The standard error of estimation (SEE) was calculated by regression analysis when estimating the reference measures (DXA and HW) from the predictor (SF-BIA4, SF-BIA8 and MF-BIA8). The differences in %TBF between the reference and the predictor, calculated by the reference minus the predictor, were plotted against the %TBF measured by the references. The MF-BIA 8 here showed the highest correspondence to the reference and the least estimation error compared with the other BIA methods. It is considered that there is a limit to directly estimate FFM from a regression equation using impedance, weight, height and age as independent variables, and that %TBF can be more accurately estimated by measuring segmental impedances using eight electrodes and multi-frequency electric currents and then estimating total body water from these impedances.


Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation.
Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft. Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR). Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4+ T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter. Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.


A quantitative nanodiffraction system for ultrahigh vacuum scanning transmission electron microscopy.
Of all the long-lived particles available as probes of condensed matter, and of all the signals available on a modern electron microscope, electron nanodiffraction patterns provide the strongest signal from the smallest volume. The technique is therefore perfectly suited to nanostructural investigations in inorganic chemistry and materials science. The Vacuum Generators HB501S, an ultrahigh vacuum (UHV) variant of the HB501 scanning transmission electron microscope (STEM), with side-entry double-tilt stage, specimen preparation and analysis chamber, three postspecimen lenses, and cold field-emission tip with integral magnetic gun lens, has therefore been modified to optimize nanodiffraction and quantitative convergent beam electron diffraction (QCBED) performance. A one-micrometer grain-size phosphor screen lying on a fiber-optic faceplate atop the instrument is fiber-optically coupled to a 2048 x 2048 charge-coupled device (CCD), 16-bit camera. This arrangement promises to provide much greater sensitivity, larger dynamic range, and a better modulation transfer function (MTF) than conventional single crystal scintillator (YAG) CCD systems, with noticeable absence of cross talk between pixels. The design of the nanodiffraction detector system is discussed, the gain of the detector is measured, the spherical aberration constant of the objective lens is measured by the Ronchigram method, and preliminary results from the modified instrument are shown.


Policymaking in a low-trust state: legitimacy, state capacity, and responses to COVID-19 in Hong Kong.
With indiscriminate geographic and socio-economic reach, COVID-19 has visited destruction of life and livelihoods on a largely unprepared world and can arguably be declared the new millennium's most trying test of state capacity. Governments are facing an urgent mandate to mobilize quickly and comprehensively in response, drawing not only on public resources and coordination capabilities but also on the cooperation and buy-in of civil society. Political and institutional legitimacy are crucial determinants of effective crisis management, and low-trust states lacking such legitimacy suffer a profound disadvantage. Social and economic crises attending the COVID-19 pandemic thus invite scholarly reflection about public attitudes, social leadership, and the role of social and institutional memory in the context of systemic disruption. This article examines Hong Kong as a case where failure to respond effectively could have been expected due to low levels of public trust and political legitimacy, but where, in fact, crisis response was unexpectedly successful. The case exposes underdevelopment in scholarly assumptions about the connections among political legitimacy, societal capacity, and crisis response capabilities. As such, this calls for a more nuanced understanding of how social behaviours and norms are structured and reproduced amidst existential uncertainties and policy ambiguities caused by sudden and convergent crises, and how these can themselves generate resources that bolster societal capacity in the fight against pandemics.


Outbreaks of acute gastroenteritis transmitted by person-to-person contact--United States, 2009-2010.
Approximately 179 million cases of acute gastroenteritis (AGE) occur in the United States each year, and outbreaks of AGE are a substantial public health problem. Although CDC has conducted national surveillance for waterborne and foodborne AGE outbreaks since 1971 and 1973, respectively, no national surveillance existed for AGE outbreaks resulting primarily from person-to-person transmission before implementation of the National Outbreak Reporting System (NORS) in 2009. 2009-2010. NORS is a national surveillance system launched in 2009 to support the reporting of all waterborne outbreaks and enteric disease outbreaks from foodborne, person-to-person, animal contact, environmental, and unknown modes of transmission. State and local public health agencies in the 50 U.S. states, the District of Columbia, five U.S. territories, and three Freely Associated States report these outbreaks to CDC via NORS using a standardized online data entry system. Data are collected on general outbreak characteristics (e.g., dates, number of illnesses, and locations), demographic characteristics of cases (e.g., age and sex), symptoms, case outcomes, and laboratory testing information and results. Only outbreaks reported in NORS with a primary mode of transmission of person-to-person contact are included in this report. During 2009-2010, a total of 2,259 person-to-person AGE outbreaks were reported in NORS from 42 states and the District of Columbia. These outbreaks resulted in 81,491 reported illnesses, 1,339 hospitalizations, and 136 deaths. No etiology was reported in approximately 40% (n = 840) of outbreaks. Of the remaining 1,419 outbreaks with a reported etiology, 1,270 (89%) were either suspected or confirmed to be caused solely by norovirus. Other reported etiologies included Shigella (n = 86), Salmonella (n = 16), Shiga toxin-producing Escherichia coli (STEC) (n = 11), and rotavirus (n = 10). Most (82%) of the 1,723 outbreaks caused by norovirus or an unknown etiology occurred during the winter months, and outbreaks caused by Shigella or another suspected or confirmed etiology most often occurred during the spring or summer months (62%, N = 53 and 60%, N = 38, respectively). A setting was reported for 1,187 (53%) of total outbreaks. Among these reported settings, nursing homes and other long-term-care facilities were most common (80%), followed by childcare centers (6%), hospitals (5%), and schools (5%). NORS provides the first national data on AGE outbreaks spread primarily through person-to-person transmission and describes the frequency of this mode of transmission. Norovirus is the most commonly reported cause of these outbreaks and, on the basis of epidemiologic characteristics, likely accounts for a substantial portion of the reported outbreaks of unknown etiology. In the United States, sporadic and outbreak-associated norovirus causes an estimated 800 deaths and 70,000 hospitalizations annually, which could increase by an additional 50% during epidemic years. During 2009-2010, norovirus outbreaks accounted for the majority of deaths and health-care visits in person-to-person AGE outbreaks reported to NORS. Prevention and control of person-to-person AGE outbreaks depend primarily on appropriate hand hygiene and isolation of ill persons. NORS surveillance data can help identify the etiologic agents, settings, and populations most often involved in AGE outbreaks resulting primarily from person-to-person transmission and guide development of targeted interventions to avert these outbreaks or mitigate the spread of infection. Surveillance for person-to-person AGE outbreaks via NORS also might be important in clarifying the epidemiology and role of certain pathogens (e.g., STEC) that have been traditionally considered foodborne but can also be transmitted person-to-person. As ongoing improvements and enhancements to NORS are introduced, participation in NORS has the potential to increase, allowing for improved estimation of epidemic person-to-person AGE and its relative importance among other modes of transmission.


Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses.
Molecular probes for selective identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying cerebral amyloidoses. Here we report the chemical design of pentameric thiophene derivatives, denoted luminescent conjugated oligothiophenes (LCOs), which could be used for real-time visualization of cerebral protein aggregates in transgenic mouse models of neurodegenerative diseases by multiphoton microscopy. One of the LCOs, p-FTAA, could be utilized for ex vivo spectral assignment of distinct prion deposits from two mouse-adapted prion strains. p-FTAA also revealed staining of transient soluble pre-fibrillar non-thioflavinophilic Abeta-assemblies during in vitro fibrillation of Abeta peptides. In brain tissue samples, Abeta deposits and neurofibrillary tangles (NFTs) were readily identified by a strong fluorescence from p-FTAA and the LCO staining showed complete co-localization with conventional antibodies (6E10 and AT8). In addition, a patchy islet-like staining of individual Abeta plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA. The major hallmarks of Alzheimer's disease, namely, Abeta aggregates versus NFTs, could also be distinguished because of distinct emission spectra from p-FTAA. Overall, we demonstrate that LCOs can be utilized as powerful practical research tools for studying protein aggregation diseases and facilitate the study of amyloid origin, evolution and maturation, Abeta-tau interactions, and pathogenesis both ex vivo and in vivo.


One foot out the door: limb function during swimming in terrestrial versus aquatic turtles.
Specialization for a new habitat often entails a cost to performance in the ancestral habitat. Although aquatic lifestyles are ancestral among extant cryptodiran turtles, multiple lineages, including tortoises (Testudinidae) and emydid box turtles (genus Terrapene), independently specialized for terrestrial habitats. To what extent is swimming function retained in such lineages despite terrestrial specialization? Because tortoises diverged from other turtles over 50 Ma, but box turtles did so only 5 Ma, we hypothesized that swimming kinematics for box turtles would more closely resemble those of aquatic relatives than those of tortoises. To test this prediction, we compared high-speed video of swimming Russian tortoises (Testudo horsfieldii), box turtles (Terrapene carolina) and two semi-aquatic emydid species: sliders (Trachemys scripta) and painted turtles (Chrysemys picta). We identified different kinematic patterns between limbs. In the forelimb, box turtle strokes most resemble those of tortoises; for the hindlimb, box turtles are more similar to semi-aquatic species. Such patterns indicate functional convergence of the forelimb of terrestrial species, whereas the box turtle hindlimb exhibits greater retention of ancestral swimming motions.


Mifepristone: is there a place in the treatment of Cushing's disease?
The purpose was to review the use of mifepristone in the treatment of Cushing's syndrome (CS) in the context of other recently published studies. We review the use of mifepristone, as published in the recent Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing's Syndrome (SEISMIC). We also review the multiple case reports and case series of mifepristone use in CS. A review of other medications used in the treatment of Cushing's disease (CD), including pasireotide and cabergoline also provides context for the discussion of the role of mifepristone in the treatment of CD. The results show that the treatment of CD has been primarily surgical with medical therapy reserved for adjuvant therapy when primary treatment fails or other therapies require time for optimal efficacy. Two recent large prospective studies, using pasireotide and mifepristone provide new clinical insights to the medical treatment of CD in particular. Mifepristone has been used to treat excessive cortisol production by blocking the action of cortisol at the level of the glucocorticoid receptor. Until recently, the majority of clinical experience with mifepristone on the treatment of excess cortisol was derived from case reports and small case series. Based on the SEISMIC study, mifepristone was FDA approved for hyperglycemia associated with CS. In conclusion the role of mifepristone in the treatment of CD remains one of adjuvant therapy. Its place among other choices for medical therapy has yet to be firmly established and an evidenced-based approach toward the use of novel medications in the treatment of CD has not been made. Selection of medication depends on drug approval and availability in individual countries and requires cautious assessment of potential adverse effects, consideration of patient comorbidities, and efficacy.


The effect of Medicare Part D on health care utilization for non-elderly Medicare recipients with disabilities.
The effect of Medicare Part D prescription drug coverage on non-elderly beneficiaries, most of whom have disabilities, has not been fully explored. The objective of this study was to estimate the impact of Medicare Part D on expenditures and utilization of prescription drugs, hospitalizations, physician office visits and emergency department visits in non-elderly Medicare beneficiaries with disabilities. Using Medical Expenditure Panel Survey (MEPS) data from 2005 to 2006, we assembled a cohort of non-elderly Medicare beneficiaries and controls using propensity score matching. We used zero-inflated negative binomial regressions and generalized linear models to examine the effect of Medicare Part D on health care utilization and expenditures, respectively. We controlled for demographic characteristics, census region of residence, and self-reported health status. We were able to match 299 Medicare non-recipients to 299 Medicare recipients. The mean (SD) age was 49.8 (10.7) years for the Medicare non-recipients and 49.9 (10.0) years for Medicare recipients. While the introduction of Medicare Part D was not associated with a significant change in the number of prescriptions consumed by this group of individuals, there was a significant decrease in out-of-pocket prescription drug expenses as well as expenses paid for by Medicaid and private insurance. Our study is the first to examine the impact of Medicare Part D on non-elderly Medicare beneficiaries. We find that the introduction of Medicare Part D did not lead to changes in prescription drug consumption, only in the method of payment.


Why do smokers try to quit without medication or counselling? A qualitative study with ex-smokers.
When tobacco smokers quit, between half and two-thirds quit unassisted: that is, they do not consult their general practitioner (GP), use pharmacotherapy (nicotine-replacement therapy, bupropion or varenicline), or phone a quitline. We sought to understand why smokers quit unassisted. Qualitative grounded theory study (in-depth interviews, theoretical sampling, concurrent data collection and data analysis). 21 Australian adult ex-smokers (aged 28-68 years; 9 males and 12 females) who quit unassisted within the past 6 months to 2 years. 12 participants had previous experience of using assistance to quit; 9 had never previously used assistance. Community, Australia. Along with previously identified barriers to use of cessation assistance (cost, access, lack of awareness or knowledge of assistance, including misperceptions about effectiveness or safety), our study produced new explanations of why smokers quit unassisted: (1) they prioritise lay knowledge gained directly from personal experiences and indirectly from others over professional or theoretical knowledge; (2) their evaluation of the costs and benefits of quitting unassisted versus those of using assistance favours quitting unassisted; (3) they believe quitting is their personal responsibility; and (4) they perceive quitting unassisted to be the 'right' or 'better' choice in terms of how this relates to their own self-identity or self-image. Deep-rooted personal and societal values such as independence, strength, autonomy and self-control appear to be influencing smokers' beliefs and decisions about quitting. The reasons for smokers' rejection of the conventional medical model for smoking cessation are complex and go beyond modifiable or correctable problems relating to misperceptions or treatment barriers. These findings suggest that GPs could recognise and respect smokers' reasons for rejecting assistance, validate and approve their choices, and modify brief interventions to support their preference for quitting unassisted, where preferred. Further research and translation may assist in developing such strategies for use in practice.


Temporal Structure in Haptic Signaling Under a Cooperative Task.
Haptic communication between humans plays an important role in society. Although this form of communication is ubiquitous at all levels of society and of human development, little is known about how synchronized coordination of motion between two persons leads to higher-order cognitive functions used in communication. In this study, we developed a novel experimental paradigm of a coin-collecting task in which participants used their hands to control a rod to jointly collect the coins on the screen. We characterized the haptic interactions between paired participants while they were taking part in a cooperative task. The individual participants first completed this task on their own and then with a randomly assigned partner for the cooperative task. Single participant experiments were used as a baseline to compare results of the paired participants. Forces applied to the rod were translated to four possible haptic states which encode the combination of the haptic interactions. As a next step, pairs of consecutive haptic states were then combined into 16 possible haptic signals which were classified in terms of their temporal patterns using a Tsallis q-exponential function. For paired participants, 80% of the haptic signals could be fit by the Tsallis q-exponential. On the other hand, only 30% of the signals found in the single-participant trials could be fit by the Tsallis q-exponential. This shows a clear difference in the temporal structures of haptic signals when participants are interacting with each other and when they are not. We also found a large difference in the number of haptic signals used by paired participants and singles. Single participants only used 1/4 of the possible haptic signals. Paired participants, on the other hand, used more than half of the possible signals. These results suggest that temporal structures present in haptic communication could be linked to the emergence of language at an evolutionary level.


Evidence for, and predictions from, forward modeling in language production.
Pickering & Garrod (P&G) put forward the interesting idea that language production relies on forward modeling operating at multiple processing levels. The evidence currently available to substantiate this idea mostly concerns sensorimotor processes and not more abstract linguistic levels (e.g., syntax, semantics, phonology). The predictions that follow from the claim seem too general, in their current form, to guide specific empirical tests.


Vascular Epiphytic Medicinal Plants as Sources of Therapeutic Agents: Their Ethnopharmacological Uses, Chemical Composition, and Biological Activities.
This is an extensive review on epiphytic plants that have been used traditionally as medicines. It provides information on 185 epiphytes and their traditional medicinal uses, regions where Indigenous people use the plants, parts of the plants used as medicines and their preparation, and their reported phytochemical properties and pharmacological properties aligned with their traditional uses. These epiphytic medicinal plants are able to produce a range of secondary metabolites, including alkaloids, and a total of 842 phytochemicals have been identified to date. As many as 71 epiphytic medicinal plants were studied for their biological activities, showing promising pharmacological activities, including as anti-inflammatory, antimicrobial, and anticancer agents. There are several species that were not investigated for their activities and are worthy of exploration. These epipythes have the potential to furnish drug lead compounds, especially for treating cancers, and thus warrant indepth investigations.


Intermittent Hypoxic Preconditioning: A Potential New Powerful Strategy for COVID-19 Rehabilitation.
COVID-19 is a highly infectious respiratory virus, which can proliferate by invading the ACE2 receptor of host cells. Clinical studies have found that the virus can cause dyspnea, pneumonia and other cardiopulmonary system damage. In severe cases, it can lead to respiratory failure and even death. Although there are currently no effective drugs or vaccines for the prevention and treatment of COVID-19, the patient's prognosis recovery can be effectively improved by ameliorating the dysfunction of the respiratory system, cardiovascular systems, and immune function. Intermittent hypoxic preconditioning (IHP) as a new non-drug treatment has been applied in the clinical and rehabilitative practice for treating chronic obstructive pulmonary disease (COPD), diabetes, coronary heart disease, heart failure, hypertension, and other diseases. Many clinical studies have confirmed that IHP can improve the cardiopulmonary function of patients and increase the cardiorespiratory fitness and the tolerance of tissues and organs to ischemia. This article introduces the physiological and biochemical functions of IHP and proposes the potential application plan of IHP for the rehabilitation of patients with COVID-19, so as to provide a better prognosis for patients and speed up the recovery of the disease. The aim of this narrative review is to propose possible causes and pathophysiology of COVID-19 based on the mechanisms of the oxidative stress, inflammation, and immune response, and to provide a new, safe and efficacious strategy for the better rehabilitation from COVID-19.


Ciprofloxacin removal via sequential electro-oxidation and enzymatic oxidation.
The combination of electro-oxidation and enzymatic oxidation was tested to evaluate the potency of this system to remove ciprofloxacin (CIP), a fluoroquinolone antibiotic, from water. For the electro-oxidation boron-doped diamond (BDD) and mixed metal oxides anodes were tested, at three current densities (4.42, 17.7 and 35.4 A/cm2). BDD anode at 35.4 A/cm2 exhibited the highest removal efficiency in the shortest time (>90 % removal in 6 min). For the enzymatic oxidation, laccase from Trametes versicolor was chosen. Laccase alone was not able to remove CIP; hence the influence of redox mediators was investigated. The addition of syringaldehyde (SA) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) resulted in enhanced CIP transformation. About 48.9±4.0 % of CIP remained after 4 h of treatment when SA-mediated laccase was applied and 87.8±6.6 % in the case of ABTS-mediated laccase. The coupling of enzymatic oxidation followed by electro-oxidation led to 73 % removal of the antibiotic. Additionally, the antimicrobial activity increased up to its original efficiency after the treatment. The combination of electro-oxidation followed by enzymatic oxidation led to 97-99 % removal of CIP. There was no antimicrobial activity of the solution after the treatment. The tests with wastewater confirmed the efficacy of the system to remove CIP from the complex matrix.


Past-future information bottleneck in dynamical systems.
Biological systems need to process information in real time and must trade off accuracy of presentation and coding costs. Here we operationalize this trade-off and develop an information-theoretic framework that selectively extracts information of the input past that is predictive about the output future, obtaining a generalized eigenvalue problem. Thereby, we unravel the input history in terms of structural phase transitions corresponding to additional dimensions of a state space. We elucidate the relation to canonical correlation analysis and give a numerical example. Altogether, this work relates information-theoretic optimization to the joint problem of system identification and model reduction.


Trace metals: inputs, sedimentation and accumulation in San Vicente Bay, Chile.
The present study deals with sediment dynamics affecting sediment-associated metal distributions in an embayment system experiencing pollution from coastal industries. Sedimentary metal content may originate from diagenetic processes of foundation rock on the bottom, allochthonous minerals from natural sources, and metals from industrial effluents along the coast. The study presents experimental estimations of quantities of metals entering the bay in industrial waste-water, measurements of metal content in particulate material captured in sediment traps, and metals distribution in surface sediments. Quantitative estimations of metals entering the system in industrial effluent showed the relation Pb > or = Zn > Cu > Cr > or = Ni > Cd. That of metals associated with particulate material from traps was Zn > Cr approximately equal to Cu > or = Pb > Ni > Cd and the abundance of metals in sediments was Zn > Cr > Cu > Pb > Ni > Cd. Finally, rates of bottom sediment accumulation are estimated in relation to the time of residence of water in the bay. The experimental data on sedimentation and sediment abundance were consistent with field observations on distribution and accumulation at sites of major sedimentation in this bay.


False-negative fluorine-18 fluorodeoxyglucose positron emission tomography of a malignant peripheral nerve sheath tumor arising from a plexiform neurofibroma in the setting of neurofibromatosis type 1.
Development of malignant peripheral nerve sheath tumors (MPNSTs) is a recognized complication in patients with neurofibromatosis type 1 (NF1). Differentiating benign from malignant lesions can be a difficult clinical problem. Positron emission tomography (PET) is an established method for making this differentiation with a high degree of sensitivity and specificity. There are several reports showing that fluorine-18 fluorodeoxyglucose (FDG) PET is an effective imaging modality for detecting malignant transformation with a sensitivity nearing 100%. There are very few reports of false-negative 18F-FDG PET in a patient with an MPNST. This case report describes a woman with NF1 and a grade 3 MPNST and a negative PET scan. Identification of malignant transformation in NF is a significant clinical challenge. It is important to recognize the potential limitations of 18F-FDG PET in these patients.


Isolation of lambda and YAC clones from defined regions of the rye genome.
A dispersed, rye-specific element has been used to isolate clones of rye origin from wheat plants containing only a single rye chromosome arm or segment. In this way a set of 23 YAC clones has been isolated from the short arm of rye chromosome 1 (1RS). This technique was extended to isolate clones from a small region of 1RS that contains a large number of agronomically important genes. The targeted cloning method allowed the isolation of 26 classes of lambda clones representing about 5% of the region. Ten of the lambda clones could be mapped to segments within this region. A third example of the application of this technique involved the isolation of clones from a very small but fully functional rye chromosome, the midget chromosome. These clones have allowed the confirmation of the origin of the midget from 1RL, and may provide a tool for the isolation of structural elements of cereal chromosomes. This technique allows the identification of clone libraries for any rye chromosome or chromosome arm, since substitution, addition and translocation lines are available for all rye chromosomes. Furthermore, the technique allows isolation of clones derived from segments of the rye genome recombined into wheat. The method is technically simple and both lambda and YAC libraries can be constructed. Synteny between the genomes of the cereals allows region-specific libraries from rye to be used to target regions of the wheat and barley genomes.


Ankle-brachial index and cardiovascular outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.
Peripheral arterial disease increases cardiovascular risk in many patient populations. The risks associated with an abnormal ankle-brachial index (ABI) in patients with type 2 diabetes and stable coronary artery disease have not been well described with respect to thresholds and types of cardiovascular events. We examined 2,368 patients in the BARI 2D trial who underwent ABI assessment at baseline. Death and major cardiovascular events (death, myocardial infarction and stroke) during follow-up (average 4.3 years) were assessed across the ABI spectrum and by categorized ABI: low (≤0.90), normal (0.91-1.3), high (>1.3), or noncompressible. A total of 12,568 person-years were available for mortality analysis. During follow-up, 316 patients died, and 549 had major cardiovascular events. After adjustment for potential confounders, with normal ABI as the referent group, a low ABI conferred an increased risk of death (relative risk [RR] 1.6, CI 1.2-2.2, P = .0005) and major cardiovascular events (RR 1.4, CI 1.1-1.7, P = .004). Patients with a high ABI had similar outcomes as patients with a normal ABI, but risk again increased in patients with a noncompressible ABI with a risk of death (RR 1.9, CI 1.3-2.8, P = .001) and major cardiovascular event (RR 1.5, CI 1.1-2.1, P = .01). In patients with coronary artery disease and type 2 diabetes, ABI screening and identification of ABI abnormalities including a low ABI (<1.0) or noncompressible artery provide incremental prognostic information.


Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes.
Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar UV light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective interactions between UV exposures and nevus and freckling genes remain largely undescribed. We conducted a longitudinal study from ages 6 through 10 years in 477 Colorado children who had annual information collected for sun exposure, sun protection behaviors, and full body skin exams. MC1R and HERC2/OCA2 rs12913832 were genotyped and linear mixed models were used to identify main and interaction effects. All measures of sun exposure (chronic, sunburns, and waterside vacations) contributed to total nevus counts, and cumulative chronic exposure acted as the major driver of nevus development. Waterside vacations strongly increased total nevus counts in children with rs12913832 blue eye color alleles and facial freckling scores in those with MC1R red hair color variants. Sunburns increased the numbers of larger nevi (≥2 mm) in subjects with certain MC1R and rs12913832 genotypes. Complex interactions between different UV exposure profiles and genotype combinations determine nevus numbers and size, and the degree of facial freckling. Our findings emphasize the importance of implementing sun-protective behavior in childhood regardless of genetic make-up, although children with particular genetic variants may benefit from specifically targeted preventive measures to counteract their inherent risk of melanoma. Moreover, we demonstrate, for the first time, that longitudinal studies are a highly powered tool to uncover new gene-environment interactions that increase cancer risk.


Enhancement of cephalosporin C production by cultivation of Cephalosporium acremonium M25 using a mixture of inocula.
To enhance the productivity of Cephalosporin C (CPC) by cultivation of Cephalosporium acremonium M25 using a mixture of inocula. Inoculum age was classified into three stages (early, intermediate and late) by image analysis. A mixture of inocula, according to the inoculum ages, was used for efficient production of CPC in the main culture. The most effective mixing ratio of inocula for CPC production in shake flasks was a 3 : 7 volume ratio of early- and late-stage inocula. This was also the case in a 1.5 l stirred-tank reactor. CPC productivity was enhanced by about 32% and 34% when using an inoculum mixture in the shake flask and 1.5 l stirred-tank reactor, respectively. The morphological characteristics of C. acremonium M25 in the seed culture were quite different according to inoculum age. The compromise of different ages of inoculum showed better production of CPC. The productivity of CPC was enhanced considerably when using mixed inocula. The results of this study can be applied to fungal cultures for efficient production of various metabolites.


Aortic intramural haematoma: pathogenesis, clinical features and imaging evaluation.
Intramural haematoma (IMH) is a localised haemorrhage within the aortic wall. Imaging plays a central role in diagnosing IMH, differentiating it from aortic dissection (AD) and assessing for complications. Imaging is also important for prognostication and to help guide clinical decision making as a number of imaging characteristics have been correlated with increased mortality rates including location, mural thickness and aortic diameter. Multidetector CT is the leading technique for diagnosis and classification of IMH owing to speed of image acquisition, multiplanar capabilities and excellent spatial resolution. MRI is rarely used to investigate the initial presentation of IMH but is frequently used for serial follow-up studies. The clinical outcome of IMH may be favourable, with spontaneous regression over time, or it may be complicated by pericardial tamponade, aortic regurgitation and development of AD. Early surgical management is the treatment of choice for patients with Stanford type A IMH whereas most patients with Stanford type B IMH have a good short-term outcome with aggressive control of hypertension. This article reviews the pathogenesis, clinical features and complications of IMH as well as the role of advanced imaging techniques in its evaluation.


Hepcidin-25 in chronic hemodialysis patients is related to residual kidney function and not to treatment with erythropoiesis stimulating agents.
Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7 ± 13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance.


Four New Species of Paraorygmatobothrium (Eucestoda: Phyllobothriidea) From Sharks of the Gulf of Mexico and the Atlantic Ocean, with Comments on Their Host Specificity.
Four new species of Paraorygmatobothrium are described from carcharhinid shark species from the Gulf of Mexico and the U.S. coast of the northwestern Atlantic Ocean. Paraorygmatobothrium bullardi n. sp. is described from Carcharhinus brevipinna as its type host, and from Carcharhinus acronotus and Carcharhinus limbatus. Paraorygmatobothrium campbelli n. sp. is described from Rhizoprionodon terraenovae. Paraorygmatobothrium deburonae n. sp. is described from Carcharhinus isodon as its type host, as well as from C. brevipinna, C. limbatus, and R. terraenovae. Paraorygmatobothrium mattisi n. sp. is described from R. terraenovae as its type host, and from C. brevipinna and C. limbatus. These 4 species differ from other species of Paraorygmatobothrium and from each other in bothridial microthrix shape, and in various combinations of features such as the total length of the worm, apical sucker size, bothridial musculature, proglottid number, testes number, and genital pore position. Difficulty in differentiating these 4 species from one another, and from other species of Paraorygmatobothrium, points to limitations in the use of morphology alone to recognize species diversity in this genus. A phylogenetic analysis of Paraorygmatobothrium and related genera, based on partial (D1-D3) 28S rDNA sequence data, confirms that the genus is not monophyletic. Genetic distances of COI revealed that sequence divergence between species of Paraorygmatobothrium is generally at least an order of magnitude larger than COI divergence within a species. Patterns of host use for 3 of the new species are consistent with previous findings that point to a lack of host specificity in Paraorygmatobothrium.


Snapping popliteus tendon within an osteochondritis dissecans lesion: an unusual case of lateral knee pain.
The popliteus muscle is an important structure in the posterior knee, coursing from the distal lateral femoral condyle to the posterior tibia, and it initiates knee flexion, protects the lateral meniscus, and resists tibial external rotation. Abnormalities in the lateral femoral condyle may result in impaired tracking of the popliteus tendon over the lateral femoral condyle, causing pain and a snapping sensation. We report a case of a snapping popliteus tendon caused by an osteochondral defect of the lateral femoral condyle. We obtained a thorough medical history, performed a detailed physical examination, and performed diagnostic ultrasonography to accurately diagnose the condition. The patient underwent open popliteus tenotomy and tibial tenodesis with excellent results and full return to activity. Any abnormality of the lateral femoral condyle may predispose patients to snapping popliteus tendon and we believe early diagnosis utilizing ultrasonography imaging and surgical intervention may benefit these patients significantly.


On the thermal effects associated with radiation force imaging of soft tissue.
Several laboratories are investigating the use of acoustic radiation force to image the mechanical properties of tissue. Acoustic Radiation Force Impulse (ARFI) imaging is one approach that uses brief, high-intensity, focused ultrasound pulses to generate radiation force in tissue. This radiation force generates tissue displacements that are tracked using conventional correlation-based ultrasound methods. The tissue response provides a mechanism to discern mechanical properties of the tissue. The acoustic energy that is absorbed by tissue generates radiation force and tissue heating. A finite element methods model of acoustic heating has been developed that models the thermal response of different tissues during short duration radiation force application. The beam sequences and focal configurations used during ARFI imaging are modeled herein; the results of these thermal models can be extended to the heating due to absorption associated with other radiation force-based imaging modalities. ARFI-induced thermal diffusivity patterns are functions of the transducer f-number, the tissue absorption, and the temporal and spatial spacing of adjacent ARFI interrogations. Cooling time constants are on the order of several seconds. Tissue displacement due to thermal expansion is negligible for ARFI imaging. Changes in sound speed due to temperature changes can be appreciable. These thermal models demonstrate that ARFI imaging of soft tissue is safe, although thermal response must be monitored when ARFI beam sequences are being developed.


Advantages of soft subdural implants for the delivery of electrochemical neuromodulation therapies to the spinal cord.
We recently developed soft neural interfaces enabling the delivery of electrical and chemical stimulation to the spinal cord. These stimulations restored locomotion in animal models of paralysis. Soft interfaces can be placed either below or above the dura mater. Theoretically, the subdural location combines many advantages, including increased selectivity of electrical stimulation, lower stimulation thresholds, and targeted chemical stimulation through local drug delivery. However, these advantages have not been documented, nor have their functional impact been studied in silico or in a relevant animal model of neurological disorders using a multimodal neural interface. We characterized the recruitment properties of subdural interfaces using a realistic computational model of the rat spinal cord that included explicit representation of the spinal roots. We then validated and complemented computer simulations with electrophysiological experiments in rats. We additionally performed behavioral experiments in rats that received a lateral spinal cord hemisection and were implanted with a soft interface. In silico and in vivo experiments showed that the subdural location decreased stimulation thresholds compared to the epidural location while retaining high specificity. This feature reduces power consumption and risks of long-term damage in the tissues, thus increasing the clinical safety profile of this approach. The hemisection induced a transient paralysis of the leg ipsilateral to the injury. During this period, the delivery of electrical stimulation restricted to the injured side combined with local chemical modulation enabled coordinated locomotor movements of the paralyzed leg without affecting the non-impaired leg in all tested rats. Electrode properties remained stable over time, while anatomical examinations revealed excellent bio-integration properties. Soft neural interfaces inserted subdurally provide the opportunity to deliver electrical and chemical neuromodulation therapies using a single, bio-compatible and mechanically compliant device that effectively alleviates locomotor deficits after spinal cord injury.


Functional significance of striatal responses during episodic decisions: recovery or goal attainment?
Memory retrieval is typically a goal-directed behavior, and as such, potentially influenced by reinforcement and motivation processes. Although striatal activation is often evident during memory retrieval, its functional significance remains unclear because typical memory paradigms do not control the motivational significance of memory decisions. We used event-related functional magnetic resonance imaging (fMRI) to investigate striatal activation during recognition with and without performance-linked monetary incentives. During initial performance in the absence of incentives, dorsal striatal activation for "Old" memory conclusions nonetheless exceeded that for "New" conclusions regardless of the accuracy of these conclusions. In contrast, subsequent scans paired incentives with either "Old" or "New" conclusions and demonstrated greater activation for whichever judgment was potentially rewarded, both with and without performance feedback. The data demonstrate that striatal activation during recognition judgments does not signal monetary reward receipt, cognitive feedback, or successful episodic retrieval. Instead, it is heavily dependent upon satisfaction of the subjective goals of the observer.


Cognitive Event-Related Potentials in Young Adults With Cerebral Palsy: A Proof-of-Concept Study.
Cerebral palsy (CP) is a movement and posture disorder often accompanied by cognitive difficulties which can be assessed using event-related potentials (ERPs), an often-overlooked tool in this population. Here we describe our assessment protocol, examine its feasibility, and validate the use of single-subject ERP analyses in adolescents and young adults with CP, an analysis approach which recognizes the heterogeneity of the clinical population. This study involved a final sample of 9 adolescents/young adults with CP participating in the "MyStory" study (age range 16-29 years, Mage = 25.0 years; 6 female; Gross Motor Function Classification System level I [n = 4], II [n = 2], III [n = 1], IV [n = 1], and V [n = 1]). ERP components were elicited over medial prefrontal and central cortex (error- and correct-related negativities [ERN/CRN], error-positivity [Pe], N100, P200, N200, P300), as well as those generated over occipital cortex (P100, N170). Group and single-subject ERP statistics were computed for ERPs recorded over both areas. Using recently developed data analysis methods (independent components analysis and robust bootstrapped single-subject statistics), we measured the number of participants demonstrating significant condition differences at the timing of each ERP component of interest. We demonstrate good validity for ERPs recorded during 2 of our 3 tasks eliciting frontal activation (eg, 4 of 6 participants with usable data showed a significant single-subject medial frontal negativity condition difference in a context-switching task) and good validity for ERPs derived from a task engaging occipital regions (eg, 8 of 9 participants each showed a significant N170 face-object condition effect).


Histone-Complexed DNA Fragments Levels are Associated with Coagulopathy, Endothelial Cell Damage, and Increased Mortality after Severe Pediatric Trauma.
The release of damage-associated molecular pattern molecules in the extracellular space secondary to injury has been shown to cause systemic activation of the coagulation system and endothelial cell damage. We hypothesized that pediatric trauma patients with increased levels of histone-complexed DNA fragments (hcDNA) would have evidence of coagulopathy and endothelial damage that would be associated with poor outcomes. We conducted a prospective observational study of 149 pediatric trauma patients and 62 control patients at two level 1 pediatric trauma centers from 2013 to 2016. Blood samples were collected upon arrival and at 24 h, analyzed for hcDNA, coagulation abnormalities, endothelial damage, and clinical outcome. Platelet aggregation was assessed with impedance aggregometry (Multiplate) and coagulation parameters were assessed by measuring prothrombin time ratio in plasma and the use of viscoelastic techniques (Rotational Thromboelastometry) in whole blood. The median age was 8.3 years, the median injury severity score (ISS) was 20, and overall mortality was 10%. Significantly higher levels of hcDNA were found on admission in patients with severe injury (ISS > 25), coagulopathy, and/or abnormal platelet aggregation. Patients with high hcDNA levels also had significant elevations in plasma levels of syndecan-1, suggesting damage to the endothelial glycocalyx. Finally, significantly higher hcDNA levels were found in non-survivors. hcDNA is released following injury and correlates with coagulopathy, endothelial glycocalyx damage, and poor clinical outcome early after severe pediatric trauma. These results indicate that hcDNA may play an important role in development of coagulation abnormalities and endothelial glycocalyx damage in children following trauma.


Epidemiology of hepatitis E virus in the United States: results from the Third National Health and Nutrition Examination Survey, 1988-1994.
Hepatitis E virus (HEV) is prevalent and causes disease worldwide, but its epidemiological profile is only partially understood. We used an enzyme immunoassay to measure anti-HEV immunoglobulin G antibodies in 18,695 serum samples collected in the Third National Health and Nutrition Examination Survey. We calculated estimates of HEV seroprevalence and examined associations with putative risk factors. The seroprevalence of HEV in the civilian noninstitutionalized United States (US) population during the period from 1988 through 1994 was 21.0% (95% confidence interval [CI], 19.0%-22.9%). Among US-born individuals, males, non-Hispanic whites, and individuals residing in the Midwest and/or in metropolitan areas had the highest seroprevalence estimates. Having a pet in the home (odds ratio [OR], 1.19 [95% CI, 1.01-1.40]) and consuming liver or other organ meats more than once per month (OR, 1.38 [95% CI, 1.01-1.88]) were significantly associated with increased odds of HEV seropositivity. Exposure to HEV is common in the US population, although hepatitis E is rarely reported. Having pets and consuming organ meats may play a role in HEV transmission in the United States, but other mechanisms of transmission may also exist. HEV may be considered a possible etiologic agent of acute and chronic hepatitis in US patients reporting no travel history.


SELDI-TOF-MS ProteinChip array profiling of tears from patients with dry eye.
Protein and peptides in tears play an important role in ocular surface diseases. In previous studies, changes have been demonstrated in the electrophoretic protein profiles of patients with dry eye. The purpose of this work was to determine the usefulness of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) ProteinChip Array (Ciphergen Biosystems, Inc., Fremont, CA) technology for the automated analysis of proteins and peptides in tear fluid. Patients with dry eye (DRY, n = 88) and healthy subjects (CTRL, n = 71) were examined. Their tear proteins were analyzed using SELDI-TOF-MS ProteinChip Arrays with three different chromatographic surfaces (CM10 cation exchange, Q10 anion exchange, and H50 reversed-phase) prepared by means of a laboratory liquid-handling robotic workstation. The data were analyzed by multivariate statistical techniques and artificial neural networks, and the most important biomarkers were purified and identified by tandem MS. Complex patterns of tear proteins and peptides were detected. The different chromatographic surfaces revealed the selective enrichment of proteins such as lipocalin and lysozyme. Discriminant analysis demonstrated highly significant changes in the protein profiles in patients with dry eye (P < 0.001). With a seven-peptide multimarker panel, an artificial neural network could differentiate between patients with dry eye and healthy individuals with a specificity and sensitivity of 90%. The identification of biomarkers revealed an increase of inflammatory markers in patients with dry eye and a decrease of some proteins that may have protective functions. The SELDI-TOF-MS technology seems to be ideally suitable for the mass screening of peptides and proteins in tears. This highly sensitive approach dramatically reduces the analysis time and provides protein profiles with great mass accuracy. Thus, it may become a very useful tool in the search for potential biomarkers for diagnosis and new therapeutics in ocular diseases such as dry eye.


Photo-spectroscopy of mixtures of catalyst particles reveals their age and type.
Within a fluid catalytic cracking (FCC) unit, a mixture of catalyst particles that consist of either zeolite Y (FCC-Y) or ZSM-5 (FCC-ZSM-5) is used in order to boost the propylene yield when processing crude oil fractions. Mixtures of differently aged FCC-Y and FCC-ZSM-5 particles circulating in the FCC unit, the so-called equilibrium catalyst (Ecat), are routinely studied to monitor the overall efficiency of the FCC process. In this study, the age of individual catalyst particles is evaluated based upon photographs after selective staining with substituted styrene molecules. The observed color changes are linked to physical properties, such as the micropore volume and catalytic cracking activity data. Furthermore, it has been possible to determine the relative amount of FCC-Y and FCC-ZSM-5 in an artificial series of physical mixtures as well as in an Ecat sample with unknown composition. As a result, a new practical tool is introduced in the field of zeolite catalysis to evaluate FCC catalyst performances on the basis of photo-spectroscopic measurements with an off-the-shelf digital single lens reflex (DSLR) photo-camera with a macro lens. The results also demonstrate that there is an interesting time and cost trade-off between single catalyst particle studies, as performed with e.g. UV-vis, synchrotron-based IR and fluorescence micro-spectroscopy, and many catalyst particle photo-spectroscopy studies, making use of a relatively simple DSLR photo-camera. The latter approach offers clear prospects for the quality control of e.g. FCC catalyst manufacturing plants.


Short-term impacts and value of a periodic no take zone (NTZ) in a community-managed small-scale lobster fishery, Madagascar.
The small-scale lobster fisheries of Madagascar's impoverished southeast coast account for the majority of national catch and export, making a significant contribution to the regional economy. Data suggests catches have declined, likely due to over-exploitation. In response, the community of Sainte Luce has established a locally managed marine area (LMMA) to manage their lobster fishery, including a 13 km2 periodic no take zone (NTZ). Participatory monitoring data were used to assess compliance, identify changes in catch per unit effort (CPUE) associated with the NTZ and consider the short-term value of the NTZ. Compliance is low for measures dictated by national legislation (minimum landing size (MLS), national closed season, prohibition on landing berried females), but may be higher for those designed by the community (NTZ). Upon NTZ opening in July 2015, an estimated 435% increase in catch was observed compared with the mean for the preceding five months, a product of increased effort and significantly higher CPUE. Zero Altered Negative Binomial modelling showed CPUE was significantly higher during the NTZ opening in 2015 and in 2016 when the opening period had been moved. Whilst it is unlikely that tangible ecological benefits have accrued from NTZ operation, there have been important socio-economic effects. Specifically, there was a 33% increase in the price fishers received, a significant effect at the bottom of the value chain. Temporary increases in catch and income acted as a catalyst, engaging neighbouring communities in fishery management, resulting in two additional NTZs. Attention is drawn to the fact that current national legislation may be sub-optimal and should be reviewed. Successful management of the regional fishery will require the state and industry to support communities in adopting community-based management. The NTZ measure considered here may be an effective tool to achieve this.


Asegúrate: An Intervention Program against Cyberbullying Based on Teachers' Commitment and on Design of Its Instructional Materials.
This article presents the impact on cyberbullying of the Asegúrate program. This educational program is based on the theory of normative social behavior, self-regulation skills, and the beliefs held by adolescents and consists in a whole package of strategies and resources to help teachers to include in the ordinary curricula. The evaluation of Asegúrate was carried out with a sample of 4779 students (48.9% girls) in 5th and 6th grade in primary education and compulsory secondary education (M = 12.76; SD = 1.67) through a quasi-experimental methodology, with two measures over time. The instrument used was the European Cyberbullying Intervention Project Questionnaire. The results show that the involvement in cyberbullying as cyber-victim, cyber-aggressor, and cyber-bully-victim increase without intervention, whereas it diminishes when intervention is carried out by the teachers who have received specific training and have used the didactic Asegúrate package. Additionally, the impact of the intervention on the different types of behaviors was analyzed, and the results show that Asegúrate is more effective with some forms than with others. Consequently, the Asegúrate program is effective for decreasing the prevalence of cyberbullying, but some modifications need to be made to impact on all the different forms it can take.


Are language and social communication intact in children with congenital visual impairment at school age?
Development of children with congenital visual impairment (VI) has been associated with vulnerable socio-communicative outcomes often bearing striking similarities to those of sighted children with autism.(1) To date, very little is known about language and social communication in children with VI of normal intelligence. We examined the presentation of language and social communication of 15 children with VI and normal-range verbal intelligence, age 6-12 years, using a standardised language assessment and parental reports of everyday social and communicative behaviours. Their profiles were compared to those of typically developing sighted children of similar age and verbal ability. Compared to their sighted peers, and relative to their own good and potentially superior structural language skills, children with VI showed significantly poorer use of language for social purposes. Pragmatic language weaknesses were a part of a broader socio-communicative profile of difficulties, present in a substantial proportion of these children and consistent with the pattern found in sighted children with autism. There are ongoing socio-communicative and pragmatic language difficulties in children with congenital VI at school age, despite their good intellectual abilities and advanced linguistic skills. Further research is required to unpack the underlying causes and factors maintaining this vulnerability in such children.


Effects of Vitamin D Status and Supplements on Anthropometric and Biochemical Indices in a Clinical Setting: A Retrospective Study.
Obesity and low vitamin D status are linked. It is not clear that weight loss through lifestyle intervention is influenced by vitamin D status. The aim of this study was to investigate the effect of baseline vitamin D status and vitamin D supplementation on weight loss and associated parameters for participants on a weight loss program in a primary care setting. A retrospective analysis of clinical records of patients who underwent an individually tailored weight loss program at a single dietetic clinic in Sydney, Australia. Primary care centers. 205 overweight and obese men and women aged from 18 to 50 years. Patients were referred to a dietetic clinic for a weight loss program. Patients with low serum 25-hydroxyvitamin D (25(OH)D) concentrations at baseline were advised to increase sun exposure and take multivitamins supplemented with 2000 IU or 4000 IU per day of vitamin D3, according to the preference of their primary care physician. Clinical parameters of weight, height, waist circumference, and serum 25(OH)D, as well as blood pressure and fasting lipid profile were collected from both baseline and three-month follow-up consultations. Subjects with sufficient baseline 25(OH)D levels (≥50 nmol/L) experienced significantly greater weight loss (-7.7 ± 5.9 kg vs. -4.2 ± 3.3 kg) and reductions in BMI (-2.6 ± 1.8 kg/m2 vs. -1.5 ± 1.1 kg/m2) and waist circumference (-5.2 ± 3.5 cm vs. -3.1 ± 3.1 cm) as compared with those who were vitamin D insufficient at baseline (p < 0.001 for all). Vitamin D insufficient patients who were supplemented with daily 2000 IU or 4000 IU vitamin D experienced significantly greater decreases in weight (-5.3 ± 3.6 kg vs. -2.3 ± 1.6 kg), BMI (-1.9 ± 1.2 kg/m2 vs. -0.8 ± 0.6 kg/m2) and waist circumference (-4.2 ± 3.4 cm vs. -1.2 ± 1.3 cm) as compared with those not supplemented (p < 0.001 for all). We also observed a greater decrease in low-density lipoprotein (LDL) cholesterol (-0.4 ± 0.5 mmol/L vs. -0.2 ± 0.5 mmol/L) in subjects insufficient at baseline and supplemented as compared with those insufficient at baseline and not supplemented (p < 0.01). In a weight loss setting in a dietetic clinic, adequate vitamin D status at baseline, or achieved at three months through supplementation, was associated with significantly greater improvement of anthropometric measures. The study has implications for the management of vitamin D status in obese or overweight patients undergoing weight loss programs.


Through-the-scope stent for malignant gastric outlet obstruction.
This report is of the technique and results for through-the-scope stent in palliating malignant gastric outlet obstruction for 17 patients. All procedures were done using conscious sedation and fluoroscopy. Enteral Wallstents with a diameter of 20 mm or 22 mm and length 60 mm or 90 mm were used and delivered over a guidewire through an endoscope with an operating channel of at least 3.7 mm. A total of 18 stents were placed. One stent failed to be deployed. One stent migrated and required insertion of a second stent. One patient required repeat endoscopy to stop bleeding from the tumour. Through-the-scope stent relieved obstructive symptoms for 14 (82%) patients. The median dysphagia score improved from 4 to 2 after through-the-scope stent (P=0.001). The median overall survival and hospital-free survival time was 6 weeks (interquartile range, 3-9 weeks) and 4 weeks (interquartile range, 1-7 weeks), respectively. To conclude, through-the-scope stent was safe and feasible, offering an alternative minimal invasive method to palliate obstructive symptoms for patients with inoperable tumours causing gastric outlet obstruction.


Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642).
Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.


The global distribution and population at risk of malaria: past, present, and future.
The aim of this review was to use geographic information systems in combination with historical maps to quantify the anthropogenic impact on the distribution of malaria in the 20th century. The nature of the cartographic record enabled global and regional patterns in the spatial limits of malaria to be investigated at six intervals between 1900 and 2002. Contemporaneous population surfaces also allowed changes in the numbers of people living in areas of malaria risk to be quantified. These data showed that during the past century, despite human activities reducing by half the land area supporting malaria, demographic changes resulted in a 2 billion increase in the total population exposed to malaria risk. Furthermore, stratifying the present day malaria extent by endemicity class and examining regional differences highlighted that nearly 1 billion people are exposed to hypoendemic and mesoendemic malaria in southeast Asia. We further concluded that some distortion in estimates of the regional distribution of malaria burden could have resulted from different methods used to calculate burden in Africa. Crude estimates of the national prevalence of Plasmodium falciparum infection based on endemicity maps corroborate these assertions. Finally, population projections for 2010 were used to investigate the potential effect of future demographic changes. These indicated that although population growth will not substantially change the regional distribution of people at malaria risk, around 400 million births will occur within the boundary of current distribution of malaria by 2010: the date by which the Roll Back Malaria initiative is challenged to halve the world's malaria burden.


Enhanced biofilm solubilization by urea in reverse osmosis membrane systems.
Chemical cleaning is routinely performed in reverse osmosis (RO) plants for the regeneration of RO membranes that suffer from biofouling problems. The potential of urea as a chaotropic agent to enhance the solubilization of biofilm proteins has been reported briefly in the literature. In this paper the efficiency of urea cleaning for RO membrane systems has been compared to conventionally applied acid/alkali treatment. Preliminary assessment confirmed that urea did not damage the RO polyamide membranes and that the membrane cleaning efficiency increased with increasing concentrations of urea and temperature. Accelerated biofilm formation was carried out in membrane fouling simulators which were subsequently cleaned with (i) 0.01M sodium hydroxide (NaOH) and 0.1M hydrochloric acid (HCl) (typically applied in industry), (ii) urea (CO(NH2)2) and hydrochloric acid, or (iii) urea only (1340 g/Lwater). The pressure drop over the flow channel was used to evaluate the efficiency of the applied chemical cleanings. Biomass removal was evaluated by measuring chemical oxygen demand (COD), adenosine triphosphate (ATP), protein, and carbohydrate content from the membrane and spacer surfaces after cleaning. In addition to protein and carbohydrate quantification of the extracellular polymeric substances (EPS), fluorescence excitation-emission matrix (FEEM) spectroscopy was used to distinguish the difference in organic matter of the remaining biomass to assess biofilm solubilization efficacy of the different cleaning agents. Results indicated that two-stage CO(NH2)2/HCl cleaning was as effective as cleaning with NaOH/HCl in terms of restoring the feed channel pressure drop (>70% pressure drop decrease). One-stage cleaning with urea only was not as effective indicating the importance of the second-stage low pH acid cleaning in weakening the biofilm matrix. All three chemical cleaning protocols were equally effective in reducing the concentration of predominant EPS components protein and carbohydrate (>50% reduction in concentrations). However, urea-based cleaning strategies were more effective in solubilizing protein-like matter and tyrosine-containing proteins. Furthermore, ATP measurements showed that biomass inactivation was up to two-fold greater after treatment with urea-based chemical cleanings compared to the conventional acid/alkali treatment. The applicability of urea as an alternative, economical, eco-friendly and effective chemical cleaning agent for the control of biological fouling was successfully demonstrated.


Spatiotemporal control of cell signalling using a light-switchable protein interaction.
Genetically encodable optical reporters, such as green fluorescent protein, have revolutionized the observation and measurement of cellular states. However, the inverse challenge of using light to control precisely cellular behaviour has only recently begun to be addressed; semi-synthetic chromophore-tethered receptors and naturally occurring channel rhodopsins have been used to perturb directly neuronal networks. The difficulty of engineering light-sensitive proteins remains a significant impediment to the optical control of most cell-biological processes. Here we demonstrate the use of a new genetically encoded light-control system based on an optimized, reversible protein-protein interaction from the phytochrome signalling network of Arabidopsis thaliana. Because protein-protein interactions are one of the most general currencies of cellular information, this system can, in principle, be generically used to control diverse functions. Here we show that this system can be used to translocate target proteins precisely and reversibly to the membrane with micrometre spatial resolution and at the second timescale. We show that light-gated translocation of the upstream activators of Rho-family GTPases, which control the actin cytoskeleton, can be used to precisely reshape and direct the cell morphology of mammalian cells. The light-gated protein-protein interaction that has been optimized here should be useful for the design of diverse light-programmable reagents, potentially enabling a new generation of perturbative, quantitative experiments in cell biology.


Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.
Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib(8), Arg(34)) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.


Brief cognitive-behavioral therapy effects on post-treatment suicide attempts in a military sample: results of a randomized clinical trial with 2-year follow-up.
The authors evaluated the effectiveness of brief cognitive-behavioral therapy (CBT) for the prevention of suicide attempts in military personnel. In a randomized controlled trial, active-duty Army soldiers at Fort Carson, Colo., who either attempted suicide or experienced suicidal ideation with intent, were randomly assigned to treatment as usual (N=76) or treatment as usual plus brief CBT (N=76). Assessment of incidence of suicide attempts during the follow-up period was conducted with the Suicide Attempt Self-Injury Interview. Inclusion criteria were the presence of suicidal ideation with intent to die during the past week and/or a suicide attempt within the past month. Soldiers were excluded if they had a medical or psychiatric condition that would prevent informed consent or participation in outpatient treatment, such as active psychosis or mania. To determine treatment efficacy with regard to incidence and time to suicide attempt, survival curve analyses were conducted. Differences in psychiatric symptoms were evaluated using longitudinal random-effects models. From baseline to the 24-month follow-up assessment, eight participants in brief CBT (13.8%) and 18 participants in treatment as usual (40.2%) made at least one suicide attempt (hazard ratio=0.38, 95% CI=0.16-0.87, number needed to treat=3.88), suggesting that soldiers in brief CBT were approximately 60% less likely to make a suicide attempt during follow-up than soldiers in treatment as usual. There were no between-group differences in severity of psychiatric symptoms. Brief CBT was effective in preventing follow-up suicide attempts among active-duty military service members with current suicidal ideation and/or a recent suicide attempt.


Evidence for an association between human resistance to Schistosoma mansoni and high anti-larval IgE levels.
The anti-larval IgE antibody response of adolescents with high or low resistance to infection by Schistosoma mansoni was evaluated before parasitological cure with oxamniquine and over an extended post-treatment period during which the least resistant subjects regained high infections. IgE from most sera, taken at several bleeding times before and after treatment, reacted, on immunoblots, with a large number of antigens (Ag) in schistosomular tegument extract. A family of 120-165-kDa cross-reacting molecules and a 85-kDa Ag were the most prominent Ag. Some of these determinants were shown to be located on the outer tegumental membrane and to be accessible to IgE on living larvae. The comparison of IgE between the two study groups showed that IgE levels were on average six-to eightfold higher (p less than 0.01) in the sera of the most resistant adolescents whereas there was no difference in patterns of Ag recognition between study groups. In contrast to IgE, anti-larval IgG and IgM levels were either similar in both groups or higher in the least resistant subjects when these exhibited high reinfection levels. IgG that competed for the binding of IgE to larval Ag were detected in most sera and their levels were higher in the least resistant group after reinfection. Finally, the treatment had no observable long-lasting effects on the levels and on the specificity of the anti-larval IgE. Altogether, these observations can be taken as evidence supporting a role of IgE in human resistance to infection by S. mansoni.


One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women.
Although soy protein and its isoflavones have been reported to reduce the risk of osteoporosis in peri- and post-menopausal women, most of these studies are of short duration (i.e. six months). The objective of this study was to examine if one year consumption of soy-containing foods (providing 25 g protein and 60 mg isoflavones) exerts beneficial effects on bone in postmenopausal women. Eighty-seven eligible postmenopausal women were randomly assigned to consume soy or control foods daily for one year. Bone mineral density (BMD) and bone mineral content (BMC) of the whole body, lumbar (L1-L4), and total hip were measured using dual energy x-ray absorptiometry at baseline and after one year. Blood and urine markers of bone metabolism were also assessed. Sixty-two subjects completed the one-year long study. Whole body and lumbar BMD and BMC were significantly decreased in both the soy and control groups. However, there were no significant changes in total hip BMD and BMC irrespective of treatment. Both treatments positively affected markers of bone formation as indicated by increased serum bone-specific alkaline phosphatase (BSAP) activity, insulin-like growth factor-I (IGF-I), and osteocalcin (BSAP: 27.8 and 25.8%, IGF-I: 12.8 and 26.3%, osteocalcin: 95.2 and 103.4% for control and soy groups, respectively). Neither of the protein supplements had any effect on urinary deoxypyridinoline excretion, a marker of bone resorption. Our findings suggest that although one year supplementation of 25 g protein per se positively modulated markers of bone formation, this amount of protein was unable to prevent lumbar and whole body bone loss in postmenopausal women.


Microgel film dynamics modulate cell adhesion behavior.
A material's mechanical properties greatly control cell behavior at the cell–substrate interface. In this work, we demonstrate that microgel multilayers have unique elastic and viscoelastic-like properties that can be modulated to produce morphological changes in fibroblasts cultured on the film. Protein adsorption is also examined and the data are contrasted with the number of cells adhered. The dynamic interaction of cell and substrate is only partially explained by conventional understanding of surface–receptor interactions and substrate elasticity. Viscoelasticity, a mechanical property not often considered, plays a significant role at cellular length and time scales for microgel films.


Determinants of systemic venous return and the impact of positive pressure ventilation.
Venous return, i.e., the blood flowing back to the heart, is driven by the pressure difference between mean systemic filling pressure and right atrial pressure (RAP). Besides cardiac function, it is the major determinant of cardiac output. Mean systemic filling pressure is a function of the vascular volume. The concept of venous return has a central role for heart lung interactions and the explanation of shock states. Mechanical ventilation during anaesthesia and critical illness may severely affect venous return by different mechanisms. In the first part of the following article, we will discuss the development of the concept of venous return, its specific components mean systemic and mean circulatory filling pressure (MCFP), RAP and resistance to venous return (RVR). We show how these pressures relate to the volume state of the circulation. Various interpretations and critiques are elucidated. In the second part, we focus on the impact of positive pressure ventilation on venous return and its components, including latest results from latest research.


Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.
Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer's disease (AD). To evaluate in FTD with the major histologies, and compare with AD and controls, neurotransmission indices, as these may help in developing treatment. Post-mortem grey matter from Brodmann Area 21, 9 and 7 of 51 brains was assayed for ten neurochemical parameters indexing neurotransmission. Repeated measures analyses of variance were carried out for each parameter comparing groups (FTD vs AD vs control) at each anatomical site. In FTD only the indices of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, serotonin (5-HT)(1A) and 5-HT(2A) receptors were significantly reduced from control values. Of the ten parameters only 5-HT(1A) receptors showed significant group x site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M(1), N-methyl-D: -aspartate, NMDA, and kainate), choline acetyltransferase (ChAT) activity, 5-HT and 5-hydroxyindoleacetic acid content and 5-HT reuptake site values were not significantly reduced from control values. Only 5-HT, 5-HT reuptake site and ChAT values were significantly higher in FTD than AD. NMDA receptor and ChAT values were significantly reduced from control only in AD. Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and 5-HT concentration, which are inhibitory on pyramidal neurones, were relatively preserved. This could lead to an excess of extraneural 5-HT causing underactivity of surviving pyramidal neurones. Pharmacotherapy with a 5-HT(1A) receptor antagonist may be indicated.


T cell receptor beta chain gene rearrangements in lymphoproliferative disorders of large granular lymphocytes/natural killer cells.
Twelve cases of T gamma LPD (lymphoproliferative disorders of Fc gamma receptor-bearing T cells) involving an expansion of large granular lymphocyte/natural killer (LGL/NK) cells were investigated for the expression of LGL/NK-associated markers and for T beta gene rearrangement. All the cases selected were classified as T gamma LPD on the basis of morphology, function, and phenotype of the circulating cells. 10 to 12 cases displayed clonal rearrangements of the T beta locus and expression of the T3 antigen, whereas the 2 remaining cases displayed the germline configuration of the T beta gene and no expression of the T3 antigen. T8, Mol, B73.1, and N901 antigens were variably expressed among both T beta+T3+ and T beta-T3- T gamma LPD cases. We suggest that individual T gamma LPD cases represent the clonal expansion of cells frozen at different stages of differentiation/activation within an individual hematopoietic LGL/NK lineage.


Pelagic sedimentation of aragonite: its geochemical significance.
The relative importance of the pelagic flux of aragonite, as compared to calcite, to the deep-sea floor has been evaluated by means of a quantitative x-ray diffraction study of samples collected from sediment traps and from an unusually shallow portion of the open Atlantic Ocean (the Rio Grande Rise). The results suggest that the aragonite flux constitutes at least 12 percent of the total flux of calcium carbonate on a worldwide basis. The presence of high-magnesium calcite in several samples suggests that some of the calcareous material falling to the deep-sea floor may be derived from the long-distance transport of debris from shallow-water beenthic organisms as well as from the settling of planktonic remains. This observation supports the contention that 12 percent represents a minimum value. Aragonite and high-magnesium calcite transported laterally from shallow-water regions, upon dissolution during settling into deeper water, may contribute to the neutralization of excess anthropogenic carbon dioxide added to the oceans.