Measuring quality care in localized renal cell cancer: use of appropriate preoperative investigations in a population-based cohort.
Obtaining appropriate preoperative risk-specific staging investigations for localized renal cell carcinoma (rcc) is a recognized quality indicator. The goal of the present work was to determine the use and appropriateness of preoperative investigations in patients undergoing curative surgery for rcc. This population-based retrospective study of patients having surgery for localized rcc recorded the use of preoperative imaging and laboratory investigations within 6 months of surgery. "Appropriate" stage-specific investigations were determined using recognized published guidelines. The study cohort consisted of 544 patients with 72.8% being stage i, 18.4% being stage ii, and 8.8% being stage iii by clinical TNM (2002) criteria. In 61.6%, chest imaging was obtained by chest radiography or computed tomography (ct) within 3 months preoperatively; in 75.6%, such imaging was obtained within 6 months. Abdominal ct imaging was obtained in 97.1% of patients before surgery, with 77.5% of patients receiving such imaging within 3 months of surgery. Complete blood count, electrolytes, and creatinine were measured in 99.1% of patients, but those tests plus other recommended blood tests including calcium, alkaline phosphatase, and liver function were measured in only 17.7%. In this study, most patients received appropriate abdominal imaging, but chest imaging was underutilized in the overall cohort. Despite being recommended, blood tests such as liver function, alkaline phosphatase, and calcium were completed in fewer than 2 of 10 patients. This analysis provides the groundwork for quality improvement initiatives directed to the use of preoperative investigations in localized rcc.


Cryptogenic stroke - How to make sense of a non-diagnostic entity.
Secondary preventive strategies in ischaemic stroke depend on the underlying aetiology. However, approximately one-third of ischaemic strokes remain unexplained, or 'cryptogenic'. There is a wide range of possible underlying causes in cryptogenic stroke, and the best approach to secondary prevention of these may differ. To date, though, the widely accepted and uniform secondary preventive strategy in this group consists of modification of vascular risk factors, and of treatment with a combination of antiplatelet therapy and antihypertensive and lipid-lowering medication. Among the potential causes for cryptogenic stroke are occult atrial fibrillation, patent foramen ovale, atrial cardiopathy, aortic arch atheroma and hypercoagulable states. While it is possible to diagnose these conditions, in individual patients there is often uncertainty over whether they have a directly causative role, are markers of disease, or are innocent bystanders. Similarly, even if the cause is found, the best secondary preventive strategies remain uncertain, which questions the benefit of extensive investigations in a clinical setting. More recently, the concept of "embolic stroke of unknown source (ESUS)" has been introduced, in the hope that anticoagulation may offer better secondary prevention than antiplatelet therapy, but trials so far have been negative. At present, there is little justification for introducing extensive new investigative strategies into the management of patients with cryptogenic stroke. Investigations should be targeted at identifying those high-risk conditions which lead to a change in management. Further investigations need to be tailored individually, according to clinical circumstances. This should include identifying patients for participation in clinical trials, as the significance and best management of many of the potential causes for cryptogenic stroke require further research.


Number of target lesions for EASL and modified RECIST to predict survivals in hepatocellular carcinoma treated with chemoembolization.
To date, most studies about the optimal number of target lesions for enhancement criteria for hepatocellular carcinoma (HCC) have focused on cross-sectional analyses of concordance. We investigated the optimal number of target lesions for European Association for the Study of the Liver (EASL) and modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines in predicting overall survival (OS). We analyzed 254 consecutive treatment-naïve patients with HCC having at least 2 measurable target lesions undergoing transarterial chemoembolization. Kappa values for intermethod agreement of treatment responses were calculated for comparisons between use of maximum of 1, 2, 3, 4, or 5 targets versus use of all target lesions. Prognostic values of radiologic assessments according to number of target lesions for predicting OS were expressed as C-index. By EASL and mRECIST guidelines, κ values between responses assessing the longest 2, 3, 4, or 5 targets and assessing all targets were 0.924, 0.977, 1.000, or 1.000 and 0.907, 0.959, 1.000, or 1.000, respectively, whereas those between responses assessing only one target and assessing all target lesions were 0.723 and 0.666, respectively. C-index when measuring the longest 1, 2, 3, 4, 5, and all targets was similar, ranging from 0.739 to 0.749 for EASL criteria and from 0.750 to 0.759 for mRECIST. From Cox regression analyses, radiologic response from each calculation method showed independently significant effects on OS for both guidelines, regardless of number of target lesions. Prognostic values for predicting OS were similar regardless of number of target lesions. Assessing the 2 largest targets rather than only 1 index lesion could be recommended considering high concordances from cross-sectional analyses.


Modulation of connective tissue metabolism by partially purified human interleukin 1.
We have investigated the relationship between the monokine interleukin 1 (IL-1) and the connective tissue-stimulating activities produced by monocytes such as mononuclear cell factor (MCF). Using almost exclusively human tissue we have monitored a wide range of MCF-like activities through the partial purification of IL-1 by gel filtration and isoelectric focusing. Activities measured include stimulation of chondrocytes to produce prostaglandins, plasminogen activator and proteoglycanase, enhancement of synovial cell proliferation, and stimulation of cartilage resorption, in addition to IL-1 (lymphocyte activating factor) activity. The activities described show the same molecular heterogeneity; the active material has similar potencies in the different systems, and removal of IL-1 activity by pretreatment with phenylglyoxal also results in loss of the connective tissue-stimulating activities. These results show that the factors responsible for this wide range of activities are very closely related to IL-1 and give further evidence in support of the possible involvement of IL-1 in the processes of joint destruction occurring in chronic inflammatory conditions such as rheumatoid arthritis.


Assessing variability of antineoplastic drugs handling practices in clinical settings.
The United States Pharmacopeia (USP) Chapter <800> guidelines will be adopted in the U.S. and Canada in 2019, requiring regular surface sampling for antineoplastic drug (AD) surface contamination as a means of environmental surveillance. USP Chapter <800> does not provide guidance on when and where to sample. Research to support the development of such guidance within a broader sampling strategy is limited. This study was conducted to help address some of the underlying information gaps by identifying surfaces pharmacy and nursing staff are likely to contact, presenting a potential dermal exposure risk. Observations were conducted at one regional and one urban clinic, providing insight into inter- and intra-worker variability and between-clinic differences based on size and patient load. Thirteen surfaces in the compounding pharmacies and 14 surfaces in the patient administration were initially selected for video observations. Following a preliminary assessment to eliminate surfaces that were touched infrequently or not at all, five commonly touched surfaces in the compounding pharmacy areas (vials, syringes, IV lines, IV bags, waste bags) and six commonly touched surfaces in the patient administration area (yellow containment bag, IV bag, IV line, patient port, computer workstation) were assessed further. Variability between healthcare staff and clinics in pharmacy staff was low for both the mean frequency and duration of touch to surfaces. Differences between clinics in frequency of contact among nursing staff in patient administration areas were significant (two-way ANOVA) for five of the six surfaces. Duration of contact was not significantly different except for duration of touching the IV pump. These insights will be used to give guidance in selecting locations for a longitudinal surveillance study and help tailor worker training to reduce exposure risks.


Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian Diabetes and Exercise Study (IDES).
This study aimed to assess the efficacy of an intensive exercise intervention strategy in promoting physical activity (PA) and improving hemoglobin A(1c)(HbA(1c)) level and other modifiable cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM). Of 691 eligible sedentary patients with T2DM and the metabolic syndrome, 606 were enrolled in 22 outpatient diabetes clinics across Italy and randomized by center, age, and diabetes treatment to twice-a-week supervised aerobic and resistance training plus structured exercise counseling (exercise group) vs counseling alone (control group) for 12 months. End points included HbA(1c) level (primary) and other cardiovascular risk factors and coronary heart disease risk scores (secondary). The mean (SD) volume of PA (metabolic equivalent hours per week) was significantly higher (P < .001) in the exercise (total PA [nonsupervised conditioning PA + supervised PA], 20.0 [0.9], and nonsupervised, 12.4 [7.4]) vs control (10.0 [8.7]) group. Compared with the control group, supervised exercise produced significant improvements (mean difference [95% confidence interval]) in physical fitness; HbA(1c) level (-0.30% [-0.49% to -0.10%]; P < .001); systolic (-4.2 mm Hg [-6.9 to -1.6 mm Hg]; P = .002) and diastolic (-1.7 mm Hg [-3.3 to -1.1 mm Hg]; P = .03) blood pressure; high-density lipoprotein (3.7 mg/dL [2.2 to 5.3 mg/dL]; P < .001) and low-density lipoprotein (-9.6 mg/dL [-15.9 to -3.3 mg/dL]; P = .003) cholesterol level; waist circumference (-3.6 cm [-4.4 to -2.9 cm]; P < .001); body mass index; insulin resistance; inflammation; and risk scores. These parameters improved only marginally in controls. This exercise intervention strategy was effective in promoting PA and improving HbA(1c) and cardiovascular risk profile. Conversely, counseling alone, though successful in achieving the currently recommended amount of activity, was of limited efficacy on cardiovascular risk factors, suggesting the need for a larger volume of PA in these high-risk subjects. Trial Registration isrctn.org Identifier: ISRCTN04252749.


Multistability, chaos, and random signal generation in semiconductor superlattices.
Historically, semiconductor superlattices, artificial periodic structures of different semiconductor materials, were invented with the purpose of engineering or manipulating the electronic properties of semiconductor devices. A key application lies in generating radiation sources, amplifiers, and detectors in the "unusual" spectral range of subterahertz and terahertz (0.1-10 THz), which cannot be readily realized using conventional radiation sources, the so-called THz gap. Efforts in the past three decades have demonstrated various nonlinear dynamical behaviors including chaos, suggesting the potential to exploit chaos in semiconductor superlattices as random signal sources (e.g., random number generators) in the THz frequency range. We consider a realistic model of hot electrons in semiconductor superlattice, taking into account the induced space charge field. Through a systematic exploration of the phase space we find that, when the system is subject to an external electrical driving of a single frequency, chaos is typically associated with the occurrence of multistability. That is, for a given parameter setting, while there are initial conditions that lead to chaotic trajectories, simultaneously there are other initial conditions that lead to regular motions. Transition to multistability, i.e., the emergence of multistability with chaos as a system parameter passes through a critical point, is found and argued to be abrupt. Multistability thus presents an obstacle to utilizing the superlattice system as a reliable and robust random signal source. However, we demonstrate that, when an additional driving field of incommensurate frequency is applied, multistability can be eliminated, with chaos representing the only possible asymptotic behavior of the system. In such a case, a random initial condition will lead to a trajectory landing in a chaotic attractor with probability 1, making quasiperiodically driven semiconductor superlattices potentially as a reliable device for random signal generation to fill the THz gap. The interplay among noise, multistability, and chaos is also investigated.


Identification, Molecular Characterization and Alternative Splicing of Three Novel Members of the Canine Kallikrein (Klk)-related Peptidase Family.
Kallikrein-related peptidases (KLKs) comprise a serine protease family with prominent roles in tissue physiology and disease pathogenesis, including cancer. Previously, we have characterized canine Klk4-10 and -14. Herein, we continue our efforts by characterizing three novel members of the canine family, i.e. Klk11-13, and investigating their expression in mammary cancer. Reverse transcription-polymerase chain reaction (RT-PCR) and DNA sequencing were used for investigating the expression and determining the nucleotide sequence of all transcripts identified, respectively. It was demonstrated that (i) unlike other Klks, (CANFA)Klk12 probably possesses a non-AUG translation initiation codon, (ii) all three Klks undergo alternative splicing, with exon 2 and 3 concurrent elimination serving as the most prominent event, (iii) all transcripts identified were detected in both tumor and normal tissues, yet with different frequencies. Having completed this work, Klk15 is the only gene remaining to experimentally resolve the entire canine Klk family. Our data lay sufficient groundwork for validation studies and await further incorporation into genetic/evolutionary studies with translational impact.


Profiles of small non-coding RNAs in Schistosoma japonicum during development.
The gene regulation mechanism along the life cycle of the genus Schistosoma is complex. Small non-coding RNAs (sncRNAs) are essential post transcriptional gene regulation elements that affect gene expression and mRNA stability. Preliminary studies indicated that sncRNAs in schistosomal parasites are generated through different pathways, which are developmentally regulated. However, the data of sncRNAs of schistosomal parasites are still fragmental and a complete expression profile of sncRNAs during the parasite development requires a deep investigation. We employed high-throughput genome-wide transcriptome analytic techniques to explore the dynamic expression of microRNAs (miRNAs) and endogenous siRNAs (endo-siRNAs) of Schistosoma japonicum covering the free-living cercarial stage and all stages in the definitive host. This led us to analyze over 70 million clean reads represented both high and low abundance of the small RNA population. Patterns of differential expression of miRNAs and endo-siRNAs were observed. MiRNAs was twice more than endo-siRNAs in cercariae, but gradually decreased along with the development of the parasite. Both small RNA types were presented in equal aboudance in lung-stage schistosomula, while endo-siRNAs accumulated to 6 times more than miRNAs in adult female worms and hepatic eggs. Further, miRNAs were found mainly derived from genes located in the intergenic regions, while endo-siRNAs were mainly generated from transposable elements (TEs). The expression pattern of TE-siRNAs, as well as the pseudogene-derived siRNAs clustered in mRNAs of cytoskeletal proteins, stress proteins, enzymes related to energy metabolism also revealed distinction throughout different developmental stages. Natural antisense transcripts (NATs)-related siRNAs accounted for minor proportion of the endo-siRNAs which were dominantly expressed in cercariae. Our results represented a comprehensive expression profile of sncRNAs in various developmental stages of S. japonicum with high accuracy and coverage. The data would facilitate a deep understanding of the parasite biology and potential discovery of novel targets for the design of anti-parasite drugs.


The ecotoxicology of nanoparticles and nanomaterials: current status, knowledge gaps, challenges, and future needs.
This paper introduces a special issue on the ecotoxicology and environmental chemistry of nanoparticles (NPs), and nanomaterials (NMs), in the journal Ecotoxicology. There are many types of NMs and the scientific community is making observations on NP ecotoxicity to inform the wider debate about the risks and benefits of these materials. Natural NPs have existed in the environment since the beginning of Earth's history, and natural sources can be found in volcanic dust, most natural waters, soils and sediments. Natural NPs are generated by a wide variety of geological and biological processes, and while there is evidence that some natural NPs can be toxic, organisms have also evolved in an environment containing natural NPs. There are concerns that natural nano-scale process could be influenced by the presence of pollution. Manufactured NPs show some complex colloid and aggregation chemistry, which is likely to be affected by particle shape, size, surface area and surface charge, as well as the adsorption properties of the material. Abiotic factors such as pH, ionic strength, water hardness and the presence of organic matter will alter aggregation chemistry; and are expected to influence toxicity. The physico-chemistry is essential to understanding of the fate and behaviour of NPs in the environment, as well as uptake and distribution within organisms, and the interactions of NPs with other pollutants. Data on biological effects show that NPs can be toxic to bacteria, algae, invertebrates and fish species, as well as mammals. However, much of the ecotoxicological data is limited to species used in regulatory testing and freshwater organism. Data on bacteria, terrestrial species, marine species and higher plants is particularly lacking. Detailed investigations of absorption, distribution, metabolism and excretion (ADME) remain to be performed on species from the major phyla, although there are some data on fish. The environmental risk assessment of NMs could be performed using the existing tiered approach and regulatory framework, but with modifications to methodology including chemical characterisation of the materials being used. There are many challenges ahead, and controversies (e.g., reference substances for ecotoxicology), but knowledge transfer from mammalian toxicology, colloid chemistry, as well as material and geological sciences, will enable ecotoxicology studies to move forward in this new multi-disciplinary field.


Dutch guidance for the treatment of chronic hepatitis C virus infection in a new therapeutic era.
A new era for the treatment of chronic hepatitis C is about to transpire. With the introduction of the first-generation protease inhibitors the efficacy of hepatitis C treatment improved significantly. Since then, the therapeutic agenda has moved further forward with the recent approval of sofosbuvir and the expected approval of agents such as simeprevir and daclatasvir. This paper, developed parallel to the approval of sofosbuvir, is to serve as a guidance for the therapeutic management of chronic hepatitis C. We performed a formal search through PubMed, Web of Science and ClinicalTrials.gov to identify all clinical trials that have been conducted with EMA-approved new agents in hepatitis C; for this version (April 2014) we focused on sofosbuvir. For each disease category, the evidence was reviewed and recommendations are based on GRADE. We identified 11 clinical trials with sofosbuvir and for each disease category recommendations for treatment are made. Not all disease categories were studied extensively and therefore in some cases we were unable to provide recommendations. The recent approval of sofosbuvir will most likely change the therapeutic landscape of chronic hepatitis C. The use of sofosbuvir-containing regimens can shorten the duration of therapy, increase efficacy and result in less side effects, compared with standard of care. The efficacy relative to standard of care needs to be weighed against the increased costs of sofosbuvir. With future approval of the other direct-acting antivirals, the outcome of hepatitis C treatment will likely improve further and this guidance will be updated.


[Depression and apathy in Parkinson disease].
Although Parkinson disease (PD) is primarily a condition of motor symptoms, an increasing amount of research has indicated that non-motor symptoms including cognitive and emotional deficits are observed even in the earliest stage of the disease. Individuals with PD may display various psychiatric and/or behavioural problems, among which depression and apathy are the most prominent symptoms. Prevalence of comorbid depression in PD has reportedly been estimated to be 7-76%. Such marked differences in the prevalence is partially attributable to different diagnostic criteria. It is useful to make a diagnosis according to standardized semi-structured diagnostic interview following DSM-IV or ICD-10. Based on such diagnostic criteria, prevalence of depression may approximate 20-40%. A half of such individuals fulfill the criteria of major depressive disorder while remaining half may be diagnosed as having dysthymia, minor depression or apathy. The second reason contributing to diversity of prevalence of depression in PD is a sampling procedure. Prevalence of depression in PD is much lower in the community-based surveys than those examined recruited patients. The third reason which makes the diagnosis of depression in PD difficult is an approach how to treat ambiguous symptoms. Caution should be paid whether the researcher is taking an inclusive or exclusive approach while they diagnose depression in PD. Concerning apathy in PD, one should be aware that typical apathy syndrome is quite different from depressive mood state. Rather, apathy syndrome is on the opposite side of depression in the sense that the former lacks serious self reproach or feeling of guilty. Neural substrate of apathy is known to include the dorsolateral, medial and orbital frontal cortices, and subcortical structures such as the basal ganglia, thalamus and internal capsule. Future researches are warranted that discriminate neural correlates and/or chemical neurotransmitters between depression and apathy.


Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds.
Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150-500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.


What strategies are effective for exercise adherence in heart failure? A systematic review of controlled studies.
Physical activity is recommended for people with stable heart failure (HF), because it is known to improve quality of life and health outcomes. However, adherence to this recommendation has been poor in many studies. A systematic review was conducted to examine the effectiveness of strategies used to promote exercise adherence in those with HF. The following databases were searched for relevant literature published between January 1980 and December 2010: British Nursing Index; CINAHL; Cochrane Library; Embase; Medline and PsycINFO. Papers with a control group focused on adults with HF that measured exercise or physical activity adherence were included. Nine randomised controlled trials were identified, involving a total of 3,231 patients (range 16-2,331). Six of these studies were informed by specific psychological theories. Positive outcomes occurred in the short-term from interventions using approaches such as exercise prescriptions, goal setting, feedback and problem-solving. However, longer-term maintenance of exercise was less successful. There was some support for interventions underpinned by theoretical frameworks, but more research is required to make clearer recommendations. Addressing self-efficacy in relation to exercise may be a particularly useful area to consider in this respect.


Complementary and alternative medicine therapies for chronic pain.
Pain afflflicts over 50 million people in the US, with 30.7% US adults suffering with chronic pain. Despite advances in therapies, many patients will continue to deal with ongoing symptoms that are not fully addressed by the best conventional medicine has to offer them. The patients frequently turn to therapies outside the usual purview of conventional medicine (herbs, acupuncture, meditation, etc.) called complementary and alternative medicine (CAM). Academic and governmental groups are also starting to incorporate CAM recommendations into chronic pain management strategies. Thus, for any physician who care for patients with chronic pain, having some familiarity with these therapies-including risks and benefits-will be key to helping guide patients in making evidence-based, well informed decisions about whether or not to use such therapies. On the other hand, if a CAM therapy has evidence of both safety and efficacy then not making it available to a patient who is suffering does not meet the need of the patient. We summarize the current evidence of a wide variety of CAM modalities that have potential for helping patients with chronic pain in this article. The triad of chronic pain symptoms, ready access to information on the internet, and growing patient empowerment suggest that CAM therapies will remain a consistent part of the healthcare of patients dealing with chronic pain.


A primitive placoderm sheds light on the origin of the jawed vertebrate face.
Extant vertebrates form two clades, the jawless Cyclostomata (lampreys and hagfishes) and the jawed Gnathostomata (all other vertebrates), with contrasting facial architectures. These arise during development from just a few key differences in the growth patterns of the cranial primordia: notably, the nasal sacs and hypophysis originate from a single placode in cyclostomes but from separate placodes in gnathostomes, and infraoptic ectomesenchyme migrates forward either side of the single placode in cyclostomes but between the placodes in gnathostomes. Fossil stem gnathostomes preserve cranial anatomies rich in landmarks that provide proxies for developmental processes and allow the transition from jawless to jawed vertebrates to be broken down into evolutionary steps. Here we use propagation phase contrast synchrotron microtomography to image the cranial anatomy of the primitive placoderm (jawed stem gnathostome) Romundina, and show that it combines jawed vertebrate architecture with cranial and cerebral proportions resembling those of cyclostomes and the galeaspid (jawless stem gnathostome) Shuyu. This combination seems to be primitive for jawed vertebrates, and suggests a decoupling between ectomesenchymal growth trajectory, ectomesenchymal proliferation, and cerebral shape change during the origin of gnathostomes.


Biallelic variants in YRDC cause a developmental disorder with progeroid features.
The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t6A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient's dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening.


Characterization of unexpected postural changes during robot-assisted gait training in paraplegic patients.
This is a retrospective study. The objectives of this study were to categorize unexpected postural changes (UPCs) during gait training in paraplegic patients with wearable gait-assist robots, to reveal the incidence of the UPC and its time-dependent changes during initial gait training period and to investigate neurological level-specific differences. This study was conducted in Fujita Health University, Aichi, Japan. We investigated five patients (46.2±14.6 years; lesion level: T6:3, T12:2). All patients had previously achieved gait with wearable robot and walker at supervision level. The UPCs were counted for 2 years and classified according to their type. The time-course data were calculated from the incidence of UPCs for 10 days from initial gait training with the walker. The neurological level-specific differences were investigated between T6 and T12 injuries. Eighty-five UPCs were observed and classified into three categories: anterior breakdown, posterior breakdown (PBD) and mal-timing. The average rate over the entire period was 0.96±0.62 (incidents/h/subject). PBD, which was defined as hyperflexion of both hip joints, occurred with the highest frequency (0.64±0.64 incidents/h/subject). During initial gait training, there was a gradual decrease in the occurrence of UPC. For neurological level-specific differences, UPCs were observed more frequently in T6 injuries (1.36±0.35 incidents/h/subject) compared with T12 injuries (0.36±0.31 incidents/h/subject). PBDs might be the result of near collisions between the trunk of the user and the walker, which make it difficult for the users to move their trunk over an anterior stance limb. Training that is focused upon well-timed forward movements of the walker might be required to avoid the occurrence of this common UPC.


Perceptual teleology: expectations of action efficiency bias social perception.
Primates interpret conspecific behaviour as goal-directed and expect others to achieve goals by the most efficient means possible. While this teleological stance is prominent in evolutionary and developmental theories of social cognition, little is known about the underlying mechanisms. In predictive models of social cognition, a perceptual prediction of an ideal efficient trajectory would be generated from prior knowledge against which the observed action is evaluated, distorting the perception of unexpected inefficient actions. To test this, participants observed an actor reach for an object with a straight or arched trajectory on a touch screen. The actions were made efficient or inefficient by adding or removing an obstructing object. The action disappeared mid-trajectory and participants touched the last seen screen position of the hand. Judgements of inefficient actions were biased towards the efficient prediction (straight trajectories upward to avoid the obstruction, arched trajectories downward towards the target). These corrections increased when the obstruction's presence/absence was explicitly acknowledged, and when the efficient trajectory was explicitly predicted. Additional supplementary experiments demonstrated that these biases occur during ongoing visual perception and/or immediately after motion offset. The teleological stance is at least partly perceptual, providing an ideal reference trajectory against which actual behaviour is evaluated.


Signaling via major histocompatibility complex class II molecules and antigen receptors enhances the B cell response to gp39/CD40 ligand.
Activated T cells induce proliferation and differentiation of resting B cells in vitro through their CD40 molecules and lymphokine receptors. However, despite constitutive B cell expression of CD40 and lymphokine receptors, widespread nonspecific polyclonal B cell activation by activated T cells is seldom observed in vivo. The present study was designed to test the hypothesis that signals delivered via the B cell antigen (Ag) receptor (membrane immunoglobulin, mIg) and major histocompatibility complex (MHC) class II molecules enhance B cell responsiveness to CD40-mediated signals, providing specificity to the Ag-nonspecific, MHC-unrestricted CD40 signal. To test this hypothesis, both an Ag-specific mouse B cell clone CH12.LX, and freshly isolated resting splenic B cells were cultured with either soluble or membrane-bound forms of the T cell ligand for CD40 (CD40L), in the presence or absence of additional signals provided by Ag or anti-IgM, interleukin-4, and class II-specific monoclonal antibody (mAb). Differentiation of CH12.LX cells and proliferation of splenic B cells in response to both forms of CD40L was greatly enhanced by exposure to mIg-mediated signals, with greatest enhancement seen when cells were cultured with Ag prior to receiving other signals. Response to CD40L was further enhanced by concurrent culture with class II-specific, but not class I-specific mAb. Enhancement was greatest at limiting concentrations of CD40L. The ability of class II MHC-mediated signals to enhance Ag-specific B cell responsiveness to CD40-mediated signaling may selectively promote the activation of B cell clones capable of cognate interactions with helper T cells.


Edentulism among Mexican adults aged 35 years and older and associated factors.
We used National Performance Evaluation Survey data to estimate the prevalence and associated factors of edentulism among noninstitutionalized adults aged 35 years and older in Mexico. Statistically, the variables positively associated with edentulism were older age (odds ratio [OR]=1.08) and female gender (OR=1.79). Nonsmoking status (OR=0.70) and having a higher wealth index score (OR=0.72) were negatively associated. This information constitutes the first large-scale evaluation in Mexico for one of the World Health Organization's priority oral health problems.


Periprandial systemic and regional lipase activity in normal humans.
An assay for plasma lipoprotein lipase activity was used without prior injection of heparin to study arteriovenous differences of lipases across skeletal muscle and adipose tissue of normal male volunteers. Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities and triglyceride?concentrations were measured in arterial plasma and in venous effluent plasma from forearm skeletal muscle and subcutaneous abdominal adipose tissue, in the postabsorptive state and after a mixed meal. Triglyceride clearance by the tissues was greater across adipose tissue than across muscle. There were no arteriovenous differences for HTGL activity. In the postabsorptive state skeletal muscle released LPL activity, but adipose tissue did not. Postprandially the arterial LPL and HTGL activities did not change. LPL activity in adipose tissue venous effluent rose, whereas that in muscle venous effluent decreased. These results show that the release of LPL from subcutaneous adipose and forearm tissues is regulated differently, reflecting in vivo differences in LPL regulation at the tissue level.


Imaging correlates of pathology in corticobasal syndrome.
Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS. This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls. All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD. Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology.


An evaluation of a coagulation system (Xprecia Stride) for utilisation in anticoagulation management.
To evaluate the reliability and performance of the Xprecia Stride coagulometer under the conditions in which it is most likely to be used. The performance of the Xprecia Stride coagulometer was compared with a local laboratory and the CoaguChek systems routinely used for international normalised ratio (INR) estimation within one primary and one secondary care based anticoagulation clinic in Birmingham. Anticoagulation clinic personnel were trained to use the Xprecia Stride. Patients attending the clinics were eligible if aged ≥18 years and had received warfarin for at least 3 months. Consenting participants provided capillary blood samples for parallel testing on the Xprecia Stride and CoaguChek systems. At the secondary care clinic, a venous blood sample was also collected for laboratory INR estimation. INR results were compared using linear regression analysis and Bland-Altman plots. A total of 102 laboratory and 205 parallel coagulometer INR tests were performed. Linear regression revealed strong correlation between the Xprecia Stride and the laboratory (r=0.83) and between the Xprecia Stride and CoaguChek systems (r=0.92). Within the therapeutic range, agreement between the systems was very good with 87% of the Xprecia Stride and laboratory INR results and 93% of the Xprecia Stride and CoaguChek INR results being within 0.5 INR units of each other. INRs tested using the Xprecia Stride system showed good agreement with the laboratory and CoaguChek systems. Findings indicate that in the hands of the intended users the Xprecia Stride is accurate, reliable and acceptable for use in a routine clinical setting.


Chemical composition of selected edible nut seeds.
Commercially important edible nut seeds were analyzed for chemical composition and moisture sorption. Moisture (1.47-9.51%), protein (7.50-21.56%), lipid (42.88-66.71%), ash (1.16-3.28%), total soluble sugars (0.55-3.96%), tannins (0.01-0.88%), and phytate (0.15-0.35%) contents varied considerably. Regardless of the seed type, lipids were mainly composed of mono- and polyunsaturated fatty acids (>75% of the total lipids). Fatty acid composition analysis indicated that oleic acid (C18:1) was the main constituent of monounsaturated lipids in all seed samples. With the exception of macadamia, linoleic acid (C18:2) was the major polyunsaturated fatty acid. In the case of walnuts, in addition to linoleic acid (59.79%) linolenic acid (C18:3) also significantly contributed toward the total polyunsaturated lipids. Amino acid composition analyses indicated lysine (Brazil nut, cashew nut, hazelnut, pine nut, and walnut), sulfur amino acids methionine and cysteine (almond), tryptophan (macadamia, pecan), and threonine (peanut) to be the first limiting amino acid as compared to human (2-5 year old) amino acid requirements. The amino acid composition of the seeds was characterized by the dominance of hydrophobic (range = 37.16-44.54%) and acidic (27.95-33.17%) amino acids followed by basic (16.16-21.17%) and hydrophilic (8.48-11.74%) amino acids. Trypsin inhibitory activity, hemagglutinating activity, and proteolytic activity were not detected in the nut seed samples analyzed. Sorption isotherms (Aw range = 0.08-0.97) indicated a narrow range for monolayer water content (11-29 mg/g of dry matter). No visible mold growth was evident on any of the samples stored at Aw < 0.53 and 25 degrees C for 6 months.


Perilipin+ embryonic preadipocytes actively proliferate along growing vasculatures for adipose expansion.
Despite the growing interest in adipose tissue as a therapeutic target of metabolic diseases, the identity of adipocyte precursor cells (preadipocytes) and the formation of adipose tissue during embryonic development are still poorly understood. Here, we clarified the identity and dynamic processes of preadipocytes in mouse white adipose tissue during embryogenesis through direct examination, lineage tracing and culture systems. Surprisingly, we found that lipid-lacking but perilipin(+) or adiponectin(+) proliferating preadipocytes started to emerge at embryonic day 16.5, and these cells underwent active proliferation until birth. Moreover, these preadipocytes resided as clusters and were distributed along growing adipose vasculatures. Importantly, the embryonic preadipocytes exhibited considerable coexpression of stem cell markers, such as CD24, CD29 and PDGFRα, and a small portion of preadipocytes were derived from PDGFRβ(+) mural cells, in contrast to the adult preadipocytes present in the stromal vascular fraction. Further analyses with in vitro and ex vivo culture systems revealed a stepwise but dynamic regulation of preadipocyte formation and differentiation during prenatal adipogenesis. To conclude, we unraveled the identity and characteristics of embryonic preadipocytes, which are crucial for the formation and expansion of adipose tissue during embryogenesis.


Sprint acceleration force-velocity-power characteristics in drafted vs non-drafted junior Australian football players: preliminary results.
This investigation aimed to compare the maximal sprint acceleration profiles of drafted and non-drafted elite junior Australian football (AF) players. Nineteen players (10 drafted and 9 non-drafted) from an elite junior AF state team participated in this study. Instantaneous velocity was measured via radar gun during maximal 30 m sprints. The velocity-time data were analysed to derive individual force-velocity-power characteristics and sprint times. No significant differences existed between groups, however drafted players reached moderately faster maximum velocity (Hedges' g = 0.70 [-0.08; 1.48] and theoretical maximum velocity (g = 0.65 [-0.13; 1.42]) than non-drafted players indicating a superior ability to apply higher amounts of force at increasing sprinting velocity. Further, drafted players produced moderately higher absolute theoretical maximum force (g = 0.72 [-0.06; 1.50]) and absolute maximum power (g = 0.83 [0.04; 1.62]) which reflects their moderately higher body mass (g = 0.61[-0.16;1.38]). Although not significant, in this sample of elite junior AF players, those drafted into the AFL displayed greater absolute sprint acceleration characteristics and maximal velocity capabilities than their non-drafted counterparts (moderate effect size). Whether force-velocity-power characteristics can be more beneficial in differentiating sprint performance of elite junior Australian footballers compared to the traditional sprint time approach warrants further investigation with a larger sample size.


Elevated Temperature Differentially Influences Effector-Triggered Immunity Outputs in Arabidopsis.
Pseudomonas syringae is a Gram-negative bacterium that infects multiple plant species by manipulating cellular processes via injection of type three secreted effectors (T3SEs) into host cells. Nucleotide-binding leucine-rich repeat (NLR) resistance (R) proteins recognize specific T3SEs and trigger a robust immune response, called effector-triggered immunity (ETI), which limits pathogen proliferation and is often associated with localized programmed cell death, known as the hypersensitive response (HR). In this study, we examine the influence of elevated temperature on two ETI outputs: HR and pathogen virulence suppression. We found that in the Arabidopsis thaliana accession Col-0, elevated temperatures suppress the HR, but have minimal influence on ETI-associated P. syringae virulence suppression, thereby uncoupling these two ETI responses. We also identify accessions of Arabidopsis that exhibit impaired P. syringae virulence suppression at elevated temperature, highlighting the natural variation that exists in coping with biotic and abiotic stresses. These results not only reinforce the influence of abiotic factors on plant immunity but also emphasize the importance of carefully documented environmental conditions in studies of plant immunity.


The origin of biased sequence depth in sequence-independent nucleic acid amplification and optimization for efficient massive parallel sequencing.
Sequence Independent Single Primer Amplification is one of the most widely used random amplification approaches in virology for sequencing template preparation. This technique relies on oligonucleotides consisting of a 3' random part used to prime complementary DNA synthesis and a 5' defined tag sequence for subsequent amplification. Recently, this amplification method was combined with next generation sequencing to obtain viral sequences. However, these studies showed a biased distribution of the resulting sequence reads over the analyzed genomes. The aim of this study was to elucidate the mechanisms that lead to biased sequence depth when using random amplification. Avian paramyxovirus type 8 was used as a model RNA virus to investigate these mechanisms. We showed, based on in silico analysis of the sequence depth in relation to GC-content, predicted RNA secondary structure and sequence complementarity to the 3' part of the tag sequence, that the tag sequence has the main contribution to the observed bias in sequence depth. We confirmed this finding experimentally using both fragmented and non-fragmented viral RNAs as well as primers differing in random oligomer length (6 or 12 nucleotides) and in the sequence of the amplification tag. The observed oligonucleotide annealing bias can be reduced by extending the random oligomer sequence and by in silico combining sequence data from SISPA experiments using different 5' defined tag sequences. These findings contribute to the optimization of random nucleic acid amplification protocols that are currently required for downstream applications such as viral metagenomics and microarray analysis.


The Development and Evaluation of a Life Skills Programme for Young Adult Offenders.
The purpose of this research project was to develop, implement, and evaluate a Life Skills programme for young adult male long-term offenders with the aim of improving their life skills that, in turn, could enable them to adjust more effectively in the correctional environment. Experimental research was used to investigate the effectiveness of the programme. In this study, 96 literate young adult male offenders between the ages of 21 and 25 years, with long sentences, were selected randomly. The participants were assigned randomly into an experimental and a control group. The Solomon four-group design was utilized to control for the effect of pretest sensitization. The measurements of the effectiveness of the programme were conducted before the programme commenced, directly (short term) after, 3 months (medium term) after, and 6 months (long term) after. The findings indicated that the programme had limited success in equipping the offenders with the necessary skills crucial to their survival in a correctional centre. The programme did, however, have significant effects, especially on problem solving and anger management in the short and medium term. These improvements were not long lived.


Family process and peer deviance influences on adolescent aggression: longitudinal effects across early and middle adolescence.
Beginning in sixth grade at an average age of 11.9 years, 416 adolescents and their parents participated in 4 waves of data collection involving family observations and multiple-reporter assessments. Ecological theory and the process-person-context-time (PPCT) model guided the hypotheses and analyses. Lagged, growth curve models revealed that family hostility and peer deviance affiliation predicted adolescent aggression in the subsequent year. Family warmth played only a minor role in protecting against adolescent aggression. In hostile or low-warmth families, peer deviance affiliation linked to a declining aggression trajectory consistent with the arena of comfort hypothesis. The longitudinal findings suggest a nonadditive, synergistic interplay between family and peer contexts across time in adding nuance to understanding the adolescent aggression.


Complete subspecies-level phylogeny of the Oriolidae (Aves: Passeriformes): Out of Australasia and return.
Old World orioles (Oriolidae) are medium-sized passerine birds confined largely to forested areas of Africa, Eurasia and Australasia. We present a new complete molecular (mtDNA) subspecies level phylogeny of the Oriolidae including all 113 taxa (35 species) together with a backbone phylogeny of 19 taxa from the main Oriolus clades based on (i) 21 nuclear genes, (ii) whole mito-genomes, and (iii) genome-wide ultraconserved elements. We use this phylogeny to assess systematic relationships and the biogeographical history of this avian family. Furthermore, we use morphological measurements to investigate the relationship between size and shape axes and upstream or back-colonization of this extensive island region from Asia. We show that several subspecies or groups of subspecies may warrant species rank and we find a continental example of two morphologically distinct species (O. mellianus/O. traillii) being genetically (mtDNA) very similar. Biogeographically, we confirm previous findings that members of the Oriolidae originated in Australo-Papua. Dispersal out of this area took place around 15 Mya to southeast Asia and Africa, and from Africa to the Palearctic followed by recolonization of the Indonesian and Philippine island region during the Plio-Pleistocene. Recolonisation of the Indonesian and Philippine islands coincided with an increase in body size, which may have facilitated the ability to co-exist with other congenerics.


Effects of pyrene exposure and temperature on early development of two co-existing Arctic copepods.
Oil exploration is expected to increase in the near future in Western Greenland. At present, effects of exposure to oil compounds on early life-stages of the ecologically important Calanus spp. are unknown. We investigated the effects of the oil compound pyrene, on egg hatching and naupliar development of the calanoid copepods Calanus glacialis and C. finmarchicus, two key species in the Disko Bay, Western Greenland. At low temperature the nauplii of C. glacialis experienced reduced growth when exposed to pyrene, and survival in both species decreased. Naupliar mortality increased with temperature at high pyrene concentration in C. finmarchicus. Both Calanus species were affected by pyrene exposure but C. finmarchicus was more sensitive compared to C. glacialis. Lowered growth rate and increased mortality of the naupliar stages entail reduced recruitment to copepod populations. Exposure to pyrene from an oil spill may reduce the standing stock of Calanus, which can lead to less energy available to higher trophic levels in the Arctic marine food web.


Evolution of the TSC1/TSC2-TOR signaling pathway.
The TSC1/TSC2-TOR signaling pathway [the signaling pathway that includes the heterodimeric TSC1 (tuberous sclerosis 1 protein)-TSC2 (tuberous sclerosis 2 protein) complex and TOR (target of rapamycin)] regulates various cellular processes, including protein synthesis, in response to growth factors and nutrient availability. Homologs of some pathway components have been reported from animals, fungi, plants, and protozoa. These observations led to the perception that the whole pathway is evolutionarily conserved throughout eukaryotes. Using complete genome sequences, we show that, contrary to this view, the pathway was built up from a simpler one, present in the ancestral eukaryote, coupling cell growth to energy supplies. Additional elements, such as TSC1 and TSC2, were "bolted on" in particular eukaryotic lineages. Our results also suggest that unikonts [Opisthokonta (including animals and fungi) and Amoebozoa] form a monophyletic group with the Excavata and Chromalveolata. A previous proposal, that the root of the eukaryotic "tree of life" lies between the unikonts and other organisms, should therefore be reevaluated.


Next Generation Antineoplastic Agents: A Review on Structurally Modified Vinblastine (VBL) Analogues.
Throughout the history of human civilizations, cancer has been a major health problem. Despite the advancements made by modern medical sciences, complete treatment or removal of cancerous cells is still a challenging task. Vinblastine, an alkaloid obtained from Catharanthus roseus (L.) G. Don is one of the prominent antineoplastic agents that is being clinically used. To improve the biological potential and reduce sideeffects of this structurally complex molecule, several related analogues have been reported. The present article reviews recently reported structurally modified vinblastine analogues and its impact on biological activity. We carried out a comprehensive database search on recently reported vinblastine analogues. Both upper (catharanthine) and lower (vindoline) structural units have been considered. The role of functional group modification on anticancer activities has been discussed. In addition, formulations based on vinblastine being considered by NIH, USA for different types of cancers have also been discussed. Around fifty papers were included in the review, including computational and experimental ones. These papers were analysed to discuss the mechanism of action of the parent vinblastine molecule and their analogues. The importance of each functionalities on its anticancer activity have been discussed. This reviewed identified the potential sites of vinblastine core where modification led to improved anticancer activity. Furthermore, several new formulations have also been discussed which are under different phases of clinical trial. The present article highlights the importance of vinblastine in cancer chemotherapy. Literature survey confirms that it is now possible to synthesize new molecules with activity in picomolar range. Not only the periphery of the molecule, the core structure of this magical molecule can be modified to achieve next generation antineoplastic agents.


Optimising medication management for polymedicated home-dwelling older adults with multiple chronic conditions: a mixed-methods study protocol.
Optimal medication management is one of the basic conditions necessary for home-dwelling older adults living with multiple chronic conditions (OAMCC) to be able to remain at home and preserve their quality of life. Currently, the reasons for such high numbers of emergency department visits and the very significant rate of hospitalisations for OAMCC, due to medication-related problems (MRPs), is poorly explored. This study aims to reveal the current state of the medication management practices of polymedicated, home-dwelling OAMCC and to make proposals for improving clinical and medication pathways through an innovative and integrated model for supporting medication management and preventing adverse health outcomes. A mixed-methods study will address the medication management of polymedicated, home-dwelling OAMCC. Its explanatory sequential design will involve two major phases conducted sequentially over time. The quantitative phase will consist of retrospectively exploiting the last 5 years of electronic patient records from a local hospital (N ≈ 50 000) in order to identify the different profiles-made up of patient-related, medication-related and environment-related factors-of the polymedicated, home-dwelling OAMCC at risk of hospitalisation, emergency department visits, hospital readmission (notably for MRPs), institutionalisation or early death. The qualitative study will involve: (a) obtaining and understanding the medication management practices and experiences of the identified profiles extracted from the hospital data of OAMCC who will be interviewed at home (N ≈ 30); (b) collecting and analysing the perspectives of the formal and informal caregivers involved in medication management at home in order to cross-reference perspectives about this important dimension of care at home. Finally, the mixed-methods findings will enable the development of an innovative, integrated model of medication management based on the Agency for Clinical Innovation framework and Bodenheimer and Sinsky's quadruple aim. Ethical approval has been obtained from the Human Research Ethics Committee of the Canton Vaud (2018-02196). Findings will be disseminated in peer-reviewed journals, professional conferences and other knowledge transfer activities with primary healthcare providers, hospital care units, informal caregivers' and patients' associations.


The prevalence of persistence and related health status: An analysis of persistently high healthcare costs in the short term and medium term.
Understanding whether high healthcare costs for individuals persist over time is critical for the development of policies that aim to reduce the prevalence of high cost patients. And while high healthcare costs will occur in any given year based on the prevalence of certain morbidities and acute conditions, a large random component of the distribution means that it is rarely the same people driving the bulk of healthcare expenditures. Using administrative data for over 250,000 Australian residents for the years between 2006 and 2011, we analyse the persistence of high annual healthcare costs. We examine the prevalence of high cost persistence in this sample, and then, we use endogenous switching models to identify the morbidity groups that are related with high cost persistence. These models also measure cases of cost amplification that are associated with a history of high cost healthcare. This analysis uses data from multiple categories of healthcare, specifically medical services, pharmaceuticals and admitted patient care. While there is a relatively low number of patients with persistent high cost (approximately 3% of the sample), this group accounted for 19% of aggregate expenditure. Pharmaceuticals were the most persistently high cost category of healthcare with 5% of the sample accounting for 32% of aggregate pharmaceutical expenditure. The morbidities associated with notable cost amplifications are morbidities that are hard to prevent or involve escalations of adverse health states that are difficult to avert. This casts doubt on whether broad policies can reduce the prevalence of individuals with persistently high healthcare costs.


Spinal alignment in surgical, multisegmental, transpedicular correction of adolescent idiopathic scoliosis.
The objective of this study was to discuss the variables influencing alignment mechanisms of the spine, with particular consideration of post-surgical alignment in adolescent idiopathic scoliosis. The analysis is based on information currently available in the literature, and on the authors' own experience, which includes surgical material from over 2200 cases of idiopathic scoliosis. Over 50% of cases of adolescent idiopathic scoliosis are decompensated before surgical treatment. Spinal alignment is most significantly influenced by the position of the pelvis. Surgical restoration of lumbar lordosis is more important than attempting to restore thoracic kyphosis in the sagittal plane. The sagittal profile has an essential impact on spinal alignment. The same curves in the coronal plane can have various 3-dimensional configurations. Clinical difficulties in the assessment of thoracic kyphosis and lumbar lordosis result from the fact that they undergo constant change with age. Thoracic hypokyphosis diagnosed before surgery is a very frequent symptom of curve progression. The presence of proximal (thoraco-thoracic) and distal (thoraco-lumbar) junctional kyphosis is very important for planning the scope of spondylodesis. The natural tendency of the spine for alignment (compensation) after surgery nowadays occurs more naturally by applying derotational forces through pedicle screws, compared to the distraction devices (eg, Harrington rod) used in the past.


The serum bank of EuroPrevall - the prevalence, cost and basis of food allergy across Europe.
EuroPrevall is an EU-funded multidisciplinary project including 62 institutions from 22 countries. EuroPrevall studies the prevalence and distribution of food allergies in infants, children, adolescents, and adults in Europe, threshold doses for allergenic foods, the role of the environment in food allergy, the socioeconomic impact of food allergy, and novel diagnostic tools for food allergies. The EuroPrevall serum bank (EPASB), containing samples from approximately 70,000 subjects, is a major tool to achieve these goals. EPASB is coordinated by the Paul-Ehrlich-Institut, Langen, Germany. Local sera collections are administered at the University of Amsterdam (NL), the University Hospital of Manchester (UK), Charité Hospital (DE) and the Paul-Ehrlich-Institut. The EPASB coordinator and managing partners distribute samples for experimental work and regulate access. The overall aim is to provide sera to fulfil EuroPrevall research goals. The EPASB coordinator and managing partners suggest appropriate sera for addressing specific scientific and diagnostic questions. The serum bank will be maintained after termination of the project, but subsequent investigations must be in accordance with the original research goals of EuroPrevall. Thus, the contributors of the sera retain control over their future use. This rule prevents investigation of questions outside the scope of EuroPrevall, e.g. the allergenicity of genetically-modified foods.


The Effects of Vehicle Redesign on the Risk of Driver Death.
This study updates a 2006 report that estimated the historical effects of vehicle design changes on driver fatality rates in the United States, separate from the effects of environmental and driver behavior changes during the same period. In addition to extending the period covered by 8 years, this study estimated the effect of design changes by model year and vehicle type. Driver death rates for consecutive model years of vehicle models without design changes were used to estimate the vehicle aging effect and the death rates that would have been expected if the entire fleet had remained unchanged from the 1985 calendar year. These calendar year estimates are taken to be the combined effect of road environment and motorist behavioral changes, with the difference between them and the actual calendar year driver fatality rates reflecting the effect of changes in vehicle design and distribution of vehicle types. The effects of vehicle design changes by model year were estimated for cars, SUVs, and pickups by computing driver death rates for model years 1984-2009 during each of their first 3 full calendar years of exposure and comparing with the expected rates if there had been no design changes. As reported in the 2006 study, had there been no changes in the vehicle fleet, driver death risk would have declined during calendar years 1985-1993 and then slowly increased from 1993 to 2004. The updated results indicate that the gradual increase would have continued through 2006, after which driver fatality rates again would have declined through 2012. Overall, it is estimated that there were 7,700 fewer driver deaths in 2012 than there would have been had vehicle designs not changed. Cars were the first vehicle type whose design safety generally exceeded that of the 1984 model year (starting in model year 1996), followed by SUVs (1998 models) and pickups (2002 models). By the 2009 model year, car driver fatality risk had declined 51% from its high in 1994, pickup driver fatality risk had declined 61% from its high in 1988, and SUV risk had declined 79% from its high in 1988. The risk of driver death in 2009 model passenger vehicles was 8% lower than that in 2008 models and about half that in 1984 models. Changes in vehicles, whether from government regulations and consumer testing that led to advanced safety designs or from other factors such as consumer demand for different sizes and types of vehicles, have been key contributors to the decline in U.S. motor vehicle occupant crash death rates since the mid-1990s. Since the early 1990s, environmental and behavioral risk factors have not shown similar improvement, until the recession of 2007, even though there are many empirically proven countermeasures that have been inadequately applied.


Transcriptome of American oysters, Crassostrea virginica, in response to bacterial challenge: insights into potential mechanisms of disease resistance.
The American oyster Crassostrea virginica, an ecologically and economically important estuarine organism, can suffer high mortalities in areas in the Northeast United States due to Roseovarius Oyster Disease (ROD), caused by the gram-negative bacterial pathogen Roseovarius crassostreae. The goals of this research were to provide insights into: 1) the responses of American oysters to R. crassostreae, and 2) potential mechanisms of resistance or susceptibility to ROD. The responses of oysters to bacterial challenge were characterized by exposing oysters from ROD-resistant and susceptible families to R. crassostreae, followed by high-throughput sequencing of cDNA samples from various timepoints after disease challenge. Sequence data was assembled into a reference transcriptome and analyzed through differential gene expression and functional enrichment to uncover genes and processes potentially involved in responses to ROD in the American oyster. While susceptible oysters experienced constant levels of mortality when challenged with R. crassostreae, resistant oysters showed levels of mortality similar to non-challenged oysters. Oysters exposed to R. crassostreae showed differential expression of transcripts involved in immune recognition, signaling, protease inhibition, detoxification, and apoptosis. Transcripts involved in metabolism were enriched in susceptible oysters, suggesting that bacterial infection places a large metabolic demand on these oysters. Transcripts differentially expressed in resistant oysters in response to infection included the immune modulators IL-17 and arginase, as well as several genes involved in extracellular matrix remodeling. The identification of potential genes and processes responsible for defense against R. crassostreae in the American oyster provides insights into potential mechanisms of disease resistance.


Universal background checks for handgun purchases can reduce homicide rates of African Americans.
Federal law requires background checks for firearms purchased from licensed dealers, but states can extend requirements to private sales of handguns and purchases at gun shows (universal background checks for handguns [UBC-HG]). Although firearm homicide disproportionately affects African Americans, little is known about how UBG-HG impacts African Americans. We hypothesized that implementation of UBC-HG would reduce rates of firearm homicide of African Americans. We collected Centers for Disease Control firearm homicide counts for African American and white populations in the 50 states, 1999 to 2017. Laws were drawn from the State Firearm Laws Database. The exposure and outcome of interest were UBC-HG adoption and firearm homicide. We included non-Hispanic African American and non-Hispanic white populations. We used Poisson regression to perform a differences-in-differences analysis. A categorical variable for state accounted for time-stable state characteristics. We controlled for year to account for trends over time unrelated to policy. We controlled for state-specific, time-variable factors, including median household income, population younger than 25 years or 65 years or older, alcohol consumption, and count of firearm laws (UBC-HG excluded). Standard errors were adjusted for clustering at the state level. The firearm homicide rate among whites was 1.8 per 100,000 (interquartile range, 1.2-2.7) ranging from 1.4 in 2011 to 1.8 in 2016. The firearm homicide rate was 15.6 per 100,000 (interquartile range, 11.6-21.0) among African Americans, ranging from 14.0 in 2009 to 19.6 in 2017. While no significant difference in firearm homicides among whites (incidence rate ratio, 0.93; 95% confidence interval, 0.73-1.20) was appreciated, the passage of UBC-HG was associated with an 19% decrease in African Americans firearm homicides (incidence rate ratio, 0.81; 95% confidence interval, 0.70-0.94; p = 0.006). Implementing UBC-HG was associated with decreased firearm homicides among African Americans-the population most at risk. Expanding UBC-HG may be an effective approach to reducing racial disparities in firearm homicides. Epidemiological, level III.


The carnegie protein trap library: a versatile tool for Drosophila developmental studies.
Metazoan physiology depends on intricate patterns of gene expression that remain poorly known. Using transposon mutagenesis in Drosophila, we constructed a library of 7404 protein trap and enhancer trap lines, the Carnegie collection, to facilitate gene expression mapping at single-cell resolution. By sequencing the genomic insertion sites, determining splicing patterns downstream of the enhanced green fluorescent protein (EGFP) exon, and analyzing expression patterns in the ovary and salivary gland, we found that 600-900 different genes are trapped in our collection. A core set of 244 lines trapped different identifiable protein isoforms, while insertions likely to act as GFP-enhancer traps were found in 256 additional genes. At least 8 novel genes were also identified. Our results demonstrate that the Carnegie collection will be useful as a discovery tool in diverse areas of cell and developmental biology and suggest new strategies for greatly increasing the coverage of the Drosophila proteome with protein trap insertions.


Detecting Blood Flow Response to Stimulation of the Human Eye.
Retinal blood supply is tightly regulated under a variety of hemodynamic considerations in order to satisfy a high metabolic need and maintain both vessel structure and function. Simulation of the human eye can induce hemodynamics alterations, and attempt to assess the vascular reactivity response has been well documented in the scientific literature. Advancements in noninvasive imaging technologies have led to the characterization of magnitude and time course in retinal blood flow response to stimuli. This allowed for a better understanding of the mechanism in which blood flow is regulated, as well as identifying functional impairments in the diseased eye. Clinically, the ability to detect retinal blood flow reactivity during stimulation of the eye offers potential for the detection, differentiation, and diagnosis of diseases.


Cu(I), Co(II) and Fe(II) coordination polymers with pyrazine and benzoate as ligands. Spin crossover, spin canting and metamagnetism phenomena.
The isolation and characterization of four coordination polymers obtained by direct reactions of metal ion salts of Cu(II), Co(II) and Fe(II) with pyrazine (pyz) and benzoic/benzoate (Bz) ligands under hydrothermal or hydrothermal microwave conditions are described. The use of copper(II) perchlorate as the starting salt allows us to obtain compounds in a selective way by changing the pH values giving rise to the formation of two 3D-coordination polymers: [Cu(pyz)2]ClO4·pyz (1) and [Cu2(pyz)4](ClO4)2·HBz·H2O (2). In both polymers, 4-connected Cu(I) uninodal coordination networks with significant structural differences between them, due to the templating effect of the solvation molecules and counterions, have been found. However, reactions carried out under similar conditions with MSO4 (M = Co and Fe) led to the isolation of two [M2(μ-Bz)2(μ-pyz)2(Bz)2]·(HBz) isostructural infinite 1D ladder chains (M = Co (3) and M = Fe (4)). These coordination polymers show a spin-canting antiferromagnetism and metamagnetism behaviour for Co(II) and HS ↔ HS/LS ↔ LS spin-crossover phenomena for Fe(II), respectively. The latter compound is the first example of a Fe(II)O4N2 coordination environment showing this phenomenon.


Hydrological modeling of the Peruvian-Ecuadorian Amazon basin using GPM-IMERG satellite-based precipitation dataset.
In the last two decades, rainfall estimates provided by the Tropical Rainfall Measurement Mission (TRMM) have proven applicable in hydrological studies. The Global Precipitation Measurement (GPM) mission, which provides the new generation of rainfall estimates, is now considered a global successor to TRMM. The usefulness of GPM data in hydrological applications, however, has not yet been evaluated over the Andean and Amazonian regions. This study uses GPM data provided by the Integrated Multi-satellite Retrievals (IMERG) (product/final run) as input to a distributed hydrological model for the Amazon Basin of Peru and Ecuador for a 16-month period (from March 2014 to June 2015) when all datasets are available. TRMM products (TMPA V7, TMPA RT datasets) and a gridded precipitation dataset processed from observed rainfall are used for comparison. The results indicate that precipitation data derived from GPM-IMERG correspond more closely to TMPA V7 than TMPA RT datasets, but both GPM-IMERG and TMPA V7 precipitation data tend to overestimate, compared to observed rainfall (by 11.1% and 15.7 %, respectively). In general, GPM-IMERG, TMPA V7 and TMPA RT correlate with observed rainfall, with a similar number of rain events correctly detected (~20%). Statistical analysis of modeled streamflows indicates that GPM-IMERG is as useful as TMPA V7 or TMPA RT datasets in southern regions (Ucayali basin). GPM-IMERG, TMPA V7 and TMPA RT do not properly simulate streamflows in northern regions (Marañón and Napo basins), probably because of the lack of adequate rainfall estimates in northern Peru and the Ecuadorian Amazon.


Tactile temporal offset cues reduce visual representational momentum.
The perception of dynamic objects is sometimes biased. For example, localizing a moving object after it has disappeared results in a perceptual shift in the direction of motion, a bias known as representational momentum. We investigated whether the temporal characteristics of an irrelevant, spatially uninformative vibrotactile stimulus bias the perceived location of a visual target. In two visuotactile experiments, participants judged the final location of a dynamic, visual target. Simultaneously, a continuous (starting with the onset of the visual target, Experiments 1 and 2) or brief (33-ms stimulation, Experiment 2) vibrotactile stimulus (at the palm of participant's hands) was presented, and the offset disparity between the visual target and tactile stimulation was systematically varied. The results indicate a cross-modal influence of tactile stimulation on the perceived final location of the visual target. Closer inspection of the nature of this cross-modal influence, observed here for the first time, reveals that the vibrotactile stimulus was likely just taken as a temporal cue regarding the offset of the visual target, but no strong interaction and combined processing of the two stimuli occurred. The present results are related to similar cross-modal temporal illusions and current accounts of multisensory perception, integration, and cross-modal facilitation.


Simple sequence is abundant in eukaryotic proteins.
All proteins of Saccharomyces cerevisiae have been compared to determine how frequently segments from one protein are present in other proteins. Proteins that are recently evolutionarily related were excluded. The most frequently present protein segments are long, tandem repetitions of a single amino acid. For some of these segments, up to 14% of all proteins in the genome were found to have similar peptides within them. These peptide segments may not be functional protein domains. Although they are the most common shared feature of yeast proteins, their ubiquity and simplicity argue that their probable function may be to simply serve as spacers between other protein motifs.


Determinants of BH3 binding specificity for Mcl-1 versus Bcl-xL.
Interactions among Bcl-2 family proteins are important for regulating apoptosis. Prosurvival members of the family interact with proapoptotic BH3 (Bcl-2-homology-3)-only members, inhibiting execution of cell death through the mitochondrial pathway. Structurally, this interaction is mediated by binding of the alpha-helical BH3 region of the proapoptotic proteins to a conserved hydrophobic groove on the prosurvival proteins. Native BH3-only proteins exhibit selectivity in binding prosurvival members, as do small molecules that block these interactions. Understanding the sequence and structural basis of interaction specificity in this family is important, as it may allow the prediction of new Bcl-2 family associations and/or the design of new classes of selective inhibitors to serve as reagents or therapeutics. In this work, we used two complementary techniques--yeast surface display screening from combinatorial peptide libraries and SPOT peptide array analysis--to elucidate specificity determinants for binding to Bcl-x(L)versus Mcl-1, two prominent prosurvival proteins. We screened a randomized library and identified BH3 peptides that bound to either Mcl-1 or Bcl-x(L) selectively or to both with high affinity. The peptides competed with native ligands for binding into the conserved hydrophobic groove, as illustrated in detail by a crystal structure of a specific peptide bound to Mcl-1. Mcl-1-selective peptides from the screen were highly specific for binding Mcl-1 in preference to Bcl-x(L), Bcl-2, Bcl-w, and Bfl-1, whereas Bcl-x(L)-selective peptides showed some cross-interaction with related proteins Bcl-2 and Bcl-w. Mutational analyses using SPOT arrays revealed the effects of 170 point mutations made in the background of a peptide derived from the BH3 region of Bim, and a simple predictive model constructed using these data explained much of the specificity observed in our Mcl-1 versus Bcl-x(L) binders.


Immunohistochemical localization of endothelial nitric oxide synthase in human villous and extravillous trophoblast populations and expression during syncytiotrophoblast formation in vitro.
We have examined the distribution of the endothelial isoform of nitric oxide synthase (eNOS) in villous and extravillous trophoblast populations by immunohistochemistry and have further studied expression of eNOS during differentiation of cytotrophoblast into syncytiotrophoblast in culture. In first trimester villous tissue, NADPH diaphorase activity and eNOS immunostaining were present in syncytiotrophoblast but not the progenitor cytotrophoblast layer. Extravillous trophoblast in the basal plate of the placenta was identified by anticytokeratin immunostaining and displayed NADPH diaphorase activity, but not eNOS immunostaining. Both amnion epithelial cells and chorion cytotrophoblast had NADPH diaphorase activity but no eNOS immunostaining, whereas eNOS immunostaining was seen in the fibroblast layer of amnion. Purified villous cytotrophoblast cells from term placentae aggregated and fused to form a syncytium with increasing time in culture as assessed by antidesmosomal protein and antinuclear antibody immunostaining. Following 24 h in culture, the majority of cells were still mononucleate cytotrophoblast which did not display eNOS immunostaining, whereas a few syncytial aggregates had formed which were both eNOS positive and hPL positive. By 3 to 5 days in culture, the majority of cells were present as syncytiotrophoblast. However, eNOS and hPL immunostaining was more diffuse and not all syncytial aggregates were positive. Of the trophoblast populations, only syncytiotrophoblast appears to express eNOS. Differentiation of cytotrophoblast into syncytiotrophoblast is associated with eNOS expression.


Towards evidence-based critical thinking medicine? Uses of best evidence in flawless argumentations.
Uses of informal logic and critical thinking methodology are increasingly taught, learnt and advantageously applied in such diverse domains as law, the military, business, and education. Health sciences are also following this trend. However, production and critical appraisal of evidence as already practiced in Evidence-Based Medicine must be coupled with equally rigorous uses in order to ensure appropriate health problem understanding and decision-making. Making most proposals and decisions in medicine is the conclusion of an argumentation process that lies behind any communication between health professionals working with patients, performing research or sharing ideas about health problems, their interpretations and solutions with numerous stakeholders in public life. Modern critical thinking and decision making in medicine is not instantly mastered, but is instead a learnt experience as anything else in professional and social interactions. The modern argument as outlined, illustrated and applied to health problems in this essay is an extension of a previously established way of thinking in Evidence-Based Medicine. Ideally, health professionals, their patients and all other stakeholders should speak the same language and it is up to us to make this possible. Evidence and critical thinking - based medicine might be a solution. As modern critical thinkers, we are at the forefront and we must see to it that patients and professional and general communities benefit from this more so even than from other remarkable historical and current contributions to the well-being of those under our care.


Kinetic optimization of a protein-responsive aptamer beacon.
Aptamers have been utilized as biosensors because they can be readily adapted to sensor platforms and signal transduction schemes through both rational design and selection. One highly generalizable scheme for the generation of the so-called aptamer beacons involves denaturing the aptamer with antisense oligonucleotides. For example, rational design methods have been utilized to adapt anti-thrombin aptamers to function as biosensors by hybridizing an antisense oligonucleotide containing a quencher to the aptamer containing a fluorescent label. In the presence of thrombin, the binding equilibrium is shifted, the antisense oligonucleotide dissociates, and the beacon lights up. By changing the affinity of the antisense oligonucleotide for the aptamer beacon, it has proven possible to change the extent of activation of the beacon. More importantly, modulating interactions between the antisense oligonucleotide and the aptamer strongly influences the kinetics of activation. Comparisons across multiple, designed aptamer beacons indicate that there is a strong inverse correlation between the thermodynamics of hybridization and the speed of activation, a finding that should prove to be generally useful in the design of future biosensors. By pre-organizing the thrombin-binding quadruplex within the aptamer the speed of response can be greatly increased. By integrating these various interactions, we were ultimately able to design aptamer beacons that were activated by threefold within 1 min of the addition of thrombin.


Genotoxic effect and rat hepatocyte death occurred after oxidative stress induction and antioxidant gene downregulation caused by long term fluoride exposure.
Studies focusing on possible genotoxic effects of excess fluoride are contradictory and inconclusive. Currently, studies have reported a probable link to oxidative stress, DNA damage and apoptosis induced by fluoride in rat hepatocytes. We developed an in vivo study administering three doses of fluoride by gavage given to rats for 60 day. Micronucleus test was applied to investigate genotoxic potential of fluoride. The TUNEL method determined DNA fragmentation and apoptosis. Biochemical parameters to investigate mitochondrial swelling and oxidative stress. Semi-quantitative RT-PCR and immunostaining to determine mRNA and protein expression of antioxidant enzymes. Analyses of the hepatic function and morphology were performed. Our results revealed the genotoxic potential of fluoride but did not confirm mitochondrial swelling nor an increase of positive TUNEL labelling induced by fluoride, indicating absence of apoptosis. Oxidative stress induction was confirmed and is probably associated to DNA damage. Cell death events such as empty nuclear spaces, cytoplasm degeneration, nuclear pyknosis, karyorrhexis and karyorrhexis followed by karyolysis were observed. Hepatic function did not appear to be significantly modified makes no evidence of necrosis and suggesting other cell death pathway, the autophagic. In conclusion, prolonged fluoride intake at chosen concentrations caused imbalance of the cellular oxidative state, affected DNA and disrupted cellular homeostasis. It is recommended that fluoride supplementation requires a fresh consideration in light of the current study.


Molecular origin of urea driven hydrophobic polymer collapse and unfolding depending on side chain chemistry.
Osmolytes affect hydrophobic collapse and protein folding equilibria. The underlying mechanisms are, however, not well understood. We report large-scale conformational sampling of two hydrophobic polymers with secondary and tertiary amide side chains using extensive molecular dynamics simulations. The calculated free energy of unfolding increases with urea for the secondary amide, yet decreases for the tertiary amide, in agreement with experiment. The underlying mechanism is rooted in opposing entropic driving forces: while urea screens the hydrophobic macromolecular interface and drives unfolding of the tertiary amide, urea's concomitant loss in configurational entropy drives collapse of the secondary amide. Only at sufficiently high urea concentrations bivalent urea hydrogen bonding interactions with the secondary amide lead to further stabilisation of its collapsed state. The observations provide a new angle on the interplay between side chain chemistry, urea hydrogen bonding, and the role of urea in attenuating or strengthening the hydrophobic effect.


Light transmission through nanostructured metallic films: coupling between surface waves and localized resonances.
We present an experimental and computational investigation of the optical properties of thin metallic films periodically perforated with nanometric apertures and show that high transmission through such a structure is attributable to the localized surface plasmon (LSP) resonances of the aperture. The periodicity-related optical phenomena, including Wood's anomaly and surface plasmon polariton (SPP) excitation, interfere with LSPs and generate Fano resonances with asymmetric spectral profiles. The transmission maximum of the Fano profile is related to the constructive interference between the LSP field and diffracted light propagating along the surface; the transmission minimum of the Fano profile is caused by the destructive interference between LSPs and SPPs. The study confirms the negative role of SPP in transmission through the structure.


By-product of Lavandula latifolia essential oil distillation as source of antioxidants.
The objective of this work was to evaluate the antioxidant properties of Lavandula latifolia waste obtained after essential oil distillation. Samples of 12 wild populations of the Lavandula genus collected between 2009 and 2010 were hydrodistilled and their by-products were analyzed using the Folin-Ciocalteu, free radical scavenging activity (2,2-diphenyl-1-picrylhydrazyl), and the ferric reducing antioxidant power (FRAP) methods. Rosmarinic acid, apigenin, and luteolin contents were analyzed by high-performance liquid chromatography-diode array detection. The mean of total phenolic content ranged from 1.89 ± 0.09 mg gallic acid equivalents/g dry weight to 3.54 ± 0.22 mg gallic acid equivalents/g dry weight. The average value of the half maximal effective concentration (EC50) for scavenging activity ranged from 5.09 ± 0.17 mg/mL to 14.30 ± 1.90 mg/mL and the variability of the EC50 in FRAP ranged from 3.72 ± 0.12 mg/mL to 18.55 ± 0.77 mg/mL. Annual variation was found among this samples and the environmental conditions of 2009 were found to be more favorable. The plants collected from Sedano showed the highest antioxidant power. Our results show that rosmarinic acid and apigenin in L. latifolia contributed to the antioxidant properties of the waste. In conclusion, the by-product of the distillation industry could be valorizing as a source of natural antioxidants.


"Near and far": social distancing in domiciled characterisations of homeless people.
For domiciled individuals, homeless people provide a disturbing reminder that all is not right with the world. Reactions to seeing homeless people frequently encompass repulsion, discomfort, sympathy and sometimes futility. This paper considers domiciled constructions of homeless people drawn from interviews with 16 participants recruited in the central business district of a New Zealand city. It documents how, when trying to make sense of this complex social problem, domiciled people draw on shared characterizations of homeless people. The concept of "social distance" is used to interrogate the shifting and sometimes incongruous reactions evident in participant accounts. "Social distancing" is conceptualised as a dynamic communal practice existing in interactions between human beings and reflected in the ways that domiciled people talk about their experiences with homeless individuals.


Option B+ in Mozambique: Formative Research Findings for the Design of a Facility-Level Clustered Randomized Controlled Trial to Improve ART Retention in Antenatal Care.
With the rollout of "Option B+" in Mozambique in 2013, initial data indicated major challenges to early retention in antiretroviral therapy (ART) among HIV-positive pregnant women. We sought to develop and test a pilot intervention in 6 large public clinics in central Mozambique to improve retention of mothers starting ART in antenatal care. The results from the formative research from this study described here were used to design the intervention. The research was initiated in early 2013 and completed in early 2014 in each of the 6 study clinics and consisted of (1) patient flow mapping and measurement of retention through collection of health systems data from antenatal care registries, pharmacy registries, ART clinic databases, (2) workforce assessment and measurement of patient waiting times, and (3) patient and worker individual interviews and focus groups. Coverage of HIV testing and ART initiation were over 90% at all sites, but retention at 30-, 60-, and 90-day pharmacy refill visits was very low ranging from only 5% at 1 site to 30% returning at 90 days. These data revealed major systemic bottlenecks that contributed to poor adherence and retention in the first month after ART initiation. Long wait times, short consultations, and poor counseling were identified as barriers. Based on these findings, we designed an intervention with these components: (1) workflow modification to redefine nurse tasks, shift tasks to community health workers, and enhance patient tracking and (2) an adherence and retention package to systematize active patient follow-up, ensure home visits by community health workers, use text messaging, and intensify counseling by health staff. This intervention is currently under evaluation using a stepped wedge design.


Detecting chirality in molecules by imaging photoelectron circular dichroism.
In this Perspective we discuss photoelectron circular dichroism (PECD), a relatively novel technique that can detect chiral molecules with high sensitivity. PECD has an enantiomeric sensitivity of typically 1-10%, which is two to three orders of magnitude larger than that of the widely employed technique of circular dichroism (CD). In PECD a chiral molecule is photoionized with circular polarized light, and the photoelectron angular scattering distribution is detected using particle imaging techniques. We present the general physical principles of photoelectron circular dichroism and we address both single- and multiphoton excitation. PECD has been measured with synchrotron radiation in single-photon ionization as well as, very recently, with femtosecond laser radiation in multiphoton ionization. We discuss the experimental implementation of PECD, focusing on velocity map coincidence imaging where the momentum distribution of both the electron and the coincident ion is measured. The coincident detection of the mass and momentum of the ion adds very powerful mass-correlated information to the PECD measurement of the chiral molecule. We illustrate the capabilities and the potential of PECD with various experimental examples and introduce computational methods that are able to model quantitatively experimental PECD results. We conclude with an outlook on novel developments and (analytical) implementations of PECD that may further broaden the application of PECD for the sensitive detection of chirality in molecules.


Outcomes of Bone Grafting of Bone Cysts After Total Ankle Arthroplasty.
The operative treatment of bone cysts after total ankle replacements (TAR) is not well described. Bone cysts may cause component migration, implant failure, and pain. Surgery is performed on cysts with the goals of reducing pain and preventing component failure. We retrospectively evaluated a consecutive series of 726 primary TARs performed between January 1998 and May 2013 and identified those who had a subsequent bone cyst grafting procedure. We identified cyst location and method of treatment. Clinical outcomes including secondary procedures, infection rate, complications, and failure rate were recorded. Thirty-one patients were treated with a total of 33 operative procedures for bone cysts after TAR. Of these patients, 22 (71.0%) were males with an average age of 62.2 and median follow-up 65.9 months. Intraoperatively, 22 tibial cysts (71.0%), 20 talar cysts (64.5%), 5 fibular cysts (16.1%), and 13 multiple cysts (41.9%) were treated. Allograft was used in 25 procedures (75.8%), calcium phosphate in 4 (12.1%), cement in 3 (9.1%), and autograft in 1 (3.0%). These procedures were supplemented by calcaneus autograft, allograft mixed with mesenchymal stem cells, platelet-rich plasma, recombinant human bone morphogenic protein-2, and demineralized bone matrix. There were no infections or wound complications. Of the 27 subjects with a successful second surgery, the success rate for bone grafting of cysts was 90.9% (95% CI: 50.8, 98.7%) at 24 months and 60.6% (95% CI: 25.1%, 83.4%) at 48 months. One patient needed a repeat bone grafting. The 4 failures observed postprocedure resulted in 3 tibial and talar component revisions, and 1 tibiotalocalcaneal (TTC) fusion. Grafting bone cysts without revision of TAR was in general an effective and safe means for treating patients with peri-prosthetic bone cysts. Treatment with grafting and supplemental materials may improve implant survivorship and might improve the structural support surrounding the implant. Further exploration of the etiology of bone cysts may aid in the prevention and treatment of cystic formation in the TAR. Level IV, case series.