Viewpoint: Evolution of cultivated chickpea: four bottlenecks limit diversity and constrain adaptation.
Chickpea (Cicer arietinum L.) is characterised by a different adaptation profile from the other crops of West Asian origin such as pea, barley, and wheat. In this paper we suggest that a series of four evolutionary bottlenecks occur in chickpea: (1) the scarcity and limited distribution of the wild progenitor, C. reticulatum Ladiz., (2) the founder effect associated with domestication, (3) the shift, early in the crop's history, from winter to spring sowing, and the attendant change from using rainfall as it occurs to a reliance on residual soil moisture, and (4) the replacement of locally evolving landraces by elite cultivars produced by modern plant breeding. While two of the bottlenecks are common to all species, the limited distribution of the wild progenitor and shift of cropping from utilisation of current rainfall to stored soil moisture is unique to chickpea. In this paper we suggest that in order to widen the genetic base of cultivated chickpea it is imperative to reintroduce traits from across the primary gene pool. Moreover, a comparative physiological approach to the study of adaptation among the annual wild relatives of chickpea may reveal adaptive strategies within the genus currently obscured by monomorphic loci. The poor state of the world collection of annual wild Cicer species severely constrains the implementation of both these imperatives. We suggest that an extensive collection of annual wild Cicer species, based on ecogeographic principles to maximise the probability of collecting diverse ecotypes, should provide a better understanding of the biology and adaptation in this ancient crop and lead to improved productivity.


Cost-Effectiveness of Physical Therapy Only and of Usual Care for Various Health Conditions: Systematic Review.
Given continually rising health care costs, interventions of health care providers should be cost-effective. This review aimed to summarize current cost-effectiveness of physical therapy. Specific aims were: (1) to analyze cost-effectiveness of physical therapy only compared with usual care only, (2) to analyze cost-effectiveness of physical therapy added to usual care compared with usual care only, and (3) to specify in which health conditions physical therapy only or physical therapy added to usual care was cost-effective. Topic-related systematic reviews were searched in MEDLINE, CINAHL, PEDro, and Cochrane Library and manually. Studies published between 1998 and 2014 that investigated the cost-effectiveness of interventions carried out by physical therapists were reviewed. The methodological quality was assessed with the Cochrane risk of bias assessment for intervention studies and with the Quality of Health Economic Analyses Scale. Effectiveness and cost data for calculating incremental cost-effectiveness ratios (ICERs) and the original authors' conclusions were extracted. The 18 included studies presented low risk of bias and contained 8 comparisons of physical therapy only with usual care only and 11 comparisons of physical therapy added to usual care with usual care only. Based on ICERs, physical therapy only or added to usual care was cost-effective in 9 out of the 19 comparisons and in 10 comparisons according to the original authors' conclusions. Physical therapy only or added to usual care implies improved health in almost all studies. The cost-effectiveness of such interventions was demonstrated in half of the studies. This result might have been influenced by the fact that different definitions of the notion of "cost-effectiveness" exist.


Clinical presentation of pyloric stenosis: the change is in our hands.
Hypertrophic pyloric stenosis classically presents as projectile vomiting during the third to fourth week of life, associated with good appetite. Additional classical presenting findings include palpation of the pyloric tumor, described as olive-shaped; a visible gastric peristaltic wave after feeding; and hypochloremic, hypokalemic metabolic alkalosis. It was recently claimed that this presentation has changed due to the easier access to gastrointestinal imaging. To validate this contention and discuss possible reasons. We conducted a retrospective chart review of all patients who underwent pyloromyotomy for HPS between 1990 and 2000. Only patients with confirmed HPS at the time of surgery were included. We also performed a comprehensive review of older studies for comparison. Seventy patients underwent pyloromyotomy over the 10 year period. Overall, 81% of patients were male infants and the mean age at diagnosis was 40 days. The mean duration of symptoms was 8 days. A firstborn child was noted in 43% of the cases. The classical symptom of projectile vomiting was absent in one-third of the patients, a pyloric tumor was not palpated in one-half of the cases, bicarbonate was higher than 28 mEq/L in 20%, and a pH of above 7.45 was present in 25% of patients. Hypochloremia was noted in about one-third. We found a good correlation between ultrasonographic width and length of the pylorus and the intraoperative findings. Pylorus length +/- 24 mm correlated with significantly longer duration of symptoms. When compared with previous studies, the main findings were not significantly different; namely, mean age at diagnosis, percentage of male gender, and duration to diagnosis. The decrease in the number of pyloric tumors palpated paralleled the increase in the use of upper gastrointestinal series and ultrasonography in particular. The clinical presentation of HPS has not actually changed despite the easier accessibility of GI imaging studies. However, the one significant change is the low percentage of pyloric tumors palpated, probably due to declining clinical skills accompanied by earlier utilization of imaging studies. The use of imaging and laboratory studies did not change the age at diagnosis but may have shortened the time for diagnosis and reduced the postoperative stay. Imaging and laboratory studies may be helpful for the subgroup with a non-classical clinical presentation.


The expert consensus guideline series. Treatment of dementia and its behavioral disturbances. Introduction: methods, commentary, and summary.
New treatment options for dementia and its behavioral disturbances have become available since publication of The Expert Consensus Guidelines on the Treatment of Agitation in Older Persons with Dementia in 1998. While only 2 cholinesterase inhibitors, donepezil and tacrine, were available in 1998, 3 new cognitive-enhancing agents have been introduced since that time as well as several new atypical antipsychotics and antidepressants. However, there are still limited data from controlled studies to guide clinicians in choosing among these agents and sequencing and combining treatments. We therefore conducted a new survey study of expert opinion on the treatment of cognitive impairment and behavioral disturbances associated with dementia. Based on a literature review, a 61-question survey was developed with 1,225 options. Most options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions. For other options, the experts were asked to write in answers. The survey was sent to 50 North American experts on dementia, 100% of whom completed it. In analyzing responses to items rated on the 9-point scale, consensus was defined as a nonrandom distribution of scores by chi-square "goodness-of-fit" test. Based on the 95% confidence interval around the mean, we assigned a categorical rank (first line/preferred, second line/alternate, third line/usually inappropriate) to each option. Guidelines indicating preferred treatment strategies were then developed for selected clinical situations. For patients at risk for dementia, the experts recommended control of hypertension and diabetes. They also recommended aspirin and would consider a lipid-lowering agent in patients at risk for vascular dementia. Cholinesterase inhibitors were an option for patients with mild cognitive impairment (i.e., at risk for Alzheimer's dementia [AD]). To slow cognitive impairment in mild/moderate AD, the experts recommended a cholinesterase inhibitor alone or combined with vitamin E. Donepezil and galantamine were the preferred cholinesterase inhibitors. The experts recommended combining a cholinesterase inhibitor with a N-methyl-D-aspartate (NMDA) antagonist (e.g., memantine) if a patient with mild/moderate dementia has an inadequate response to monotherapy. Control of hypertension and diabetes was the treatment of choice, in patients with mild/moderate vascular or mixed AD/vascular dementia, with aspirin another first-line option. Cholinesterase inhibitors were also a first-line option for mild/moderate mixed AD/vascular dementia. Among nonpharmacological interventions for mild/moderate dementia, the experts recommended caregiver education, supportive therapy for caregivers, referral to day treatment, exercise programs, and respite care. For moderate/severe AD or mixed AD/vascular dementia, the experts recommended combining an NMDA antagonist with a cholinesterase inhibitor. For moderate/severe vascular or mixed AD/vascular dementia, they recommended control of hypertension and diabetes. The experts' ratings underscore the importance of nonpharmacological strategies aimed at reducing caregiver burden in more severe dementia. Management of agitation and other behavioral disturbances was another focus of this study. The experts recommended using an atypical antipsychotic for agitation associated with delirium, psychosis, aggression, or anger. They would also consider divalproex to manage anger with a risk of physical aggression. Selective serotonin reuptake inhibitors were recommended for the treatment of depression or anxiety in patients with dementia. Benzodiazepines or atypical antipsychotics were viewed as short-term options for acute anxiety. Trazodone was recommended for insomnia. The experts also gave recommendations concerning dosage levels, duration of treatment, and choice of medications for patients with different complicating conditions. The experts reached high levels of consensus on key steps in treating dementia and associated behavioral disturbances. Within the limits of expert opinion and with the expectation that new research data will take precedence, these guidelines may provide direction for clinicians offering care to patients with dementia.


Verbal and novel multisensory associative learning in adults.
To date, few studies have focused on the behavioural differences between the learning of multisensory auditory-visual and intra-modal associations. More specifically, the relative benefits of novel auditory-visual and verbal-visual associations for learning have not been directly compared. In Experiment 1, 20 adult volunteers completed three paired associate learning tasks: non-verbal novel auditory-visual (novel-AV), verbal-visual (verbal-AV; using pseudowords), and visual-visual (shape-VV). Participants were directed to make a motor response to matching novel and arbitrarily related stimulus pairs. Feedback was provided to facilitate trial and error learning. The results of Signal Detection Theory analyses suggested a multisensory enhancement of learning, with significantly higher discriminability measures (d-prime) in both the novel-AV and verbal-AV tasks than the shape-VV task. Motor reaction times were also significantly faster during the verbal-AV task than during the non-verbal learning tasks. Experiment 2 (n = 12) used a forced-choice discrimination paradigm to assess whether a difference in unisensory stimulus discriminability could account for the learning trends in Experiment 1. Participants were significantly slower at discriminating unisensory pseudowords than the novel sounds and visual shapes, which was notable given that these stimuli produced superior learning. Together the findings suggest that verbal information has an added enhancing effect on multisensory associative learning in adults.


Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation.
Studies of the human immune system have been limited by the lack of an appropriate in vivo model. For this reason, efforts have been made to develop murine models with a functional human immune system. We report here that cotransplantation of human fetal thymus/liver tissues and CD34(+) hematopoietic stem/progenitor cells led to the development of sustained human hematopoiesis and a functional human immune system in immunodeficient NOD/SCID mice. The humanized mice showed systemic repopulation with a comprehensive array of human lymphohematopoietic cells, including T cells, B cells, and dendritic cells, and the formation of secondary lymphoid organs. Furthermore, these mice produce high levels of human IgM and IgG antibodies and mediate strong immune responses in vivo as demonstrated by skin xenograft rejection. Thus, the humanized NOD/SCID mice described in this paper provide a powerful model system to study human immune function.


Fibre electronics: towards scaled-up manufacturing of integrated e-textile systems.
The quest for a close human interaction with electronic devices for healthcare, safety, energy and security has driven giant leaps in portable and wearable technologies in recent years. Electronic textiles (e-textiles) are emerging as key enablers of wearable devices. Unlike conventional heavy, rigid, and hard-to-wear gadgets, e-textiles can lead to lightweight, flexible, soft, and breathable devices, which can be worn like everyday clothes. A new generation of fibre-based electronics is emerging which can be made into wearable e-textiles. A suite of start-of-the-art functional materials have been used to develop novel fibre-based devices (FBDs), which have shown excellent potential in creating wearable e-textiles. Recent research in this area has led to the development of fibre-based electronic, optoelectronic, energy harvesting, energy storage, and sensing devices, which have also been integrated into multifunctional e-textile systems. Here we review the key technological advancements in FBDs and provide an updated critical evaluation of the status of the research in this field. Focusing on various aspects of materials development, device fabrication, fibre processing, textile integration, and scaled-up manufacturing we discuss current limitations and present an outlook on how to address the future development of this field. The critical analysis of key challenges and existing opportunities in fibre electronics aims to define a roadmap for future applications in this area.


PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication.
Intrinsic antiviral resistance mediated by constitutively expressed cellular proteins is one arm of defence against virus infection. Promyelocytic leukaemia nuclear bodies (PML-NBs, also known as ND10) contribute to host restriction of herpes simplex virus type 1 (HSV-1) replication via mechanisms that are counteracted by viral regulatory protein ICP0. ND10 assembly is dependent on PML, which comprises several different isoforms, and depletion of all PML isoforms decreases cellular resistance to ICP0-null mutant HSV-1. We report that individual expression of PML isoforms I and II partially reverses the increase in ICP0-null mutant HSV-1 plaque formation that occurs in PML-depleted cells. This activity of PML isoform I is dependent on SUMO modification, its SUMO interaction motif (SIM), and each element of its TRIM domain. Detailed analysis revealed that the punctate foci formed by individual PML isoforms differ subtly from normal ND10 in terms of composition and/or Sp100 modification. Surprisingly, deletion of the SIM motif from PML isoform I resulted in increased colocalisation with other major ND10 components in cells lacking endogenous PML. Our observations suggest that complete functionality of PML is dependent on isoform-specific C-terminal sequences acting in concert.


The relationship of platelet reactivity to the occurrence of post-stenting ischemic events: emergence of a new cardiovascular risk factor.
The reactivity of platelets to agonists plays a central role in the genesis of thrombosis following percutaneous coronary intervention (PCI) and spontaneous plaque rupture. Antiplatelet therapy has reduced the occurrence of thrombotic events following PCI, including myocardial infarction and stent thrombosis. Because the platelet is a fundamental component in the generation of an arterial thrombus and the stimulus for thrombosis is marked in PCI, it is logical to predict that patients with superior platelet inhibition would have the best outcomes with respect to ischemic events post PCI. However, until recently there was little information linking measurements of high ex vivo platelet reactivity to the occurrence of ischemic events. An emerging body of data, mostly from small studies, supports the pivotal link between periprocedural platelet physiology and increased risk of adverse thrombotic events. This review explores the available information linking platelet reactivity during and after PCI to the occurrence of adverse events, including myocardial infarction, recurrent ischemia within 6 months, and stent thrombosis.


Chronic effect of losartan in a murine model of dilated cardiomyopathy: comparison with captopril.
The long-term effects of losartan, an angiotensin II subtype-I receptor antagonist, were compared with those of captopril in a murine model of dilated cardiomyopathy caused by encephalomyocarditis virus. Four weeks after viral inoculation, 42 DBA/2 mice were given oral losartan 1.2 mg/kg/day (n = 8), 12 mg/kg/day (n = 8) or 60 mg/kg/day (n = 8) or captopril 7.5 mg/kg/day (n = 8) in drinking water or distilled water (n = 10). Mice were killed at the end of the 12-wk treatment period. Heart weight, left ventricular thickness, left ventricular cavity dimension and myocardial fiber diameter were significantly lower in mice given losartan 60 mg/kg as compared with the infected untreated group. Captopril had a similar effect on all parameters. The pathologic score of cardiac fibrosis was significantly lower in the mice treated with captopril but was not reduced in the mice treated with losartan. Moreover, as compared with the age- and sex-matched normal mice, cardiac mass and myocardial fiber diameter were significantly lower in normal mice treated with losartan 60 mg/kg. This study suggests that long-term treatment with losartan may prevent thickening of left ventricular wall and cavity dimension in dilated cardiomyopathy caused by encephalomyocarditis virus. The potency, and perhaps the efficacy, of losartan appear to be less than those of captopril.


Gly126Arg substitution causes anomalous behaviour of α-skeletal and β-smooth tropomyosins during the ATPase cycle.
To investigate how TM stabilization induced by the Gly126Arg mutation in skeletal α-TM or in smooth muscle β-TM affects the flexibility of TMs and their position on troponin-free thin filaments, we labelled the recombinant wild type and mutant TMs with 5-IAF and F-actin with FITC-phalloidin, incorporated them into ghost muscle fibres and studied polarized fluorescence at different stages of the ATPase cycle. It has been shown that in the myosin- and troponin-free filaments the Gly126Arg mutation causes a shift of TM strands towards the outer domain of actin, reduces the number of switched on actin monomers and decreases the rigidity of the C-terminus of α-TM and increases the rigidity of the N-terminus of β-TMs. The binding of myosin subfragment-1 to the filaments shifted the wild type TMs towards the inner domain of actin, decreased the flexibility of both terminal parts of TMs, and increased the number of switched on actin monomers. Multistep alterations in the position of α- and β-TMs and actin monomers in the filaments and in the flexibility of TMs and F-actin during the ATPase cycle were observed. The Gly126Arg mutation uncouples a correlation between the position of TM and the number of the switched on actin monomers in the filaments.


Actions of phencyclidine on the action potential and membrane currents of single guinea-pig myocytes.
The direct actions of phencyclidine (PCP) on mammalian sarcolemma were examined by determination of the drug's effects on the action potentials of isolated guinea-pig ventricular cells, and on the underlying ionic currents. PCP (10(-6) to 10(-4) M) did not alter the resting membrane potential but produced a dose-dependent prolongation of the duration of the action potential, and a reduction of the rate of depolarization of phase 0 (Vmax) of the action potential. Voltage clamp experiments revealed that PCP blocks both myocardial Ca++ channels and myocardial time-dependent K+ channels. The K+ channel blockade was shown to exhibit an apparent voltage-dependence. The effects of PCP on these ionic channels could explain previous reports of it prolonging myocardial action potentials and conflicting reports of positive and negative inotropism.


Effect of maternal smoking on some markers of iron status in umbilical cord blood.
Iron deficiency relatively often observed in pregnant women is assumed to be enhanced by cigarette smoking. The present studies are designed to determine the effect of maternal cigarette smoking during pregnancy on iron status of newborns. The levels of ferritin, as well as other iron-markers were determined in placenta tissue and in serum of umbilical cord blood. Placenta tissues and umbilical cord blood from healthy women (n = 30) were divided into smoking and non-smoking groups according to mothers plasma and urine cotinine levels. It is shown that total iron concentration in serum of umbilical cord was similar in both studied groups. In smoking group it was accompanied by higher total iron binding capacity which indicated that functional iron deficiency is possible. Iron storage ferritin in umbilical cord blood was 94 ng/ml and 163 ng/ml in smoking and non-smoking respectively. In placenta tissue mean level of ferritin was 252 micrograms/g in the smoking women whereas in the group of tobacco abstinent it was 320 micrograms/g. Low concentration of ferritin both in placenta and umbilical cord blood indicated that smoking during pregnancy could lead to subclinical iron deficiency in matched maternal-cord pairs.


The Role of Difficulty in Identifying and Describing Feelings in Non-Suicidal Self-Injury Behavior (NSSI): Associations With Perceived Attachment Quality, Stressful Life Events, and Suicidal Ideation.
Objective: Core alexithymic features, such as the difficulty in identifying and describing feelings, are associated with poor attachment styles and emotional trauma, which influence the capacity to regulate affect. Additionally, emotional regulation has been found to be the most commonly identified function associated with non-suicidal self-injury behavior (NSSI) in adolescents as they attempt to modulate strong emotions. However, few studies have examined the link between difficulty in identifying and describing feelings (core components of alexithymia), NSSI behaviors, quality of attachment, life stressors and suicidal ideation in healthy early adolescents. Consequently, this study aims to investigate these constructs and the relationship among them in a large non-clinical sample of adolescents. Methods: Seven hundred and nine middle school students (50.4% males), aged 10-15 years (M = 12.6; SD = 1.06) were involved in this study. In order to investigate the variables considered in the study, the following measures were administered: the Deliberate Self-Harm Inventory exploring non-suicidal self-injurious behaviors; the Alexithymia Questionnaire for Children examining difficulty in identifying and describing feelings; the Inventory of Parent and Peer Attachment assessing the quality of parental and peer attachment; the Life Stressor Checklist-Revised outlining stressful/traumatic events and the Children's Depression Inventory evaluating suicidal ideation. Results: We found significantly positive relationships among difficulty in identifying and describing feelings, NSSI behaviors, stressful events, and suicidal ideation. Data indicated a significant negative association of difficulty in identifying and describing feelings with quality of attachment to parents and peers. Further findings highlighted that difficulty in identifying and describing feelings significantly mediated the effect of quality of attachment (parent and peer) on NSSI and suicidal ideation. Conclusion: The ability to identify and describing feelings is important to managing emotional expression and understanding the feelings of others, both crucial in attaining successful interpersonal relationships. Our data revealed that, while controlling for stressful life events, low levels of attachment may increase adolescents' difficulty in identifying and describing their own feelings, which in turn may increase the risk of both NSSI and suicidal ideation.


The effects of different bisphenol derivatives on oxidative stress, DNA damage and DNA repair in RWPE-1 cells: A comparative study.
Bisphenol A (BPA) is a well-known endocrine disruptor and it is widely used mainly in the plastics industry. Due to recent reports on its possible impact on health (particularly on the male reproductive system), bisphenol F (BPF) and bisphenol S (BPS) are now being used as alternatives. In this study, RWPE-1 cells were used as a model to compare cytotoxicity, oxidative stress-causing potential and genotoxicity of these chemicals. In addition, the effects of the bisphenol derivatives were assessed on DNA repair proteins. RWPE-1 cells were incubated with BPA, BPF, and BPS at concentrations of 0-600 μM for 24 h. The inhibitory concentration 20 (IC20 , concentration that causes 20% of cell viability loss) values for BPA, BPF, and BPS were 45, 65, and 108 μM, respectively. These results indicated that cytotoxicity potentials were ranked as BPA > BPF > BPS. We also found alterations in superoxide dismutase, glutathione peroxidase and glutathione reductase activities, and glutathione and total antioxidant capacity in all bisphenol-exposed groups. In the standard and modified Comet assay, BPS produced significantly higher levels of DNA damage vs the control. DNA repair proteins (OGG1, Ape-1, and MyH) involved in the base excision repair pathway, as well as p53 protein levels were down-regulated in all of the bisphenol-exposed groups. We found that the BPA alternatives were also cytotoxic and genotoxic, and changed the expressions of DNA repair enzymes. Therefore, further studies are needed to assess whether they can be used safely as alternatives to BPA or not.


Survival outcomes for first-line antiretroviral therapy in India's ART program.
Little is known about survival outcomes of HIV patients on first-line antiretroviral therapy (ART) on a large-scale in India, or facility level factors that influence patient survival to guide further improvements in the ART program in India. We examined factors at the facility level in addition to patient factors that influence survival of adult HIV patients on ART in the publicly-funded ART program in a high- and a low-HIV prevalence state. Retrospective chart review in public sector ART facilities in the combined states of Andhra Pradesh and Telangana (APT) before these were split in 2014 and in Rajasthan (RAJ), the high- and a low-HIV prevalence states, respectively. Records of adults initiating ART between 2007-12 and 2008-13 in APT and RAJ, respectively, were reviewed and facility-level information collected at all ART centres and a sample of link ART centres. Survival probability was estimated using Kaplan-Meier method, and determinants of mortality explored with facility and patient-level factors using Cox proportional hazard model. Based on data from 6581 patients, the survival probability of ART at 60 months was 76.3 % (95 % CI 73.0-79.2) in APT and 78.3 % (74.4-81.7) in RAJ. The facilities with cumulative ART patient load above the state average had lower mortality in APT (Hazard ratio [HR] 0.74, 0.57-0.95) but higher in RAJ (HR 1.37, 1.01-1.87). Facilities with higher proportion of lost to follow-up patients in APT had higher mortality (HR 1.47, 1.06-2.05), as did those with higher ART to pre-ART patient ratio in RAJ (HR 1.62, 1.14-2.29). In both states, there was higher hazard for mortality in patients with CD4 count 100 cells/mm3 or less at ART initiation, males, and in patients with TB co-infection. These data from the majority of facilities in a high- and a low-HIV burden state of India over 5 years reveal reasonable and similar survival outcomes in the two states. The facilities with higher ART load in the longer established ART program in APT had better survival, but facilities with a higher ART load and a higher ratio of ART to pre-ART patients in the less experienced ART program in RAJ had poorer survival. These findings have important implications for India's ART program planning as it expands further.


Physical therapy services utilization and length of stay for obese patients following traumatic leg fracture.
Obesity is an increasing epidemic that can complicate the treatment of simple injuries and can increase health care costs. The purpose of the present study was to determine whether obesity is a factor in the utilization of inpatient physical therapy services and length of stay following a traumatic lower leg fracture. A retrospective study of patients admitted to the hospital in 2005 and 2006 with a primary discharge diagnosis of lower leg or ankle fracture was conducted. Inclusion criteria were age > or = 18 years, only 1 involved lower extremity, and nonweight-bearing on the affected extremity per physician orders. Patients were excluded from the study if they had a fibular fracture only, pathological fractures, multiple trauma, severe cardiac or vascular comorbidities, or cognitive impairments. Data were compiled into 3 categories on the basis of body mass index (BMI): < 30, 30-35, > 35. Physical therapy services were measured in 15-minute units of time. These data were analyzed by within-group and between-group comparisons and with regression analysis. A total of 181 patients with a primary discharge diagnosis of distal lower extremity or ankle fracture were included in the study. Patients with a BMI >35 used more physical therapy services (mean services, 9.8 units) than did patients with a BMI of 30-35 (mean services, 6.2 units) or a BMI <30 (mean services, 5.6 units) (P = .001). Length of stay was also highest among patients with a BMI >35. Factors other than BMI may be associated with length of stay and physical therapy use and may confound the association. Previous studies have shown that there is an increase in health care utilization among the bariatric population. The present study demonstrates similar findings for physical therapy services. Increased length of stay and physical therapy utilization among the bariatric population also result in increased staff utilization and equipment costs.


Direct interaction between substrates and endogenous steroids in the active site may change the activity of cytochrome P450 3A4.
CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrate including endogenous steroids and some drugs that coexist at the active site. To clarify the mechanism of the effect of endogenous steroids on the drug metabolism, the interaction between substrates, nevirapine (NVP) and carbamazepine (CBZ), and endogenous steroids was investigated by theoretical calculations. When the activities of NVP 2-hydroxylation and CBZ 10,11-epoxidation by expressed CYP3A4 were measured in the presence of steroids, NVP 2-hydroxylation was found to be remarkably increased by aldosterone and inhibited by estradiol. CBZ 10,11-epoxidation was increased by androstenedione. Three-dimensional computer modeling has shown that the active site of CYP3A4 is especially large, permitting access of two substrate molecules. The interactions between NVP and aldosterone and between CBZ and androstenedione were estimated by theoretical calculations assuming the substrate and steroids to be present in the active site at the same time. It was shown that NVP or CBZ would be stably fixed close to the oxygen atom at the sixth ligand of heme by interaction with steroids, suggesting that NVP and CBZ may be hydroxylated more easily due to the interaction with steroids. Estradiol was also expected to interact with NVP via a pi/pi interaction between a benzene ring, in which the NVP hydroxylation site is located, and a benzene ring of estradiol, suggested to inhibit the reaction. From these results, interactions between the substrate and endogenous steroids in the active site may change the activity of CYP3A4.


A Systematic Review of Vancomycin Dosing and Monitoring in Burn Patients.
Vancomycin pharmacokinetics are significantly altered following burn injury, requiring a higher total daily dose to achieve adequate serum concentrations. Wide interpatient variability necessitates close, frequent monitoring of serum concentrations for efficacy and safety. The aim of this study is to systematically evaluate published data regarding vancomycin pharmacokinetic alterations in burn patients, to determine whether evidence-based recommendations for dosing and monitoring can be formulated, and to identify future research opportunities. The systematic review included studies published in English, involved human subjects with at least a 10% TBSA burn who received vancomycin intravenously, and obtained serum concentration(s). Database searches returned 130 titles for review. Twelve studies met a priori inclusion criteria. The most common dosing regimens in adult and pediatric patients were 5 to 20 mg/kg/dose every 6 to 8 hours. Mean trough concentrations were 7.24 ± 1.5 mg/L. Only 12.5% of reported trough concentrations were within the currently recommended range of 10 to 20 mg/L. Although no consistent dosing recommendations were provided, all studies recommended close monitoring of trough concentrations. Based on limited clinical outcomes data, standardized recommendations for vancomycin dosing and monitoring in burn patients cannot be made. Higher total daily doses (40-70 mg/kg/day) and increased dosing frequency (every 6-12 hr in adults) may be necessary to achieve current target trough concentrations. Future research goals include prospective investigation of clinical outcomes related to initial doses, loading doses, monitoring peak and trough concentrations, and adverse effects. Further data on the effects of burn size, concomitant diseases, inhalation injury, and time since injury may improve the accuracy of vancomycin dosing in burn patients.


Brain-Machine Interface in Chronic Stroke: Randomized Trial Long-Term Follow-up.
Brain-machine interfaces (BMIs) have been recently proposed as a new tool to induce functional recovery in stroke patients. Here we evaluated long-term effects of BMI training and physiotherapy in motor function of severely paralyzed chronic stroke patients 6 months after intervention. A total of 30 chronic stroke patients with severe hand paresis from our previous study were invited, and 28 underwent follow-up assessments. BMI training included voluntary desynchronization of ipsilesional EEG-sensorimotor rhythms triggering paretic upper-limb movements via robotic orthoses (experimental group, n = 16) or random orthoses movements (sham group, n = 12). Both groups received identical physiotherapy following BMI sessions and a home-based training program after intervention. Upper-limb motor assessment scores, electromyography (EMG), and functional magnetic resonance imaging (fMRI) were assessed before (Pre), immediately after (Post1), and 6 months after intervention (Post2). The experimental group presented with upper-limb Fugl-Meyer assessment (cFMA) scores significantly higher in Post2 (13.44 ± 1.96) as compared with the Pre session (11.16 ± 1.73; P = .015) and no significant changes between Post1 and Post2 sessions. The Sham group showed no significant changes on cFMA scores. Ashworth scores and EMG activity in both groups increased from Post1 to Post2. Moreover, fMRI-BOLD laterality index showed no significant difference from Pre or Post1 to Post2 sessions. BMI-based rehabilitation promotes long-lasting improvements in motor function of chronic stroke patients with severe paresis and represents a promising strategy in severe stroke neurorehabilitation.


WE-F-211-01: The Evolving Landscape of Scientific Publishing.
The dissemination of scientific advances has changed little since the first peer-reviewed journal was published in 1665 - that is, until this past decade. The print journal, delivered by mail and stored on office shelves and in library reading rooms around the world, has been transformed by immediate, on-demand access to scientific discovery in electronic form. At the same time, the producers and consumers of that scientific content have greatly increased in number, and the balance between supply and demand has required innovations in the world of scientific publishing. In light of technological advances and societal expectations, the dissemination of scientific knowledge has assumed a new form, one that is dynamic and rapidly changing. The academic medical physicist must understand this evolution to ensure that appropriate decisions are made with regard to journal submission strategies and that relevant information on new findings is obtained in a timely manner. Medical Physics is adapting to these changes in substantive ways. This new scientific publishing landscape has implications for subscription models, targeted access through semantic enrichment, user interactivity with content, customized content delivery, and advertising opportunities. Many organizations, including the AAPM, depend on scientific publishing as a significant source of revenue, but web-based delivery raises the expectation that access should be free and threatens this model. The purpose of this symposium is to explore the factors that have contributed to the current state of scientific publishing, to anticipate future directions in this arena, and to convey how medical physicists may benefit from the expanded opportunities, both as authors and as readers. 1. To appreciate the importance of scientific and clinical practice communication for the advancement of the medical physics field 2. To understand the roles of the Editorial Board and the Journal Business Management Committee in the promotion and advancement of Medical Physics 3. To explore technology-driven content delivery mechanisms and their role in facilitating content access and driving content usage 4. To understand the potential benefits and pitfalls of various economic and editorial models of scientific publications and the recent shifts away from the traditional role of libraries.


Awe expands people's perception of time, alters decision making, and enhances well-being.
When do people feel as if they are rich in time? Not often, research and daily experience suggest. However, three experiments showed that participants who felt awe, relative to other emotions, felt they had more time available (Experiments 1 and 3) and were less impatient (Experiment 2). Participants who experienced awe also were more willing to volunteer their time to help other people (Experiment 2), more strongly preferred experiences over material products (Experiment 3), and experienced greater life satisfaction (Experiment 3). Mediation analyses revealed that these changes in decision making and well-being were due to awe's ability to alter the subjective experience of time. Experiences of awe bring people into the present moment, and being in the present moment underlies awe's capacity to adjust time perception, influence decisions, and make life feel more satisfying than it would otherwise.


Systemic therapy in stage IV pancreatic cancer: a population-based analysis using the National Cancer Data Base.
Pancreatic cancer accounts for approximately 7% of all cancer deaths. More than half of all pancreatic cancers are stage IV at diagnosis, where systemic chemotherapy is used with the goal of life prolongation as well as palliation. The patient characteristics and health system factors that drive the use of systemic therapy are unknown. This is a retrospective study of stage IV pancreatic cancer patients (n = 140,210) diagnosed between 2000 and 2011 in the NCDB. NCDB contains approximately 70% of new cancer diagnosis from more than 1500 accredited cancer programs in the United States and Puerto Rico. Chi-squared test was used to determine any differences in characteristics of patients who did or did not receive systemic therapy. Our study demonstrated that only 49.1% of stage IV pancreatic cancer patients received systemic therapy. The use of systemic therapy is significantly lower in female, African American/Hispanic, patients older than 40 years, those without insurance or with Medicare and Medicaid, higher Charlson Comorbidity Score, poor economic and educational status and in nonacademic centers. This is the largest study to evaluate the determinants of systemic therapy use in stage IV pancreatic cancer. The use of systemic therapy was significantly lower in patients older than 40 years, lower educational status, nonprivate insurance and with higher Charlson Comorbidity Scores. In addition, the use of systemic therapy was lower with female sex, African Americans/Hispanic, and lower socio-economic status. Understanding the barriers in the use of systemic therapy as well as appropriate utilization of systemic therapy can both optimize cancer care.


Pif1 regulates telomere length by preferentially removing telomerase from long telomere ends.
Telomerase, a ribonucleoprotein complex, is responsible for maintaining the telomere length at chromosome ends. Using its RNA component as a template, telomerase uses its reverse transcriptase activity to extend the 3'-end single-stranded, repetitive telomeric DNA sequence. Pif1, a 5'-to-3' helicase, has been suggested to regulate telomerase activity. We used single-molecule experiments to directly show that Pif1 helicase regulates telomerase activity by removing telomerase from telomere ends, allowing the cycling of the telomerase for additional extension processes. This telomerase removal efficiency increases at longer ssDNA gaps and at higher Pif1 concentrations. The enhanced telomerase removal efficiency by Pif1 at the longer single-stranded telomeric DNA suggests a way of how Pif1 regulates telomerase activity and maintains telomere length.


A Novel Metal-Based Imaging Probe for Targeted Dual-Modality SPECT/MR Imaging of Angiogenesis.
Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for in vivo targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with 99mTc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. In vitro cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. Fe3O4-DMSA-SMCC-BCZM-99mTc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. In vitro cell binding studies showed the ability of the Fe3O4-DMSA-SMCC-BCZM-99mTc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The ex vivo biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The Fe3O4-DMSA-SMCC-BCZM-99mTc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of Fe3O4-DMSA-SMCC-BCZM-99mTc for targeted dual-modality imaging. Our findings indicate that Fe3O4-DMSA-SMCC-BCZM-99mTc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer.


A natural killer cell receptor specific for a major histocompatibility complex class I molecule.
Target cell expression of major histocompatibility complex (MHC) class I molecules correlates with resistance to lysis by natural killer (NK) cells. Prior functional studies of the murine NK cell surface molecule, Ly-49, suggested its role in downregulating NK cell cytotoxicity by specifically interacting with target cell H-2Dd molecules. In support of this hypothesis, we now demonstrate a physical interaction between H-2Dd and Ly-49 in both qualitative and quantitative cell-cell binding assays employing a stable transfected Chinese hamster ovary (CHO) cell line expressing Ly-49 and MHC class I transfected target cells. Binding occurred only when CHO cells expressed Ly-49 at high levels and targets expressed H-2Dd by transfection. Monoclonal antibody blocking experiments confirmed this interaction. These studies indicate that the specificity of natural killing is influenced by NK cell receptors that engage target cell MHC class I molecules.


Optimization of xanthones for antimalarial activity: the 3,6-bis-omega-diethylaminoalkoxyxanthone series.
Hydroxyxanthones have been identified as novel antimalarial agents. The compounds are believed to exert their activity by complexation to heme and inhibition of hemozoin formation. Modification of the xanthone structure was pursued to improve their antimalarial activity. Attachment of R-groups bearing protonatable nitrogen atoms was conducted to enhance heme affinity through ionic interactions with the propionate side chains of the metalloporphyrin and to facilitate drug accumulation in the parasite food vacuole. A series of 3,6-bis-omega-diethylaminoalkoxyxanthones with side chains ranging from 2 to 8 carbon atoms were prepared and evaluated. Measurement of heme affinity for each of the derivatives revealed a strong correlation (R(2) = 0.97) between affinity and antimalarial potency. The two most active compounds in the series contained 5- and 6-carbon side chains and exhibited low nanomolar 50% inhibitory concentration (IC(50)) values against strains of chloroquine-susceptible and multidrug-resistant Plasmodium falciparum in vitro. Both of these xanthones exhibit stronger heme affinity (8.26 x 10(5) and 9.02 x 10(5) M(-1), respectively) than either chloroquine or quinine under similar conditions and appear to complex heme in a unique manner.


P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells.
Overexpression of P-glycoprotein (Pgp/ABCB1) in tumor cells is associated with a classic phenotype of multidrug resistance (MDR). Moreover, some members of the inhibitor of apoptosis protein (IAP) family, such as survivin, contribute to an apoptosis-resistant phenotype, by inhibiting chemotherapy-induced cell death and promoting MDR. By using Western blotting, qRT-PCR, Annexin V and immunofluorescence assays we have demonstrated a relationship between Pgp and survivin in a prior sensitive chronic myeloid leukemia (CML) cell line (K562). A high dose of vincristine induced a concomitant overexpression of Pgp and survivin, which was associated with a low apoptotic index in the K562 cell line. In addition, we observed a cytoplasmic co-localization of Pgp and survivin, suggesting a functional association between these two proteins in apoptosis control by a common mechanism. In summary, our data suggest that Pgp and survivin should be analyzed in aggregate because they may have significant impact on drug resistance in CML cells.


Biofilm formation at the air-liquid interface by the Pseudomonas fluorescens SBW25 wrinkly spreader requires an acetylated form of cellulose.
The wrinkly spreader (WS) genotype of Pseudomonas fluorescens SBW25 colonizes the air-liquid interface of spatially structured microcosms resulting in formation of a thick biofilm. Its ability to colonize this niche is largely due to overproduction of a cellulosic polymer, the product of the wss operon. Chemical analysis of the biofilm matrix shows that the cellulosic polymer is partially acetylated cellulose, which is consistent with predictions of gene function based on in silico analysis of wss. Both polar and non-polar mutations in the sixth gene of the wss operon (wssF ) or adjacent downstream genes (wssGHIJ ) generated mutants that overproduce non-acetylated cellulose, thus implicating WssFGHIJ in acetylation of cellulose. WssGHI are homologues of AlgFIJ from P. aeruginosa, which together are necessary and sufficient to acetylate alginate polymer. WssF belongs to a newly established Pfam family and is predicted to provide acyl groups to WssGHI. The role of WssJ is unclear, but its similarity to MinD-like proteins suggests a role in polar localization of the acetylation complex. Fluorescent microscopy of Calcofluor-stained biofilms revealed a matrix structure composed of networks of cellulose fibres, sheets and clumped material. Quantitative analyses of biofilm structure showed that acetylation of cellulose is important for effective colonization of the air-liquid interface: mutants identical to WS, but defective in enzymes required for acetylation produced biofilms with altered physical properties. In addition, mutants producing non-acetylated cellulose were unable to spread rapidly across solid surfaces. Inclusion in these assays of a WS mutant with a defect in the GGDEF regulator (WspR) confirmed the requirement for this protein in expression of both acetylated cellulose polymer and bacterial attachment. These results suggest a model in which WspR regulation of cellulose expression and attachment plays a role in the co-ordination of surface colonization.


The influence of the tonometer position on canine intraocular pressure measurements using the Tonovet® rebound tonometer.
The objective of this study was to assess the variability of readings made using the Tonovet® rebound tonometer for measurement of intraocular pressure (IOP) in the peripheral cornea and in angulated positions on the canine corneal surface. Forty-six client-owned dogs admitted for ophthalmic evaluation at the Queen's Veterinary School Hospital, University of Cambridge were included in the study. IOP readings were taken at a variety of locations and using the tonometer at a number of different angles to the cornea: 1) Perpendicularly at center of the cornea (CC); 2) At the center of the cornea but with the tonometer positioned at four angles, and 3) At four different points on the peripheral cornea. All values were compared with the values recorded at the recommended CC position. IOP values were significantly underestimated in seven positions, with median and interquartile range from 12.1 ± 4 mmHg (nasal on periphery) to 15 ± 5 mmHg (laterally angled at center), varying between 0 mmHg to 2.9 mmHg from the CC value. While dorsally angled in the central cornea were not significantly different from those at CC (p = 0.09). Median values were lower for measurements in peripheral positions when compared to angled central positions. These results demonstrate that angling the tonometer or measuring in peripheral regions can result in small but statistically significant underestimation of IOP values.


Cytochrome P450-mediated metabolism of xanthotoxin by Papilio multicaudatus.
Within the genus Papilio, the P. glaucus group contains the most polyphagous Papilio species within the Papilionidae. The majority of Papilio species are associated with hostplants in the families Rutaceae and Apiaceae, and characterizing most are secondary metabolites called furanocoumarins. Recent phylogenetic studies suggest that furanocoumarin metabolism is an ancestral trait, with the glaucus group derived from ancestors associated with furanocoumarin-containing Rutaceae. In this study, we examined this relationship by conducting a gravimetric analysis of growth that used various concentrations of the furanocoumarin xanthotoxin. Papilio multicaudatus, the putative ancestor of the glaucus group, includes at least one furanocoumarin-containing rutaceous species among its hostplants; this species can consume leaf tissue containing up to 0.3% xanthotoxin with no detectable effect on relative growth rate, relative consumption rate, or efficiency of conversion of ingested food. As is the case for other Papilio species, xanthotoxin metabolism is mediated by cytochrome P450 monooxygenases (P450s). Ingestion of xanthotoxin by ultimate instar P. multicaudatus increases activity up to 30-fold in a dose-dependent fashion. Midguts of induced larvae can also effectively metabolize six other furanocoumarins, including both linear (bergapten, isopimpinellin, imperatorin) and angular (angelicin, sphondin) forms. A metabolite of xanthotoxin in the frass from xanthotoxin-treated larvae, identified as 6-(7-hydroxy-8-methoxycoumaryl)-acetic acid by MS-MS and NMR analyses, is identical to one from the frass of P. polyxenes. The occurrence of this metabolite in two swallowtails and the presence of a second metabolite of xanthotoxin, 6-(7-hydroxy-8-methoxycoumaryl)-hydroxyethanol in the frass of both P. polyxenes and Depressaria pastinacella are consistent with the suggestion that lepidopterans share as the first step of xanthotoxin metabolism the P450-mediated epoxidation of the furan ring 2'-3' double bond.


Activated Notch1 is a stronger astrocytic stimulus than leukemia inhibitory factor for rat neural stem cells.
Neural stem cells (NSC) self-renew and generate specialized cell types. There are reports indicating that Notch and Leukemia Inhibitory Factor (LIF) signaling are involved in cell determination of NSC, either preventing differentiation or promoting astrocytic fate. In this work, we aimed to compare the astrocytogenic effect of activated Notch with that induced by LIF. To this end, rat cerebral cortex neural progenitors/NSC were transduced with retroviral vectors in order to express green fluorescent protein (GFP), or a fusion protein of GFP with the active Notch1 intracellular domain (NICD). In parallel, other cultures were treated with increasing concentrations of LIF. We confirmed, in proliferating NSC, that LIF activated intracellular effectors by measuring STAT3 phosphorylation and Socs3 transcription. In NICD-expressing cells, Hes5 mRNA was induced, an effect not present in GFP-transduced NSC. We quantified the proportion of cells expressing Nestin in the presence of Fibroblast Growth Factor-2 (FGF-2) with LIF or NICD treatments. LIF significantly increased the proportion of cells co-expresssing Nestin and Glial Fibrillary Acidic Protein (GFAP), an effect absent in cells with activated Notch. After FGF2 withdrawal to promote differentiation, Nestin was markedly down-regulated, and neuronal and glial markers appeared in control cultures. LIF treatment caused a significant increase in the proportion of GFAP-positive cells, but cells expressing NICD showed a significantly higher percentage of astrocytes than control and LIF-treated cultures. These experiments show that cells stimulated with NICD differentiate more readily to astrocytes than LIF-treated NSC.


Use of CRISPR systems in plant genome editing: toward new opportunities in agriculture.
Initially discovered in bacteria and archaea, CRISPR-Cas9 is an adaptive immune system found in prokaryotes. In 2012, scientists found a way to use it as a genome editing tool. In 2013, its application in plants was successfully achieved. This breakthrough has opened up many new opportunities for researchers, including the opportunity to gain a better understanding of plant biological systems more quickly. The present study reviews agricultural applications related to the use of CRISPR systems in plants from 52 peer-reviewed articles published since 2014. Based on this literature review, the main use of CRISPR systems is to achieve improved yield performance, biofortification, biotic and abiotic stress tolerance, with rice (Oryza sativa) being the most studied crop.


Image-based color ink diffusion rendering.
This paper proposes an image-based painterly rendering algorithm for automatically synthesizing an image with color ink diffusion. We suggest a mathematical model with a physical base to simulate the phenomenon of color colloidal ink diffusing into absorbent paper. Our algorithm contains three main parts: a feature extraction phase, a Kubelka-Munk (KM) color mixing phase, and a color ink diffusion synthesis phase. In the feature extraction phase, the information of the reference image is simplified by luminance division and color segmentation. In the color mixing phase, the KM theory is employed to approximate the result when one pigment is painted upon another pigment layer. Then, in the color ink diffusion synthesis phase, the physically-based model that we propose is employed to simulate the result of color ink diffusion in absorbent paper using a texture synthesis technique. Our image-based ink diffusing rendering (IBCIDR) algorithm eliminates the drawback of conventional Chinese ink simulations, which are limited to the black ink domain, and our approach demonstrates that, without using any strokes, a color image can be automatically converted to the diffused ink style with a visually pleasing appearance.


Comparing ε-Aminocaproic Acid and Tranexamic Acid in Reducing Postoperative Transfusions in Total Knee Arthroplasty.
Multiple studies have shown tranexamic acid (TXA) to reduce blood loss and transfusion rates in patients undergoing total knee arthroplasty (TKA). Accordingly, TXA has become a routine blood conservation agent for TKA. In contrast, ε-aminocaproic acid (EACA), a similar acting antifibrinolytic to TXA, has been less frequently used. This study evaluated whether EACA is as efficacious as TXA in reducing postoperative blood transfusion rates and compared the cost per surgery between agents. A multicenter retrospective chart review of elective unilateral TKA from April 2012 through December 2014 was performed. Five hospitals within a health care system participated. Data collected included age, gender, severity of illness score, use of antifibrinolytic and dose, red blood cell (RBC) transfusions and the number of units, and preadmission and discharge hemoglobin (Hb). Dosing of the antifibrinolytic differed based on the agent used, 5 or 10 g (based on weight) for EACA versus 1 g for TXA. The institutional acquisition cost of each antifibrinolytic was obtained and averaged over the study period. Of 2,922 primary unilateral TKA cases, 820 patients received EACA, 610 patients received TXA, and 1,492 patients received no antifibrinolytic (control group). Compared with the control group both EACA and TXA groups had significantly fewer patients transfused (EACA 2.8% [p < 0.0001], TXA 3.2% [p < 0.0001] vs. control 10.8%) and lower mean RBC units transfused per patient (EACA 0.05 units/patient [pt] [p < 0.0001], TXA 0.05 units/pt [p < 0.0001] vs. control 0.19 units/pt]. There was no difference in mean RBC units transfused per patient, percentage of patients transfused, and discharge Hb levels between the EACA and TXA groups (p = 0.822, 0.236, and 0.322, respectively). Medication acquisition cost for EACA averaged $2.23 per surgery compared with TXA at $39.58 per surgery. Administration of EACA or TXA significantly decreased postoperative transfusion rates compared with no antifibrinolytic therapy. Utilization of EACA for unilateral TKA proved to be comparable to TXA in all studied aspects at a lower cost. The level of evidence for the study is Level 3.


Enhancing computer literacy and information retrieval skills: A rural and remote nursing and midwifery workforce study.
Nurses and midwives collectively, represent the largest workforce category in rural and remote areas of Australia. Maintaining currency of practice and attaining annual licensure with the Australian Health Practitioners Regulatory Authority (AHPRA) present challenges for individual nurses and midwives and for their health service managers. Engagement with information and communication technologies, in order for geographically isolated clinicians to access ongoing education and training, is considered a useful strategy to address such challenges. This paper presents a pre- and post-test study design. It examines the impact of an online continuing professional development (CPD) program on Australian rural nurses and midwives. The aims of the program were to increase basic skill acquisition in the utilisation of common computer software, the use of the Internet and the enhancement of email communication. Findings from the study demonstrate that participants who complete a relevant CPD program gain confidence in the use of information and communication technologies. Further, increased confidence leads to increased access to contemporary, reliable and important health care information on the Internet, in addition to clinicians adopting email as a regular method of communication. Health care employers commonly assume employees are skilled users of information and communication technologies. However, findings from this study contradict such assumptions. It is argued in the recommendations that health care employees should be given regular access to CPD programs designed to introduce them to information and communication technologies. Developing knowledge and skills in this area has the potential to improve staff productivity, raise health care standards and improve patient outcomes.


Short relative leg length is associated with overweight and obesity in Mexican immigrant women.
Prior research suggests that undernutrition and enteric infections predispose children to stunted growth. Undernutrition and infections have been associated with limited access to healthy diets, lack of sanitation, and access barriers to healthcare - all associated with human rights. Stunting has also been documented to be a major determinant of subsequent obesity and non-communicable diseases. Short leg length relative to stature during adulthood seems to be a good proxy indicator tracking such barriers, and has been reported to be associated with adverse health effects during adulthood. Our objective was to examine the association between relative leg length (as measured by the leg length index, LLI) and measures of adiposity - based on body mass index (BMI) and waist circumference (WC) - in a population of recent Mexican immigrant women to the New York City Area. The analysis was based on a cross-sectional survey of 200 Mexican immigrant women aged 18 to 70 years, whose data were collected between April and November 2008; although for purposes of the current study we restricted the sample to those aged 18 to 59 years. The dependent variables were BMI and WC, both transformed into categorical variables. The main independent variable was LLI, and other correlates were controlled for (i.e. age, education, having had children, characteristics of the community of origin, acculturation, chronic conditions, sedentary behaviors, access to fresh fruits and vegetables). Two probit models were estimated: the first one analyzed the effect of LLI on BMI categories and the second one estimated the effect of LLI on WC. The probit assessing the effect of LLI on overweight/obesity suggested that having a short LLI increased the probability of overweight/obesity by 21 percentage points. Results from the probit model estimating the effect of LLI on WC indicated that having a short LLI increased the probability of having abdominal adiposity by 39 percentage points. Both results were statistically significant at p < 0.05. The study found an association between having shorter legs relative to one's height and increased risk of overweight/obesity and abdominal adiposity. Findings support the epidemiological evidence regarding the association between short leg length, early life socioeconomic conditions (i.e. limited access to basic rights), and increased risk of adverse health effects later in life.


The information needs and preferences of persons with longstanding inflammatory bowel disease.
Understanding the information needs and preferred vehicles of information delivery to patients with inflammatory bowel disease (IBD) will enhance their care. To survey persons with longstanding IBD as to their information needs and preferred vehicles of information delivery. The population-based Manitoba IBD Cohort (n=271, mean disease duration 11 years) was surveyed to assess its information needs across 23 issues, both retrospectively at the time of diagnosis and currently. Most participants (64%) were initially diagnosed by a gastroenterologist, or otherwise by a family physician (19%) or surgeon (12%). Recalling time of diagnosis, at least 80% rated as very important information about common symptoms of IBD, possible complications, long-term prognosis, medication side effects, self management of symptoms and when to involve the doctor, yet only 10% to 36% believed they received the right amount of information about these issues. Dietary guidance was also regarded as important by 80% to 89%, yet only 8% to 16% received the correct amount of information. Regarding current needs, a large proportion believed it would be very helpful to have more information about long-term prognosis (66%) and diet considerations (60% to 68%). The following information sources were regarded as very acceptable: medical specialist (81%); brochure (79%); family doctor (64%); and website (64%), with 51% ranking the medical specialist as the first choice. In a comparison of the responses of this cohort to those of a recently diagnosed sample, there was remarkable consistency in the information needs and most desired sources of information. In the present population-based cohort with longstanding disease, dietary information was regarded as the least adequately addressed. There was clear openness to receiving information through other routes than just the medical specialist, suggesting that optimizing brochures and websites would be an important adjunct source of information. Approximately 10 years after diagnosis, only a small percentage of persons with IBD believed they received the correct amount of information about the issues they regarded as most important to have discussed at diagnosis.


Adaptations to in situ feeding: novel nutrient acquisition pathways in an ancient vertebrate.
During feeding, hagfish may immerse themselves in the body cavities of decaying carcasses, encountering high levels of dissolved organic nutrients. We hypothesized that this feeding environment might promote nutrient acquisition by the branchial and epidermal epithelia. The potential for Pacific hagfish, Eptatretus stoutii, to absorb amino acids from the environment across the skin and gill was thus investigated. l-alanine and glycine were absorbed via specific transport pathways across both gill and skin surfaces, the first such documentation of direct organic nutrient acquisition in a vertebrate animal. Uptake occurred via distinct mechanisms with respect to concentration dependence, sodium dependence and effects of putative transport inhibitors across each epithelium. Significant differences in the absorbed amino acid distribution between the skin of juveniles and adults were noted. The ability to absorb dissolved organic matter across the skin and gill may be an adaptation to a scavenging lifestyle, allowing hagfish to maximize sporadic opportunities for organic nutrient acquisition. From an evolutionary perspective, hagfish represent a transitory state between the generalized nutrient absorption pathways of aquatic invertebrates and the more specialized digestive systems of aquatic vertebrates.


Genetic diversity patterns in five protist species occurring in lakes.
Little is known about the extent of the genetic diversity and its structuring patterns in protist species living in lakes. Here, we have investigated the genetic diversity patterns within five dinoflagellate species (Peridinium aciculiferum, Peridinium cinctum, Peridiniopsis borgei, Polarella glacialis, Scrippsiella aff. hangoei) that are present in lakes and sometimes, in marine habitats located in polar and temperate regions. A total of 68 clonal strains were investigated using Amplified Fragment Length Polymorphism (AFLP), a sensitive genetic fingerprinting technique. All used strains within each species had identical ITS nuclear ribosomal DNA sequences, a characteristic that indicates that they likely belong to the same species. We found a wide variability in the genetic diversity among species (between 20% and 90% of polymorphic loci; Nei's gene diversity between 0.08 and 0.37). In some cases, our analyses suggested the presence of different genetically homogeneous subgroups (genetic populations) within the same water body. Thus, it appears that different genetic populations can coexist within the same lake despite the likely occurrence of recombination that tends to homogenize the gene pool. Overall, our results indicated that a large number of dinoflagellate genotypes are present in lake populations, instead of a few dominating ones. In addition, our study shows that protists with identical ITS sequences can harbor considerable amounts of genetic diversity.


[Colonic balantidiasis: report of a fatal case and review of the literature].
Balantidiasis is a zoonosis produced by Balantidium coli, which inhabits the large intestine of the pig and man. Infection is uncommon in humans and mainly affects the colon. It occurs more frequently in developing countries, tropical and subtropical regions. Colonic balantidiasis can occur in most cases asymptomatically and reach in the most severe cases such as dysenteric diarrhea that can be complicated by low digestive bleeding and even perforation. We present the case of a 72-year-old man, from the Peruvian highlands, who was a farmer and breeder of swine and sheep, who came for 3 months of illness, initially characterized by liquid stools with bloodless mucus, abdominal pain, nausea, vomiting and in the last month of illness he presents dysenteric diarrhea. Colonoscopy was performed due to suspicion of infectious colitis, Balantidium coli trophozoites were found in the fresh sample and colonic tissue biopsy. Patient receives treatment with amebicide and antibacterial without clinical improvement, presenting as a complication multiple perforation in the sigmoid colon, treated with resection and terminal colostomy. Finally, the patient died despite receiving medical and surgical treatment.


Clinically meaningful effect of strontium ranelate on symptoms in knee osteoarthritis: a responder analysis.
The aim of this study was to assess the efficacy of strontium ranelate in improving symptoms in knee OA. Symptoms were assessed over 3 years in patients with primary knee OA receiving strontium ranelate 2 g/day (n = 454), 1 g/day (n = 445) or placebo (n = 472) in the Strontium Ranelate Efficacy in Knee Osteoarthritis Trial. Clinical response was evaluated using WOMAC subscores, minimal perceptible clinical improvement (MPCI), minimal clinically important improvement (MCII) and a modified OMERACT-Osteoarthritis Research Society International (OARSI) responder definition. Patients who withdrew prematurely from the study were considered non-responders. There was no significant effect on symptoms for strontium ranelate 1 g/day. At the dosage of 2 g/day, strontium ranelate was associated with greater response than placebo in terms of ≥20% improvement in WOMAC pain from baseline to the last visit (58% vs 47%, P = 0.002) and ≥50% improvement in WOMAC pain (42% vs 36%, P = 0.083). Significant differences were found in MPCI response for WOMAC pain (52% vs 40%, P < 0.001), stiffness (47% vs 39%, P = 0.009) and physical function (46% vs 37%, P = 0.009) and in MCII response for WOMAC physical function (46% vs 37%, P = 0.013). There were also more OMERACT-OARSI-like responders with strontium ranelate (44% vs 35%, P = 0.004). The treatment-placebo difference in MPCI response for WOMAC pain was significant after 6 months (P = 0.024), while that in MPCI and MCII response for WOMAC physical function reached significance after 12 months (P = 0.027 and P = 0.019, respectively). Treatment with strontium ranelate 2 g/day over 3 years is associated with a clinically meaningful improvement in pain from 6 months as well as physical function and stiffness as assessed by the number of responders above thresholds of clinical relevance. Current Controlled Trials. http://www.controlled-trials.com/ (ISRCTN41323372).


Evaluation of a Targeted COVID-19 Community Outreach Intervention: Case Report for Precision Public Health.
Cameron County, a low-income south Texas-Mexico border county marked by severe health disparities, was consistently among the top counties with the highest COVID-19 mortality in Texas at the onset of the pandemic. The disparity in COVID-19 burden within Texas counties revealed the need for effective interventions to address the specific needs of local health departments and their communities. Publicly available COVID-19 surveillance data were not sufficiently timely or granular to deliver such targeted interventions. An agency-academic collaboration in Cameron used novel geographic information science methods to produce granular COVID-19 surveillance data. These data were used to strategically target an educational outreach intervention named "Boots on the Ground" (BOG) in the City of Brownsville (COB). This study aimed to evaluate the impact of a spatially targeted community intervention on daily COVID-19 test counts. The agency-academic collaboration between the COB and UTHealth Houston led to the creation of weekly COVID-19 epidemiological reports at the census tract level. These reports guided the selection of census tracts to deliver targeted BOG between April 21 and June 8, 2020. Recordkeeping of the targeted BOG tracts and the intervention dates, along with COVID-19 daily testing counts per census tract, provided data for intervention evaluation. An interrupted time series design was used to evaluate the impact on COVID-19 test counts 2 weeks before and after targeted BOG. A piecewise Poisson regression analysis was used to quantify the slope (sustained) and intercept (immediate) change between pre- and post-BOG COVID-19 daily test count trends. Additional analysis of COB tracts that did not receive targeted BOG was conducted for comparison purposes. During the intervention period, 18 of the 48 COB census tracts received targeted BOG. Among these, a significant change in the slope between pre- and post-BOG daily test counts was observed in 5 tracts, 80% (n=4) of which had a positive slope change. A positive slope change implied a significant increase in daily COVID-19 test counts 2 weeks after targeted BOG compared to the testing trend observed 2 weeks before intervention. In an additional analysis of the 30 census tracts that did not receive targeted BOG, significant slope changes were observed in 10 tracts, of which positive slope changes were only observed in 20% (n=2). In summary, we found that BOG-targeted tracts had mostly positive daily COVID-19 test count slope changes, whereas untargeted tracts had mostly negative daily COVID-19 test count slope changes. Evaluation of spatially targeted community interventions is necessary to strengthen the evidence base of this important approach for local emergency preparedness. This report highlights how an academic-agency collaboration established and evaluated the impact of a real-time, targeted intervention delivering precision public health to a small community.


Macroscale patterns in body size of intertidal crustaceans provide insights on climate change effects.
Predicting responses of coastal ecosystems to altered sea surface temperatures (SST) associated with global climate change, requires knowledge of demographic responses of individual species. Body size is an excellent metric because it scales strongly with growth and fecundity for many ectotherms. These attributes can underpin demographic as well as community and ecosystem level processes, providing valuable insights for responses of vulnerable coastal ecosystems to changing climate. We investigated contemporary macroscale patterns in body size among widely distributed crustaceans that comprise the majority of intertidal abundance and biomass of sandy beach ecosystems of the eastern Pacific coasts of Chile and California, USA. We focused on ecologically important species representing different tidal zones, trophic guilds and developmental modes, including a high-shore macroalga-consuming talitrid amphipod (Orchestoidea tuberculata), two mid-shore scavenging cirolanid isopods (Excirolana braziliensis and E. hirsuticauda), and a low-shore suspension-feeding hippid crab (Emerita analoga) with an amphitropical distribution. Significant latitudinal patterns in body sizes were observed for all species in Chile (21° - 42°S), with similar but steeper patterns in Emerita analoga, in California (32°- 41°N). Sea surface temperature was a strong predictor of body size (-4% to -35% °C-1) in all species. Beach characteristics were subsidiary predictors of body size. Alterations in ocean temperatures of even a few degrees associated with global climate change are likely to affect body sizes of important intertidal ectotherms, with consequences for population demography, life history, community structure, trophic interactions, food-webs, and indirect effects such as ecosystem function. The consistency of results for body size and temperature across species with different life histories, feeding modes, ecological roles, and microhabitats inhabiting a single widespread coastal ecosystem, and for one species, across hemispheres in this space-for-time substitution, suggests predictions of ecosystem responses to thermal effects of climate change may potentially be generalised, with important implications for coastal conservation.


Cannabis clubs in Uruguay: The challenges of regulation.
The Uruguayan Cannabis Clubs (UCCs) constitute one of three ways to obtain cannabis under the new cannabis regulation laws. These organizations, formed by up to 45 adults and with a legal limit to grow up to 99 plants, appear to provide a safe method of procuring cannabis in a country that is trying to regulate aspects of cannabis production and distribution. This article describes the operations of the UCCs and the challenges these organizations face. The paper draws on data from in-depth interviews conducted with representatives of UCCs and conversations with government officials conducted between March and August of 2015. We collected information about membership, facilities and forms of organization, methods of cannabis cultivation and distribution, and activities within the community. This article describes how UCCs are formed, their resources, rules for cannabis production and distribution; and their relationships with government institutions and the community. Data show that UCCs face four main challenges: compliance with the extant regulation, financial sustainability, tolerance from the community, and collective action dilemmas. Organizational challenges are as frequent in Uruguay as in other country where cannabis clubs exist, however this paper shows that in order to be sustainable, UCCs need to address issues of collective action, financial sustainability, and possible competition with cannabis distribution via pharmacies that could diminish membership. In the case of Uruguay, UCCs are part of a regulation effort, though they may not be preferred over other legal alternatives already in place.


Effect of adding upper limb rehabilitation to botulinum toxin-A on upper limb activity after stroke: Protocol for the InTENSE trial.
Rationale Although clinical practice guidelines recommend that management of moderate to severe spasticity include the use of botulinum toxin-A in conjunction with therapy, there is currently no evidence to support the addition of therapy. Aims To determine the effect and cost-benefit of adding evidence-based movement training to botulinum toxin-A. Sample size estimate A total of 136 participants will be recruited in order to be able to detect a between-group difference of seven points on the Goal Attainment Scale T-score with 80% power at a two-tailed significance level of 0.05. Methods and design The InTENSE trial is a national, multicenter, Phase III randomized trial with concealed allocation, blinded assessment and intention-to-treat analysis. Stroke survivors who are scheduled to receive botulinum toxin-A in any muscle(s) that cross the wrist because of moderate to severe spasticity after a stroke greater than three months ago, who have completed formal rehabilitation and have no significant cognitive impairment will be randomly allocated to receive botulinum toxin-A plus evidence-based movement training or botulinum toxin-A alone. Study outcomes The primary outcomes are goal attainment (Goal Attainment Scaling) and upper limb activity (Box and Block Test) at three months (end of intervention) and at 12 months (beyond the intervention). Secondary outcomes are spasticity, range of motion, strength, pain, burden of care and health-related quality of life. Direct costs, personal costs and health system costs will be collected at 12 months. Discussion The results of the InTENSE trial are anticipated to directly influence intervention for moderate to severe spasticity after stroke. Trial Registration ANZCTR12615000616572.


"Perhaps I will die young." Fears and worries regarding disease and death among Danish adolescents and young adults with cancer. A mixed method study.
A cross-sectional national study was initiated in order to evaluate healthcare services and survivorship from the perspective of Danish adolescents and young adults (AYAs) with cancer. The purpose of the paper was to examine (Q1) to what extend Danish AYAs experienced fears and worries about dying; (Q2) with whom, if anyone, they had shared those worries; and finally, (Q3) how fears and worries influenced their daily life. The emphasis will be on Q3. A 151-item questionnaire (including two closed- and one open-ended questions about fears of death and dying) was distributed among all 15-29-year-old Danes registered with a cancer diagnosis from 2009 to 2013. A total study population of 822 persons participated. Data was analyzed using a mixed design of descriptive statistics and qualitative content analysis. Q1: Almost 80 % of AYAs with cancer expressed some worries about death; hereof, more than half of them expressed quite a bit or very much. The analysis showed significant gender differences, whereas age and duration of disease did not have any significant impact on such thoughts. Q2: One third had not talked to anybody about his or her worries. Q3: The analysis resulted in three overall categories: fear of disease and death having little or no influence (n = 100), fear influencing in various ways (n = 215), and fear of disease and death having a substantial influence (n = 75). The majority of AYAs had experienced fears and worries about dying, but one third of them had not talked to anybody about those thoughts. It is an important clinical point that young age does not preclude fears and worries about dying in AYAs with cancer.


Seroprevalence study of Toscana virus and viruses belonging to the Sandfly fever Naples antigenic complex in central and southern Italy.
Sandfly fever viruses are transmitted by the bite of phlebotomine sandflies; serotypes sandfly fever Naples virus, sandfly fever Sicilian virus and sandfly fever Cyprus virus cause febrile illness, whereas Toscana virus (TOSV) may cause neuroinvasive infections. Although TOSV is an important cause of aseptic meningitis in central and southern Italy, in many cases the infection is asymptomatic, leading to underestimation of the actual spread of the virus. This serosurvey aimed to assess the seroprevalence of TOSV in a random population in Siena (Tuscany, central Italy) in 2003-2004 and 2013-2014 and Bari (Apulia, southern Italy) in 2004 and 2015. 2132 serum samples were tested for the presence of anti-TOSV/SFNV IgG by means of ELISA and IFA commercial tests. Seroprevalence rates were compared in the two cities and over a ten-year period in the same city. Seroprevalence results in the Siena population (22.95% in 2003-2004 vs 26.75% in 2013-2014) confirmed the endemic circulation of TOSV and closely related viruses in central Italy, without major changes over the last decade, while no significant prevalence was observed in Bari (2.90% in 2004 vs 1.85% in 2015).


Endogenous ways to stimulate brown adipose tissue in humans.
Obesity is the result of disequilibrium between energy intake and energy expenditure (EE). Successful long-term weight loss is difficult to achieve with current strategies for the correction of this caloric imbalance. Non-shivering thermogenesis (NST) in brown adipose tissue (BAT) is a possible therapeutic target for the prevention and treatment of obesity and associated metabolic diseases. In recent years, more knowledge about the function and stimulation of bat has been obtained. The sympathetic nervous system (SNS) is currently seen as the main effector for brown fat function. Also, interplay between the thyroid axis and SNS plays an important role in BAT thermogenesis. Almost daily new pathways for the induction of BAT thermogenesis and 'browning' of white adipose tissue (WAT) are identified. Especially the activation of BAT via endogenous pathways has received strong scientific attention. Here we will discuss the relevance of several pathways in activating BAT and their implications for the treatment of obesity. In this review we will focus on the discussion of the most promising endocrine and paracrine pathways to stimulate BAT, by factors and pathways that naturally occur in the human body.


HOX-4 genes and the morphogenesis of mammalian genitalia.
We examined the temporal and spatial expression patterns of the homeo box HOX-4 complex genes during the morphogenesis of the genitalia of mice. The results show that only those Hox-4 genes that are expressed very posteriorly in the trunk, or very distally in the limbs, seem to be involved in the patterning of the genital tubercle. This is consistent with the idea of "temporal colinearity", which suggests that the very last structure to require patterning during vertebrate development will express Hox genes located at the 5' extremity of the HOX complexes. We also show that genital tubercle mesenchyme can respecify pattern in the chicken wing bud. This finding reinforces the concept of the uniformity in the patterning mechanisms along the various axes of the body.


Matrix metalloproteinase induction of Rac1b, a key effector of lung cancer progression.
Lung cancer is more deadly than colon, breast, and prostate cancers combined, and treatment improvements have failed to improve prognosis significantly. Here, we identify a critical mediator of lung cancer progression, Rac1b, a tumor-associated protein with cell-transforming properties that are linked to the matrix metalloproteinase (MMP)-induced epithelial-mesenchymal transition (EMT) in lung epithelial cells. We show that expression of mouse Rac1b in lung epithelial cells of transgenic mice stimulated EMT and spontaneous tumor development and that activation of EMT by MMP-induced expression of Rac1b gave rise to lung adenocarcinoma in the transgenic mice through bypassing oncogene-induced senescence. Rac1b is expressed abundantly in stages 1 and 2 of human lung adenocarcinomas and, hence, is an attractive molecular target for the development of new therapies that prevent progression to later-stage lung cancers.


Chemodiversity and biodiversity of fungi associated with the pine weevil Hylobius abietis.
The pine weevil Hylobius abietis is a severe pest of conifer seedlings in reforestation areas. Weevils lay eggs in the root bark or in the soil near roots of recently dead trees and cover the eggs with frass (feces combined with chewed bark), possibly to avoid conspecific egg predation. The aim of the present investigation focused on isolation, identification, and volatile production of fungi from pine-weevil feces and frass. Fungi were isolated from weevil frass and feces separately, followed by identification based on ITS sequencing. Fifty-nine isolates belonging to the genera Penicillium, Ophiostoma, Mucor, Leptographium, Eucasphaeria, Rhizosphaera, Debaryomyces, and Candida were identified. Volatile organic compounds (VOCs) produced by the fungal community and fungal isolates cultured on weevil-frass broth were identified by SPME-GCMS. Major VOCs emitted from the fungal community and pure isolates were species- and strain specific and included isopentylalcohol, styrene, 3-octanone, 6-protoilludene, methyl salicylate, 3-methylanisole, 2-methoxyphenol, and phenol. Some of these are known to influence the orientation of pine weevils when tested among highly attractive newly planted conifer seedlings.


Comparison of the Diagnostic Performance of Coronary Computed Tomography Angiography-Derived Fractional Flow Reserve in Patients With Versus Without Diabetes Mellitus (from the MACHINE Consortium).
Coronary computed tomography angiography-derived fractional flow reserve (CT-FFR) is a noninvasive application to evaluate the hemodynamic impact of coronary artery disease by simulating invasively measured FFR based on CT data. CT-FFR is based on the assumption of a normal coronary microvascular response. We assessed the diagnostic performance of a machine-learning based application for on-site computation of CT-FFR in patients with and without diabetes mellitus with suspected coronary artery disease. The study population included 75 diabetic and 276 nondiabetic patients who were enrolled in the MACHINE consortium. The overall diagnostic performance of coronary CT angiography alone and in combination with CT-FFR were analyzed with direct invasive FFR comparison in 110 coronary vessels of the diabetic group and in 415 coronary vessels of the nondiabetic group. Per-vessel discrimination of lesion-specific ischemia by CT-FFR was assessed by the area under the receiver operating characteristic curves. The overall diagnostic accuracy of CT-FFR in diabetic patients was 83% and in nondiabetic patients 75% (p = 0.088), showing improvement over the diagnostic accuracy of coronary CT angiography, which was 58% and 65% (p = 0.223), respectively. In addition, the diagnostic accuracy of CT-FFR was similar between diabetic and nondiabetic patients per stratified CT-FFR group (CT-FFR < 0.6, 0.6 to 0.69, 0.7 to 0.79, 0.8 to 0.89, ≥0.9). The area under the curves for diabetic and nondiabetic patients were also comparable, 0.88 and 0.82 (p = 0.113), respectively. In conclusion, on-site machine-learning CT-FFR analysis improved the diagnostic performance of coronary CT angiography and accurately discriminated lesion-specific ischemia in both diabetic and nondiabetic patients suspected of coronary artery disease.


Biomechanical evaluation of two plating configurations for critical-sized defects of the mandible in dogs.
OBJECTIVE To compare the biomechanical behavior of mandibular critical-sized defects stabilized with 2 plating configurations under in vitro conditions resembling clinical situations. SAMPLE 24 mandibles harvested from 12 adult canine cadavers. PROCEDURES 8 mandibles were kept intact as control samples. A critical-sized defect was created in 16 mandibles; these mandibles were stabilized by use of a single locking plate (LP [n = 8]) or an LP combined with an alveolar miniplate (LMP [8]). Mandibles were loaded in cantilever bending in a single-load-to-failure test with simultaneous recording of load and actuator displacement. Stiffness, yield, and failure properties were compared among groups. Mode of failure was recorded. Radiographic evidence of tooth root and mandibular canal damage was quantified and compared between groups. RESULTS Stiffness and yield loads of single LP and LMP constructs were < 30% of values for intact mandibles, and failure loads were < 45% of values for intact mandibles. There were no consistent biomechanical differences at failure between single LP and LMP constructs, but the LMP construct had greater stiffness and strength prior to yield. Frequency of screw penetration of teeth and the mandibular canal was significantly greater for LMP than for single LP constructs. CONCLUSIONS AND CLINICAL RELEVANCE Both fixation methods were mechanically inferior to an intact mandible. The LMP construct was mechanically stronger than the LP construct but may not be clinically justifiable. Addition of an alveolar miniplate provided additional strength to the construct but resulted in more frequent penetration of tooth roots and the mandibular canal.


Serum uric acid, predicts heart failure in a large Italian cohort: search for a cut-off value the URic acid Right for heArt Health study.
To assess the prognostic cut-off values of serum uric acid (SUA) in predicting fatal and morbid heart failure in a large Italian cohort in the frame of the Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension. The URic acid Right for heArt Health (URRAH) study is a nationwide, multicentre, cohort study involving data on individuals aged 18-95 years, recruited on a community basis from all regions of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 128 ± 65 months. Incident heart failure was defined on the basis of International Classification of Diseases Tenth Revision codes and double-checked with general practitioners and hospital files. Multivariate Cox regression models having fatal and morbid heart failure as dependent variables, adjusted for sex, age, SBP, diabetes, estimated glomerular filtration rate, smoking habit, ethanol intake, BMI, haematocrit, LDL cholesterol, previous diagnosis of heart failure and use of diuretics as possible confounders, were used to search for an association between SUA as a continuous variable and heart failure. By means of receiver operating characteristic curves, two prognostic cut-off values (one for all heart failure and one for fatal heart failure) were identified as able to discriminate between individuals doomed to develop the event. These cut-off values were used as independent predictors to divide individuals according to prognostic cut-off values in a multivariate Cox models, adjusted for confounders. A total of 21 386 individuals were included in the analysis. In Cox analyses, SUA as a continuous variable was a significant predictor of all [hazard ratio 1.29 (1.23-1.359), P < 0.0001] and fatal [hazard ratio 1.268 (1.121-1.35), P < 0.0001] incident heart failure. Cut-off values of SUA able to discriminate all and fatal heart failure status were identified by mean of receiver operating characteristic curves in the whole database: SUA more than 5.34 mg/dl (confidence interval 4.37-5.6, sensitivity 52.32, specificity 63.96, P < 0.0001) was the univariate prognostic cut-off value for all heart failure, whereas SUA more than 4.89 mg/dl (confidence interval 4.78-5.78, sensitivity 68.29, specificity 49.11, P < 0.0001) for fatal heart failure. The cut-off for all heart failure and the cut-off value for fatal heart failure were accepted as independent predictors in the Cox analysis models, the hazard ratios being 1.645 (1.284-2.109, P < 0.0001) for all heart failure and 1.645 (1.284-2.109, P < 0.0001) for fatal heart failure, respectively. The results of the current study confirm that SUA is an independent risk factor for all heart failure and fatal heart failure, after adjusting for potential confounding variables and demonstrate that a prognostic cut-off value can be identified for all heart failure (>5.34 mg/dl) and for fatal heart failure (>4.89 mg/dl).


NDs@PDA@ICG Conjugates for Photothermal Therapy of Glioblastoma Multiforme.
The growing incidence of cancer is a problem for modern medicine, since the therapeutic efficacy of applied modalities is still not satisfactory in terms of patients' survival rates, especially in the case of patients with brain tumors. The destructive influence of chemotherapy and radiotherapy on healthy cells reduces the chances of full recovery. With the development of nanotechnology, new ideas on cancer therapy, including brain tumors, have emerged. Photothermal therapy (PTT) is one of these. It utilizes nanoparticles (NPs) that can convert the light, preferably in the near-infrared (NIR) region, into heat. In this paper, we report the use of nanodiamonds (NDs) conjugated with biomimetic polydopamine (PDA) and indocyanine green (ICG) for glioblastoma cancer PTT therapy. The obtained materials were thoroughly analyzed in terms of their PTT effectiveness, as well as their physicochemical properties. The performed research demonstrated that NDs@PDA@ICG can be successfully applied in the photothermal therapy of glioblastoma for PTT and exhibited high photothermal conversion efficiency η above 40%, which is almost 10 times higher than in case of bare NDs. In regard to our results, our material was found to lead to a better therapeutic outcome and higher eradication of glioblastoma cells, as demonstrated in vitro.


Holographic waveguide display with a combined-grating in-coupler.
Volume holographic gratings are widely used as couplers in eyewear waveguide display systems, but they show a relative lower TM polarized energy compared to transverse-electric (TE) incidence. In this paper, we propose a novel holographic waveguide display system with a combined-grating as the in-coupler. When used as an in-coupler for a holographic waveguide display system, a subwavelength metal grating is designed onto the volume holographic grating to increase the total diffraction efficiency of the coupling gratings. Theoretical calculations show that this design increases the diffraction efficiency by 16.4% for TM polarization, 4.3% for TE mode, and 10.0% for unpolarized light, compared to a single volume holographic grating. Calculations also show that the use of this design as an in-coupler for a holographic waveguide system increases the luminance efficiency for these three modes by 26.8%, 9.0%, and 15.6%, respectively.