Illness narratives and preferences for treatment among older veterans living with treatment-resistant depression and insomnia.
Despite the prevalence of comorbid late-life treatmentresistant depression (LLTRD) and insomnia in older adults, there is a gap in the literature describing patient factors, such as patients' beliefs about their illnesses and preferences for treatment, that can facilitate recovery. Therefore, we explored the perceptions and treatment preferences of older veterans with LLTRD and insomnia. Semi-structured interviews were completed with 11 older veterans. A thematic analysis of the interviews was conducted. Four main themes were identified: 1. Insomnia and medical problems were considered to be significant contributors to depression, which was defined by low mood and anhedonia; 2. "Overthinking" was thought to be a cause of insomnia; 3. Participants' preference for psychotherapy was driven by their past experiences with therapy; and 4. Participants viewed patient education as a facilitator for compliance. Older veterans with LLTRD and insomnia have a preference for behavioral interventions. However, they lack knowledge about available treatment options, such as behavioral interventions for sleep that can improve both their sleep and mood while being a good fit with their illness narratives, such as "overthinking." There is a need for patient education, which should be offered early and often during treatment.


The effect of truncated human alpha-synuclein (1-120) on dopaminergic cells in a transgenic mouse model of Parkinson's disease.
Alpha-Synuclein is thought to play an important role in the pathology of Parkinson's disease (PD). Truncated forms of this protein can be found in PD brain extracts, and these species aggregate faster and are more susceptible to oxidative stress than the full-length protein. We investigated the effect of truncated alpha-synuclein on dopaminergic cells using a transgenic mouse expressing alpha-synuclein (1-120) driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background. We found a selective reduction in the yield of dopaminergic cells from transgenic embryonic ventral mesencephalic cell cultures. However, in vivo the substantia nigra/ventral tegmentum dopaminergic cell counts were not reduced in transgenics, although these mice are known to have reduced striatal dopamine. When transplanted to the striatum in the unilateral 6-hydroxydopamine-lesioned mouse model of PD, dopaminergic cells derived from transgenic embryonic ventral mesencephala were significantly smaller at 6 weeks, and showed a trend towards being less effective at ameliorating rotational asymmetry than those from control alpha-synuclein null mice. These results suggest that alpha-synuclein (1-120) renders dopaminergic cells more susceptible to stress, which may have important implications as to how this truncated protein might contribute to dopaminergic cell death in sporadic PD.


Human seroprevalence of Borrelia miyamotoi in Manitoba, Canada, in 2011-2014: a cross-sectional study.
Hard tick-borne relapsing fever caused by Borrelia miyamotoi has been reported in Russia, the Netherlands, Germany, Japan and the northeastern and upper midwestern United States. We sought to investigate the presence of B. miyamotoi infection in humans in Manitoba, Canada. Two hundred fifty sera collected from residents of Manitoba with suspected Lyme disease between 2011 and 2014 were tested for Borrelia burgdorferi antibody using a C6 peptide enzyme-linked immunosorbent assay (ELISA) followed by Western blot. Residual sera were then anonymized, stored at -80°C and subsequently thawed and tested for B. miyamotoi antibody using a 2-step glycerosphosphodiester phosphodiesterase-based ELISA and Western blot assay. Twenty-four of the 250 (9.6%) sera tested positive for B. miyamotoi immunoglobulin G. Participants who were B. miyamotoi seropositive were predominantly male (54%) and younger on average than those who were seronegative (32 and 44 yr of age, respectively). Participants who were seropositive for B. burgdorferi were significantly more likely to be B. miyamotoi seropositive than those who were B. burgdorferi seronegative (20.3% v. 6.6%, respectively, odds ratio 3.6, 95% confidence interval 1.5-8.5). This initial report of human B. miyamotoi infection in Canada should raise awareness of hard tick-borne relapsing fever among clinicians and residents of areas in Canada and western North America where Lyme disease is endemic.


[Clinical and laboratory characteristics of pregnant women with preeclampsia versus gestational hypertension].
To compare clinical and laboratory characteristics, obstetric and perinatal outcomes of patients with pre-eclampsia versus gestational hypertension. A retrospective study was carried out to analyze medical records of patients diagnosed with pre-eclampsia and gestational hypertension whose pregnancies were resolved within a period of 5 years, for a total of 419 cases. We collected clinical and laboratory data, obstetric and perinatal outcomes. Comparisons between groups were performed using the test suitable for the variable analyzed: unpaired t test, Mann-Whitney U test or χ2 test, with the level of significance set at p<0.05. Were evaluated 199 patients in the gestational hypertension group (GH) and 220 patients in the pre-eclampsia group (PE). Mean body mass index was 34.6 kg/m2 in the GH group and 32.7 kg/m2 in the PE group, with a significant difference between groups. The PE group showed higher systolic and diastolic blood pressure and higher rates of abnormal values in the laboratory tests, although the mean values were within the normal range. Cesarean section was performed in 59.1% of cases of PE and in 47.5% of the GH group; and perinatal outcomes in terms of gestational age and birth weight were significantly lower in the PE group. Women with gestational hypertension exhibit epidemiological characteristics of patients at risk for chronic diseases. Patients with pre-eclampsia present clinical and laboratory parameters of greater severity, higher rates of cesarean delivery and worse maternal and perinatal outcomes.


Learning what to inhibit: The influence of repeated testing on the encoding of gender and age information.
Psychological research has devoted considerable attention to the relationship between the multiple category dimensions that can be extracted from faces. In the present studies, we investigated the role of experience and learning on the way the social perceiver deals with multiple category dimensions. Specifically, we tested whether learning which of 2 dimensions is the most relevant to the task at hand influences the encoding and retrieval of both task-relevant and irrelevant dimensions. In our studies, participants went through several cycles, each consisting of a study and a test phase. We manipulated the structure of the tests such that participants were probed on only 1 category dimension (age or gender), despite viewing faces of both category dimensions in all study phases. We hypothesized that when participants were repeatedly tested on 1 dimension, they would proactively control their attention toward that specific dimension and away from the nonrelevant dimension. Five studies demonstrated that: (a) participants learned which dimension was test-relevant such that they gradually became faster and more accurate on that dimension; (b) when the gender dimension was test-relevant, participants were faster and more accurate retrieving information concerning the target faces' gender than age, while the opposite did not happen when the age dimension was test-relevant; and (c) this dominance of the gender dimension is mainly caused by the inhibition of the age dimension. Implications about the importance of previous experience and control for research on social categorization in general and research examining the interplay between gender and age are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.
The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.


Simulating sensory-motor incongruence in healthy volunteers: implications for a cortical model of pain.
Conflict between motor-sensory central nervous processing has been suggested as one cause of pain in those conditions where a demonstrable or local nociceptive aetiology cannot be convincingly established (e.g. complex regional pain syndrome type 1, repetitive strain injury, phantom limb pain and focal hand dystonia). The purpose of this study was to discover whether pain could be induced in pain-free healthy volunteers when this conflict was generated transiently in a laboratory setting. Forty-one consecutively recruited healthy adult volunteers without a history of motor or proprioceptive disorders performed a series of bilateral upper and lower limb movements whilst viewing a mirror/whiteboard, which created varied degrees of sensory-motor conflict during congruent/incongruent limb movements. A qualitative method recorded any changes in sensory experience. Twenty-seven subjects (66%) reported at least one anomalous sensory symptom at some stage in the protocol despite no peripheral nociceptive input. The most frequent symptoms occurred when incongruent movement was performed whilst viewing the reflected limb in the mirror condition, the time of maximum sensory-motor conflict. Symptoms of pain were described as numbness, pins and needles, moderate aching and/or a definite pain. Other sensations included perceived changes in temperature, limb weight, altered body image and disorientation. There were indications that some individuals were more susceptible to symptom generation than others. Our findings support the hypothesis that motor-sensory conflict can induce pain and sensory disturbances in some normal individuals. We propose that prolonged sensory-motor conflict may induce long-term symptoms in some vulnerable subjects.


General and health-related Internet use among an urban, community-based sample of HIV-positive women: implications for intervention development.
Internet-based HIV interventions are increasingly common, although little focus has been on HIV-positive women. To understand the feasibility of using the Internet to deliver behavioral interventions to HIV-positive women, we sought to describe patterns of Internet use for general and health-related purposes and to explore differences between Internet-using and non-using women. From February 2014 to April 2014, 103 women were recruited at six community-based organizations in the Bronx, NY that provide services to HIV-positive persons. Women completed a 30-minute interview and answered a brief survey of socio-demographic factors, risk behavior and clinical characteristics. We performed χ(2) and Kruskal-Wallis tests to compare Internet users and non-users. Sixty-one percent of participants were current Internet users, most of whom used a personal electronic device (e.g., cellphone/smartphone) to access the Internet. While higher proportions of Internet users were passively engaged (e.g., signed up to receive email updates [42.9%] or watched an online video [58.7%] for health-related purposes), smaller proportions (12.7-15.9%) were involved in more interactive activities such as posting comments, questions, or information about health-related issues in an online discussion or a blog. A majority of Internet non-users (60.0%) expressed interest in going online. Lack of computer or Internet access (37.5%) and Internet navigation skills (37.5%) were the primary reasons for non-use. Compared with non-users, Internet users were more likely to be younger, to have higher socioeconomic status, and to report low health-related social support. Despite having a lower proportion of Internet users in our study than the general population, Internet-using women in our study had relatively high levels of online engagement and went online for both general and health-related purposes. However, Internet-based interventions targeting HIV-positive women will likely need to include providing computer and/or Internet access as well as training participants in how to navigate the Internet.


Integration of DNA barcoding into an ongoing inventory of complex tropical biodiversity.
Inventory of the caterpillars, their food plants and parasitoids began in 1978 for today's Area de Conservacion Guanacaste (ACG), in northwestern Costa Rica. This complex mosaic of 120 000 ha of conserved and regenerating dry, cloud and rain forest over 0-2000 m elevation contains at least 10 000 species of non-leaf-mining caterpillars used by more than 5000 species of parasitoids. Several hundred thousand specimens of ACG-reared adult Lepidoptera and parasitoids have been intensively and extensively studied morphologically by many taxonomists, including most of the co-authors. DNA barcoding - the use of a standardized short mitochondrial DNA sequence to identify specimens and flush out undisclosed species - was added to the taxonomic identification process in 2003. Barcoding has been found to be extremely accurate during the identification of about 100 000 specimens of about 3500 morphologically defined species of adult moths, butterflies, tachinid flies, and parasitoid wasps. Less than 1% of the species have such similar barcodes that a molecularly based taxonomic identification is impossible. No specimen with a full barcode was misidentified when its barcode was compared with the barcode library. Also as expected from early trials, barcoding a series from all morphologically defined species, and correlating the morphological, ecological and barcode traits, has revealed many hundreds of overlooked presumptive species. Many but not all of these cryptic species can now be distinguished by subtle morphological and/or ecological traits previously ascribed to 'variation' or thought to be insignificant for species-level recognition. Adding DNA barcoding to the inventory has substantially improved the quality and depth of the inventory, and greatly multiplied the number of situations requiring further taxonomic work for resolution.


Understanding the Importance of Context: A Qualitative Study of a Location-Based Exergame to Enhance School Childrens Physical Activity.
Many public health interventions are less effective than expected in 'real life settings', yet little work is undertaken to understand the reasons why. The effectiveness of complex public health interventions can often be traced back to a robust programme theory (how and why an intervention brings about a change in outcome(s)) and assumptions that are made about the context in which it is implemented. Understanding whether effectiveness (or lack thereof) is due to the intervention or the context is hugely helpful in decisions about whether to a) modify the intervention; b) modify the context; c) stop providing the intervention. Exergames-also known as Active Video Games or AVGS-are video games which use the player's bodily movements as input and have potential to increase physical activity in children. However, the results of a recent pilot randomised controlled trial (RCT) of a location-based exergame (FitQuest) in a school setting were inconclusive; no significant effect was detected for any of the outcome measures. The aim of this study was to explore whether the programme theory for FitQuest was correct with respect to how and why it would change children's perceptions of physical activity (PA) and exercise self-efficacy in the school setting. A further aim was to investigate the features of the school setting (context) that may impact on FitQuest's implementation and effectiveness. Qualitative data (gathered during the RCT) were gathered from interviews with teachers and children, and observation of sessions using FitQuest. Thematic analysis indicated that whilst children enjoyed playing the game, engaged with goal setting within the game context and undertook low to vigorous physical activity, there were significant contextual factors that prevented it from being played as often as intended. These included environmental factors (e.g. size of the playground), school factors (cancellations due to other activities), school technology policy (rules relating to mobile phone usage) and teacher factors (engagement with the intervention). A revised logic model for the FitQuest intervention indicates how both the design of exergame technology (intervention) and features of the school environment (context) could be improved to increase chances of effectiveness in the future.


Sequence Analysis of Drug Target Genes with Suicidal Behavior in Bipolar Disorder Patients.
A number of genes have been implicated in recent genome-wide association studies of suicide attempt in bipolar disorder. More focused investigation of genes coding for protein targets of existing drugs may lead to drug repurposing for the treatment and/or prevention of suicide. We analyzed 2,457 DNA variants across 197 genes of interest to GlaxoSmithKline across the pipeline in our sample of European patients suffering from bipolar disorder (N = 219). We analyzed these variants for a possible association with the suicide severity score (ranging from suicidal ideation/plan to serious suicide attempt) from the Schedule for Clinical Assessment in Neuropsychiatry. We conducted tests of individual variants and gene-based tests. We found a number of DNA variants in the transforming growth factor beta receptor 1 gene (TGFBR1) to be suggestively associated with suicide severity scores (p < 0.005). The gene-based tests also pointed to TGFBR1 to be associated with suicide severity (p = 0.0001). However, these findings were not replicated in an independent bipolar disorder sample. We report no significant association between DNA sequences of drug target genes and suicidal behavior. Additional larger sequencing studies could further interrogate associations between variants in drug target genes and suicidal behavior.


Early life microbial exposure, child neurocognition and behaviour at 2 years of age: A birth cohort study.
To investigate the relationship between factors which influence external microbial exposures (FEMEs), previously identified to be protective or to increase the risk of the development of allergic disease, and cognition and behaviour in infants 2 years of age in an Australian population. The Barwon Infant Study is a birth cohort (n = 1074) in Victoria, Australia. Comprehensive questionnaire, clinical and biological measures were collected at multiple time oints. Multiple linear regression was used to evaluate the associations between 56 FEMEs and 3 outcomes; cognition (Bayley Scales of Infant and Toddler Development (BAYLEY-III)) (n = 667, mean (standard deviation) age = 2.45 (0.14) years), internalising and externalising behaviour (Child Behavior Checklist) (n = 666, mean (standard deviation) age = 2.45 (0.14) years). Overall, there were no consistent patterns or dose response found within an outcome nor across all three outcomes, although there was some evidence for individual associations. Breastfeeding and child care were associated with higher cognitive scores (adjusted mean difference (95% confidence interval) = 3.20 (0.23-6.17) and 0.68 (0.12-1.24), respectively), and increasing sibling number was associated with lower internalising behaviour (adjusted mean difference (95% confidence interval) = -4.13 (-6.34, -1.91)). In contrast to allergic disease, there was an absence of epidemiological evidence to support the association between these FEMEs and cognition and behaviour. Direct investigations into the relationship between exposures which influence gut-microbial composition and cognition and behaviour are now needed.


Vascular endothelial growth factor administration in chronic myocardial ischemia.
Vascular endothelial growth factor (VEGF) is a potent mitogen capable of stimulating angiogenesis. We examined the effect of VEGF administration in a model of chronic porcine myocardial ischemia. Nineteen pigs were instrumented with proximal left circumflex coronary artery (LCX) Ameroid constrictors. In eight animals VEGF (2 microgram) with heparin (50 U) was administered extraluminally to the LCX myocardium with an osmotic pump for 4 wk and 11 other animals served as controls. VEGF-treated animals demonstrated higher flow in the LCX territory during both rest and pacing compared with untreated controls (rest: 1.35 +/- 0.1 vs. 0.80 +/- 0.09 ml.min-1.g-1; pacing; 2.01 +/- 0.37 vs. 1.01 +/- 0.07 ml.min-1.g-1, P < 0.05, VEGF vs. controls). The observed improvement in regional coronary flow in VEGF-treated animals resulted in better preservation of endothelium-dependent microvessel relaxation as well as fractional LV shortening in the LCX territory during pacing in the VEGF-treated than in control animals (controls: 7.1 +/ 2.6 vs. 3.6 +/- 2.0%, rest vs. pacing; VEGF: 6.9 +/- 2.9 vs. 6.3 +/- 2.9%, rest vs. pacing). We conclude that VEGF administration in a gradual coronary occlusion model in pigs results in improvement of coronary flow and preservation of regional hemodynamics in the compromised myocardium.


A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.
PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.


Perinatal methadone exposure produces physical dependence and altered behavioral development in the rat.
Pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that the following prenatal/postnatal exposure groups were obtained: water/water, methadone/water, water/methadone and methadone/methadone. Methadone slightly reduced litter size, particularly the number of male offspring, and reduced litter birth weight. The induction or maintenance of physical dependence in the postnatal methadone exposure groups was confirmed by an experiment in which PD19 pups were challenged with naloxone (1 mg/kg, s.c.). Methadone concentrations were assayed in pup brain on postnatal days 4, 10 and 22. Postnatal exposure to methadone via maternal milk produced measurable levels of methadone which decreased with age. Neuromuscular and physical development were assessed. Exposure to methadone accelerated acquisition of the righting reflex, but tended to delay the acquisition of the negative geotaxic response. Postnatal exposure to methadone was associated with decreased somatic growth as measured through postnatal day 21. The older pups (postnatal day 21) exposed to methadone exhibited variations in activity levels: pups exposed to methadone both prenatally and postnatally exhibited the least amount of spontaneous locomotor activity and pups exposed only postnatally exhibited the most activity. Therefore, it is possible to induce and/or maintain physical dependence via lactation in rat pups fostered to methadone-treated dams. Perinatal exposure to methadone by this route produces several subtle disruptions of pup development in the absence of gross maternal or fetal toxicity.


Non-covalent albumin-binding ligands for extending the circulating half-life of small biotherapeutics.
Peptides and small protein scaffolds are gaining increasing interest as therapeutics. Similarly to full-length antibodies, they can bind a target with a high binding affinity and specificity while remaining small enough to diffuse into tissues. However, despite their numerous advantages, small biotherapeutics often suffer from a relatively short circulating half-life, thus requiring frequent applications that ultimately restrict their ease of use and user compliance. To overcome this limitation, a large variety of half-life extension strategies have been developed in the last decades. Linkage to ligands that non-covalently bind to albumin, the most abundant serum protein with a circulating half-life of ∼19 days in humans, represents one of the most successful approaches for the generation of long-lasting biotherapeutics with improved pharmacokinetic properties and superior efficacy in the clinic.


Proof-of-principle study of steam ablation as novel thermal therapy for saphenous varicose veins.
During the last decade, thermal ablation techniques such as endovenous laser ablation have been challenging the position of traditional surgery for the treatment of saphenous varicose veins. The newest method of thermal ablation is pulsated steam, which works by heating the vein with steam at 120°C. This study assessed the effectiveness of steam ablation of varicose veins in sheep and in humans. The safety of the procedure in sheep was assessed by cardiovascular monitoring during treatment. We used ultrasound imaging to examine occlusion of the veins. Changes in treated veins were examined microscopically. In a pilot study, 20 veins in 19 patients with insufficiency of the great or the small saphenous vein were treated with pulsated steam ablation. Anatomic success, patient satisfaction, and complications were investigated for 6 months after the procedure. All veins in the sheep were occluded. No cardiovascular changes occurred during treatment. Histologic examination of treated veins showed typical changes of the vein wall, such as disappearance of the endothelial layer, fibrotic thrombosis, and major alterations in collagen fibers in the media. Steam ablation was effective in the 19 patients: 13 of 20 veins were completely closed, and 7 showed a very small segment of recanalization after 6 months of follow-up that did not seem to be clinically relevant. Nine patients had some ecchymoses at the puncture site, and one patient had a transient superficial phlebitis. A median maximal pain score of 1 (range, 0-10) was reported. No serious side effects, such as deep vein thrombosis, nerve injury, skin burns, or infections, were reported. Patients were very satisfied with the treatment, with a median satisfaction score of 9.25 (range, 0-10). In this proof-of-principle study, pulsated steam ablation was an effective treatment for saphenous varicose veins.


The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
The current manuscript is the second update of the original Practical Guide, published in 2013 [Heidbuchel et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with atrial fibrillation (AF) and have emerged as the preferred choice, particularly in patients newly started on anticoagulation. Both physicians and patients are becoming more accustomed to the use of these drugs in clinical practice. However, many unresolved questions on how to optimally use these agents in specific clinical situations remain. The European Heart Rhythm Association (EHRA) set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group identified 20 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 20 topics are as follows i.e., (1) Eligibility for NOACs; (2) Practical start-up and follow-up scheme for patients on NOACs; (3) Ensuring adherence to prescribed oral anticoagulant intake; (4) Switching between anticoagulant regimens; (5) Pharmacokinetics and drug-drug interactions of NOACs; (6) NOACs in patients with chronic kidney or advanced liver disease; (7) How to measure the anticoagulant effect of NOACs; (8) NOAC plasma level measurement: rare indications, precautions, and potential pitfalls; (9) How to deal with dosing errors; (10) What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a potential risk of bleeding; (11) Management of bleeding under NOAC therapy; (12) Patients undergoing a planned invasive procedure, surgery or ablation; (13) Patients requiring an urgent surgical intervention; (14) Patients with AF and coronary artery disease; (15) Avoiding confusion with NOAC dosing across indications; (16) Cardioversion in a NOAC-treated patient; (17) AF patients presenting with acute stroke while on NOACs; (18) NOACs in special situations; (19) Anticoagulation in AF patients with a malignancy; and (20) Optimizing dose adjustments of VKA. Additional information and downloads of the text and anticoagulation cards in different languages can be found on an EHRA website (www.NOACforAF.eu).


Cerebral salt wasting syndrome in post-operative pediatric brain tumor patients.
Cerebral salt wasting syndrome (CSWS) and the syndrome of inappropriate antidiuretic hormone (SIADH) are both causes of hyponatremia in pediatric neurosurgical patients often with similar presenting symptoms; however, despite similar clinical characteristics the treatment for CSWS and SIADH can be drastically different, which makes the distinction critical for post-operative treatment. Further complicating matters, are the exact mechanism for CSWS which remains unclear, and the incidence and severity of CSWS is not well studied in pediatric neurosurgical patients. We hypothesized that CSWS occurs frequently in post-operative brain tumor patients and is an important cause of post-operative hyponatremia in these patients. We designed a single institution retrospective cohort study of all pediatric brain tumor patients undergoing craniotomy for tumor resection at our institution between January 2005 and December 2009. Of the 282 patients undergoing 291 operations, post-operative CSWS was identified in 15 cases (5%), and was more frequently observed than SIADH (nine cases, 3%). Median onset of CSWS was on post-operative day 3, lasting a median of 2.5 days. Patients with CSWS were more likely to have suffered post-operative stroke (40 vs. 4.6%, P < 0.001), have chiasmatic/hypothalamic tumors (40 vs. 3.8%, P = 0.002), and be younger (mean age 5.9 vs. 9.7 years, P = 0.01) than eunatremic patients. In addition, nearly half of the patients with CSWS (47%) had post-operative hyponatremic seizures. The diagnosis of CSWS should be strongly considered in hyponatremic pediatric patients with significant natriuresis following brain tumor resection, and a treatment initiated promptly to prevent neurologic sequeleae.


Plasmodium falciparum STEVOR proteins impact erythrocyte mechanical properties.
Infection of erythrocytes with the human malaria parasite, Plasmodium falciparum, results in dramatic changes to the host cell structure and morphology. The predicted functional localization of the STEVOR proteins at the erythrocyte surface suggests that they may be involved in parasite-induced modifications of the erythrocyte membrane during parasite development. To address the biologic function of STEVOR proteins, we subjected a panel of stevor transgenic parasites and wild-type clonal lines exhibiting different expression levels for stevor genes to functional assays exploring parasite-induced modifications of the erythrocyte membrane. Using this approach, we show that stevor expression impacts deformability of the erythrocyte membrane. This process may facilitate parasite sequestration in deep tissue vasculature.


Tooth bleaching with hydrogen peroxide and nano-hydroxyapatite: a 9-month follow-up randomized clinical trial.
The aim of this study was to compare the amount of tooth colour change, rebound rate and tooth sensitivity in patients submitted to a bleaching technique with 6% hydrogen peroxide (HP) with or without 2% nano-hydroxyapatite (n-HA). Sixty subjects were included in this examiner-blinded, randomized clinical trial using a 6% HP gel with or without 2% n-HA. Tooth colour and tooth sensitivity were analysed before and after treatment. All data were analysed statistically. After bleaching, both treatments demonstrated significant improvements in tooth shade (P < 0.05 for both groups). At the 9-month recall, tooth shade remained significantly lighter than at baseline (P < 0.05 for both groups). However, a relapse of the tooth shade was observed compared with the immediate post-bleaching result (P < 0.05). 6% HP with 2% n-HA produced significantly lower sensitivity (P < 0.05) than the bleaching product without n-HA. Colour change evaluation resulted in no difference between the two groups. Both treatments demonstrated significant improvements in tooth shade. The bleaching effectiveness of the tested products was comparable. The use of 6% HP with 2% n-HA reduced the incidence of sensitivity during the bleaching treatment compared to a bleaching agent that did not contain n-HA.


Parathyroid hormone stimulation and PKA signaling of latent transforming growth factor-beta binding protein-1 (LTBP-1) mRNA expression in osteoblastic cells.
Parathyroid hormone (PTH) regulates bone remodeling and calcium homeostasis by acting on osteoblasts. Recently, the gene expression profile changes in the rat PTH (1-34, 10(-8)M)-treated rat osteoblastic osteosarcoma cell line, UMR 106-01, using DNA microarray analysis showed that mRNA for LTBP-1, a latent transforming growth factor (TGF-beta)-binding protein is stimulated by PTH. Latent TGF-beta binding proteins (LTBPs) are required for the proper folding and secretion of TGF-beta, thus modifying the activity of TGF-beta, which is a local factor necessary for bone remodeling. We show here by real time RT-PCR that PTH-stimulated LTBP-1 mRNA expression in rat and mouse preosteoblastic cells. PTH also stimulated LTBP-1 mRNA expression in all stages of rat primary osteoblastic cells but extended expression was found in differentiating osteoblasts. PTH also stimulated TGF-beta1 mRNA expression in rat primary osteoblastic cells, indicating a link between systemic and local factors for intracellular signaling in osteoblasts. An additive effect on LTBP-1 mRNA expression was found when UMR 106-01 cells were treated with PTH and TGF-beta1 together. We further examined the signaling pathways responsible for PTH-stimulated LTBP-1 and TGF-beta1 mRNA expression in UMR 106-01 cells. The PTH stimulation of LTBP-1 and TGF-beta1 mRNA expression was dependent on the PKA and the MAPK (MEK and p38 MAPK) pathways, respectively in these cells, suggesting that PTH mediates its effects on osteoblasts by several intracellular signaling pathways. Overall, we demonstrate here that PTH stimulates LTBP-1 mRNA expression in osteoblastic cells and this is PKA-dependent. This event may be important for PTH action via TGF-beta in bone remodeling.


DARK Classics in Chemical Neuroscience: Psilocybin.
Psilocybin is found in a family of mushrooms commonly known as "magic mushrooms" that have been used throughout history to induce hallucinations. In the late 1950s Albert Hofmann, of Sandoz Laboratories, identified and synthesized the psychoactive compounds psilocybin and psilocin which are found in psilocybe mushrooms. Psilocybin was marketed by Sandoz as Indocybin for basic psychopharmacological and therapeutic clinical research. Psilocybin saw a rapid rise in popularity during the 1960s and was classed as a Schedule I drug in 1970. This led to a significant decrease in psilocybin research. Recently, however, preliminary studies with psilocybin have shown promise as potential for the treatment of obsessive compulsive disorder, alcohol addiction, tobacco addiction, and major depressive disorder, and the treatment of depression in terminally ill cancer patients. This review describes in detail the synthesis, metabolism, pharmacology, adverse drug reactions, and importance of psilocybin to neuroscience in the past and present.


Selective vulnerability of the hippocampus to the cytotoxic edema; magnetic resonance imaging and fluorescence microscopy studies in the rats.
Changes in the hippocampus induced by water intoxication were studied using fluorescence microscopy (FM) and magnetic resonance imaging (MRI). In three animals (rats), intracellular/extracellular distribution of Evans blue (EB) in cerebral cortex and hippocampus of both hemispheres was revealed by injection of EB into the internal carotid artery (ICA) in hyperhydrated rats (water intoxication, WI). A total of 8 experimental rats were used for the MRI study. The animals were scanned before WI, then the experimental brain edema was induced by WI and MR scanning was performed at day 1 and day 8 after WI. Besides standard T2-weighted imaging an apparent diffusion coefficient (ADC) and transverse relaxation time (T2) were evaluated. Hyperhydration brought about the largest intracellular deposits of EB in CA3 hippocampal region, followed by the cerebral cortex and CA1 hippocampal region with the lowest amount of intracellular EB in the dentate gyrus. A higher apparent diffusion coefficient (corresponding to a vasogenic edema) was found the first day after hyperhydration in the cortex and in the CA1 and CA3 regions with no changes in dentate gyrus. Both FM and MRI confirmed a selectively higher vulnerability to hyperhydration and hyponatremia (achieved by water intoxication) of the hippocampal cells compared to dentate gyrus cells.


Evaluation of flood and landslide risk to the population of Italy.
We have compiled a database of floods and landslides that occurred in Italy between AD 1279 and 2002 and caused deaths, missing persons, injuries, and homelessness. Analysis of the database indicates that more than 50,593 people died, went missing, or were injured in 2580 flood and landslide events. Harmful events were inventoried in 26.3% of the 8103 Italian municipalities. Fatal events were most frequent in the Alpine regions of northern Italy and were caused by both floods and landslides. In southern Italy, landslides were the principal agents of fatalities and were most numerous in the Campania region. Casualties were most frequent in the autumn. Fast-moving landslides, including rock falls, rockslides, rock avalanches, and debris flows, caused the largest number of deaths. In order to assess the overall risk posed by these processes, we merged the historical catalogs and identified 2682 "hydrogeomorphological" events that triggered single or multiple landslides and floods. We estimated individual risk through the calculation of mortality rates for both floods and landslides and compared these rates to the death rates for other natural, medical, and human-induced hazards in Italy. We used the frequency distribution of events with fatalities to ascertain the magnitude and frequency of the societal risks posed by floods and landslides. We quantified these risks in a Bayesian model that describes the probabilities of fatal flood and landslide events in Italy.


Plasmon dispersion diagram and localization effects in a three-cavity commensurate grating.
Commensurate gratings of deep-metallic grooves have highly localized cavity resonances which do not exist for purely periodic gratings. In this paper we present the experimental dispersion diagram of the resonances of a commensurate grating with three sub-wavelength cavities per period. We observe selective light localization within the cavities, transition from a localized to a delocalized mode and modifications of the coupling of modes with the external plane-wave that may lead to the generation of black modes. This unexpected complexity is analyzed via a theoretical study in full agreement with the experiments. These results open a way to the control of wavelength-dependent hot spot predicted in more complex commensurate gratings.


Mechanism of the antibiotic action pyocyanine.
Exposure of Escherichia coli growing in a rich medium to pyocyanine resulted in increased intracellular levels of superoxide dismutase and of catalase. When these adaptive enzyme syntheses were prevented by nutritional paucity, the toxic action of pyocyanine was augmented. The antibiotic action of pyocyanine was dependent upon oxygen and was diminished by superoxide dismutase and by catalase, added to the suspending medium. Pyocyanine slightly augmented the respiration of E. coli suspended in a rich medium, but greatly increased the cyanide-resistant respiration. Pyocyanine was able to cause the oxidation of reduced nicotinamide adenine dinucleotide, with O2- production, in the absence of enzymatic catalysis. It is concluded that pyocyanine diverts electron flow and thus increases the production of O2- and H2O2 and that the antibiotic action of this pigment is largely a reflection of the toxicity of these products of oxygen reduction.


Rapid Lymphatic Dissemination of Encapsulated Group A Streptococci via Lymphatic Vessel Endothelial Receptor-1 Interaction.
The host lymphatic network represents an important conduit for pathogen dissemination. Indeed, the lethal human pathogen group A streptococcus has a predilection to induce pathology in the lymphatic system and draining lymph nodes, however the underlying basis and subsequent consequences for disease outcome are currently unknown. Here we report that the hyaluronan capsule of group A streptococci is a crucial virulence determinant for lymphatic tropism in vivo, and further, we identify the lymphatic vessel endothelial receptor-1 as the critical host receptor for capsular hyaluronan in the lymphatic system. Interference with this interaction in vivo impeded bacterial dissemination to local draining lymph nodes and, in the case of a hyper-encapsulated M18 strain, redirected streptococcal entry into the blood circulation, suggesting a pivotal role in the manifestation of streptococcal infections. Our results reveal a novel function for bacterial capsular polysaccharide in directing lymphatic tropism, with potential implications for disease pathology.


Iron Scavenging in Aspergillus Species: Structural and Biochemical Insights into Fungal Siderophore Esterases.
Fungi utilize high-affinity chelators termed siderophores with chemically diverse structures to scavenge the essential nutrient iron from their surroundings. Since they are among the strongest known Fe3+ binding agents, intracellular release of the heavy metal atom is facilitated by the activity of specific hydrolases. In this work, we report the characterization and X-ray crystal structures of four siderophore esterases: AfEstB and AfSidJ from Aspergillus fumigatus, as well as AnEstB and AnEstA from Aspergillus nidulans. Even though they all display the conserved α/β-hydrolase fold, we found significant structural and enzymatic discrepancies in their adaption to both related and chemically diverse substrates. A structure of AfEstB in complex with its substrate triacetylfusarinine C gives insight into the active enzyme and shows tetrahedral coordination between the catalytic serine and the scissile ester bond.


On the spatial specificity of audiovisual crossmodal exogenous cuing effects.
It is generally-accepted that the presentation of an auditory cue will direct an observer's spatial attention to the region of space from where it originates and therefore facilitate responses to visual targets presented there rather than from a different position within the cued hemifield. However, to date, there has been surprisingly limited evidence published in support of such within-hemifield crossmodal exogenous spatial cuing effects. Here, we report two experiments designed to investigate within- and between-hemifield spatial cuing effects in the case of audiovisual exogenous covert orienting. Auditory cues were presented from one of four frontal loudspeakers (two on either side of central fixation). There were eight possible visual target locations (one above and another below each of the loudspeakers). The auditory cues were evenly separated laterally by 30° in Experiment 1, and by 10° in Experiment 2. The potential cue and target locations were separated vertically by approximately 19° in Experiment 1, and by 4° in Experiment 2. On each trial, the participants made a speeded elevation (i.e., up vs. down) discrimination response to the visual target following the presentation of a spatially-nonpredictive auditory cue. Within-hemifield spatial cuing effects were observed only when the auditory cues were presented from the inner locations. Between-hemifield spatial cuing effects were observed in both experiments. Taken together, these results demonstrate that crossmodal exogenous shifts of spatial attention depend on the eccentricity of both the cue and target in a way that has not been made explicit by previous research.


Political systems affect mobile and sessile species diversity--a legacy from the post-WWII period.
Political ideologies, policies and economy affect land use which in turn may affect biodiversity patterns and future conservation targets. However, few studies have investigated biodiversity in landscapes with similar physical properties but governed by different political systems. Here we investigate land use and biodiversity patterns, and number and composition of birds and plants, in the borderland of Austria, Slovenia and Hungary. It is a physically uniform landscape but managed differently during the last 70 years as a consequence of the political "map" of Europe after World War I and II. We used a historical map from 1910 and satellite data to delineate land use within three 10-kilometre transects starting from the point where the three countries meet. There was a clear difference between countries detectable in current biodiversity patterns, which relates to land use history. Mobile species richness was associated with current land use whereas diversity of sessile species was more associated with past land use. Heterogeneous landscapes were positively and forest cover was negatively correlated to bird species richness. Our results provide insights into why landscape history is important to understand present and future biodiversity patterns, which is crucial for designing policies and conservation strategies across the world.


Variability and change over time of weight and BMI among adolescents and adults with Prader-Willi syndrome: a 6-month text-based observational study.
Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder in which hyperphagia (excessive appetite) is a hallmark feature. Understanding how weight changes over time in this population is important for capturing the contemporary natural history of the disorder as well as assessing the impact of new treatments for hyperphagia. Therefore, we aimed to determine the feasibility of a remote assessment of weight change over time in PWS. We developed a text message-based, prospective cohort study of adolescents and adults with PWS to assess changes in weight and body mass index (BMI) over a six-month period. Weight was collected weekly, while changes in height, living situation, access to food, activity level, and medication were collected at three-month intervals. One hundred and sixty-five participants enrolled in the study, with a mean age of 19.7 years (range 12-48). There was considerable variability in weight across participants (range: 76.8-207.7 kg). Thirty-three percent of the participants were normal weight, while 15% were overweight and 52% were obese. Overall, the weight of the study participants increased over the study period (mean weight change + 2.35%), while BMI was relatively stable, albeit high (mean BMI of 31.4 at baseline, mean BMI percent change + 1.42%). Changes in living situation, activity, food access, and medication had limited impact on weight and BMI changes. Multivariable analysis found that time, sex, age, and percentage of life on growth hormone (GH) therapy were statistically significant fixed effects. Participants submitted more than 95% of possible weight data points across the 26 weeks of the study. This remote, observational study of weight change in PWS showed small increases in weight and BMI over a six-month period. Participants were highly compliant with this text message-based study, suggesting that mobile technology-based data collection was manageable for the participants. We anticipate that the results of this study will inform clinical trials for hyperphagia/obesity related therapies in PWS and provide a basis for understanding the efficacy of new therapies for hyperphagia in the real-world setting.


Influence of diet on the gut microbiome and implications for human health.
Recent studies have suggested that the intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically evaluates current data regarding the effects of several common dietary components on intestinal microbiota. We show that consumption of particular types of food produces predictable shifts in existing host bacterial genera. Furthermore, the identity of these bacteria affects host immune and metabolic parameters, with broad implications for human health. Familiarity with these associations will be of tremendous use to the practitioner as well as the patient.


Childhood tuberculosis infection and disease: a spatial and temporal transmission analysis in a South African township.
Tuberculosis (TB) remains a leading cause of mortality and morbidity in South Africa. While adult TB results from both recent and past infection, childhood TB results from recent infection and reflects ongoing transmission despite current TB control strategies. A South African community with high rates of TB and HIV disease. A Geographic Information System was used to spatially and temporally define the relationships between TB exposure, infection and disease in children < 15 years of age with exposure to adult HIV-positive and HIV-negative TB disease on residential plots between 1997 and 2007. During the study period the annual adult TB notification rate increased from 629 to 2 106/100 000 and the rate in children aged < 15 years ranged between 664/100 000 and 1 044/100 000. The mean number of exposures to adult TB for TB-uninfected children, latently TB-infected children and TB cases were 5.1%, 5.4% and 33% per annum and the mean number of adult smear-positive cases per exposed child was 1.0, 1.6 and 1.9, respectively. Acquisition of TB infection was not associated with HIV status of the adult TB case to which the child was exposed, and 36% of child TB cases were diagnosed before the temporally closest adult case on their plot. Childhood infection and disease were quantitatively linked to infectious adult TB prevalence in an immediate social network. Childhood infection should be monitored in high-burden settings as a marker of ongoing TB transmission. Improved knowledge of township childhood and adult social networks could also facilitate targeted active case finding, which may provide an adjunct to currently failing TB control strategies.


Spatial optical solitons supported by mutual focusing.
We study composite spatial optical solitons supported by two-wave mutual focusing induced by cross-phase modulation in Kerr-like nonlinear media. We find the families of both single- and two-hump solitons and discuss their properties and stability. We also reveal remarkable similarities between recently predicted holographic solitons in photorefractive media and parametric solitons in quadratic nonlinear crystals.


Effect of ultrasound on the kinetics of cation exchange in NaX zeolite.
In this study, we focused on the effect of ultrasound on ion exchange kinetics to obtain the Li-, Ca- and Ce-rich NaX zeolite. The results were compared to those obtained from the traditional batch exchange method under similar conditions. Contact time and initial cation concentration (fold equivalent excess) were studied. Ultrasound enhanced the replacement of Na(+) ion with Li(+), Ca(2+) and Ce(3+) ions in the extra-framework of zeolite up to 76%, 72% and 66%, respectively. The intraparticle diffusion is the rate limiting step in the ion exchange for both exchange methods. As compared to the traditional exchange method, the ultrasonic method applied in this study was found to be very effective on the exchange amount at equilibrium.


D2 Region of the 28S RNA Gene: A Too-Conserved Fragment for Inferences on Phylogeny of South American Triatomines.
The brasiliensis complex is composed of five triatomine species, and different approaches suggest that Triatoma lenti and Triatoma petrochiae may be the new members. Therefore, this study sought to analyze the phylogenetic relationships within this complex by means of the D2 region of the 28S RNA gene, and to analyze the degree of polymorphism and phylogenetic significance of this gene for South American triatomines. Phylogenetic analysis by using sequence fragments of the D2 domain did not allow to perform phylogenetic inferences on species within the brasiliensis complex, because the gene alignment composed of a matrix with 37 specimens exhibited only two variable sites along the 567 base pairs used. Furthermore, if all South American species are included, only four variable sites were detected, reflecting the high degree of gene conservation. Therefore, we do not recommend the use of this gene for phylogenetic reconstruction for this group of Chagas disease vectors.


Adenosine A1 receptor-mediated activation of phospholipase C-beta 3 in intestinal muscle: dual requirement for alpha and beta gamma subunits of Gi3.
Four native and cloned adenosine receptors (ARs), designated A1AR, A2aAR, A2bAR, and A3AR, have been characterized functionally and by radioligand binding. In the present study, we have used selective antibodies to identify the G protein subunits and phospholipase C (PLC)-beta isoform coupled to A1ARs in smooth muscle membranes and permeabilized muscle cells from rabbit intestine. Immunoblot analysis disclosed the presence of a full complement of G proteins. Adenosine caused contraction of dispersed muscle cells and increases in D-myo-inositol-1,4,5-trisphosphate, intracellular calcium, and cAMP levels. Contraction and the increases in D-myo-inositol-1,4,5-trisphosphate and intracellular calcium levels were abolished by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine and augmented by the A2 antagonist CGS-15943; the reverse occurred with cAMP. A selective A1AR agonist, cyclopentyladenosine, inhibited forskolin-stimulated cAMP accumulation; the inhibition was reversed by treatment of the cells with pertussis toxin or a G alpha i3-specific antibody. The pattern of inhibition implied coexistence of A1ARs and A2ARs coupled to interactive signaling pathways, with A2ARs mediating activation of adenylyl cyclase and A1ARs mediating activation of PLC and inhibition of adenylyl cyclase. Adenosine-stimulated PLC activity in muscle membranes was selectively blocked by G alpha i3- and G beta-specific antibodies, as well as by a PLC-beta 3-specific antibody, but not by antibodies to other PLC-beta isoforms or G proteins. A combination of maximally effective concentrations of G alpha i3- and G beta-specific antibodies did not elicit greater inhibition than did either alone. In contrast, cholecystokinin-stimulated PLC activity was selectively blocked by PLC-beta 1- and G alpha q/11-specific antibodies. Adenosine-stimulated contraction and 45Ca2+ efflux in permeabilized muscle cells were also selectively blocked by G alpha i3-, G beta-, and PLC-beta 3-specific antibodies, whereas cholecystokinin-stimulated contraction was selectively blocked by PLC-beta 1- and G alpha q/11-specific antibodies. The results indicate that A1ARs are coupled to PLC-beta 3 via both alpha and beta gamma subunits of Gi3.


An incident-based comparison of female and male sexual offenders.
Identifying the ways in which male and female sex offenders differ is an important but understudied topic. Studies that do exist have been challenged by a reliance on small and select samples. Improving on these limitations, we use the National Incident-Based Reporting System (NIBRS) to compare male and female sex offenders among all 802,150 incidents of sexual assault reported to police across 37 states between 1991 and 2011. Findings indicated some broad similarities between groups, including the most prominent offense location (home), most common victim-offender relationship (acquaintance), and the rarity of injuries or drug abuse during crimes. However, the data also showed several important differences between male and female sexual offenders. Most notably, females offended with male accomplices in more than 30% of their sexual crimes--far more often than occurred among male sexual offenders (2%). Likewise, females offended against a victim of the same sex in nearly half of their crimes, yet this was only true in approximately 10% of male sexual offenses. Implications for future research are discussed.


Systematic review of studies of quality of clinical care in general practice in the UK, Australia and New Zealand.
Little is known about the quality of clinical care provided outside the hospital sector, despite the increasingly important role of clinical generalists working in primary care. In this study we aimed to summarise published evaluations of the quality of clinical care provided in general practice in the UK, Australia, and New Zealand. A systematic review of published studies assessing the quality of clinical care in general practice for the period 1995-9. General practice based care in the UK, Australia, and New Zealand. Main outcome measures-Study design, sampling strategy and size, clinical conditions studied, quality of care attained for each condition (compared with explicit or implicit standards for the process of care), and country of origin for each study. Ninety papers fulfilled the entry criteria for the review, 80 from the UK, six from Australia, and four from New Zealand. Two thirds of the studies assessed care in self-selected practices and 20% of the studies were based in single practices. The majority (85.5%) examined the quality of care provided for chronic conditions including cardiovascular disease (22%), hypertension (14%), diabetes (14%), and asthma (13%). A further 12% and 2% examined preventive care and acute conditions, respectively. In almost all studies the processes of care did not attain the standards set out in national guidelines or those set by the researchers themselves. For example, in the highest achieving practices 49% of diabetic patients had had their fundii examined in the previous year and 47% of eligible patients had been prescribed beta blockers after an acute myocardial infarction. This study adopts an overview of the magnitude and the nature of clinical quality problems in general practice in three countries. Most of the studies in the systematic review come from the UK and the small number of papers from Australia and New Zealand make it more difficult to draw conclusions about the quality of care in these two countries. The review helps to identify deficiencies in the research, clinical and policy agendas in a part of the health care system where quality of care has been largely ignored to date. Further work is required to evaluate the quality of clinical care in a representative sample of the population, to identify the reasons for substandard care, and to test strategies to improve the clinical care provided in general practice.


Diffusion Tensor Imaging (DTI) Correlates of Self-Reported Sleep Quality and Depression Following Mild Traumatic Brain Injury.
Background: Mild traumatic brain injuries (mTBIs) are a significant social, sport, and military health issue. In spite of advances in the clinical management of these injuries, the underlying pathophysiology is not well-understood. There is a critical need to advance objective biomarkers, allowing the identification and tracking of the long-term evolution of changes resulting from mTBI. Diffusion-weighted imaging (DWI) allows for the assessment of white-matter properties in the brain and shows promise as a suitable biomarker of mTBI pathophysiology. Methods: 34 individuals within a year of an mTBI (age: 24.4 ± 7.4) and 18 individuals with no history of mTBI (age: 23.2 ± 3.4) participated in this study. Participants completed self-report measures related to functional outcomes, psychological health, post-injury symptoms, and sleep, and underwent a neuroimaging session that included DWI. Whole-brain white matter was skeletonized using tract-based spatial statistics (TBSS) and compared between groups as well as correlated within-group with the self-report measures. Results: There were no statistically significant anatomical differences between the two groups. After controlling for time since injury, fractional anisotropy (FA) demonstrated a negative correlation with sleep quality scores (higher FA was associated with better sleep quality) and increasing depressive symptoms in the mTBI participants. Conversely, mean (MD) and radial diffusivity (RD) demonstrated positive correlations with sleep quality scores (higher RD was associated with worse sleep quality) and increasing depressive symptoms. These correlations were observed bilaterally in the internal capsule (anterior and posterior limbs), corona radiata (anterior and superior), fornix, and superior fronto-occipital fasciculi. Conclusion: The results of this study indicate that the clinical presentation of mTBI, particularly with respect to depression and sleep, is associated with reduced white-matter integrity in multiple areas of the brain, even after controlling for time since injury. These areas are generally associated not only with sleep and emotion regulation but also cognition. Consequently, the onset of depression and sleep dysfunction as well as cognitive impairments following mTBI may be closely related to each other and to white-matter integrity throughout the brain.


The Effects of Feed Restriction and Isolated or Group Rearing on the Measurement of Individual Feed Intake and Estimation of Feed Conversion Ratio in Juvenile Nile Tilapia (Oreochromis niloticus) for Selective Breeding Purposes.
Accurately measuring the phenotype at the individual level is critical to the success of selective breeding programs. Feed efficiency is a key sustainability trait and is typically approached through feed conversion ratio (FCR). This requires measurements of body weight gain (BWG) and feed intake (FI), the latter being technically challenging in fish. We assessed two of the principal methods for measuring feed intake in fish over consecutive days: (1) group rearing 10 fish per group and video recording the meals and (2) rearing fish individually on a restricted ration. Juvenile Nile tilapia (Oreochromis niloticus) from the Genetically Improved Farmed Tilapia (GIFT) strain and the Cirad strain were entered into the study (128 GIFT and 109 Cirad). The GIFT strain were reared over three consecutive periods of 7 days each under different feeding, recording, and rearing scenarios (i) in groups fed an optimal ration (g100) or (ii) fed a 50% restricted ration (g50) both with video records of all meals and (iii) reared in isolation and fed a 50% restrictive ration. The Cirad strain were tested similarly but only for scenarios (i) and (iii). All fish were fed twice daily with a calculated ration. Correlations showed the same trends for the GIFT and the Cirad strains. For the GIFT strain, correlations were positive and significant for BWG and FI measured in scenarios (i) and (ii), 0.49 and 0.63, respectively, and FI measured in scenarios (i) and (iii) (0.50) but not for BWG measured in scenarios (i) and (iii) (0.29, NS). The phenotypic correlation estimated for FCR between scenarios (i) and (ii) with fish fed an optimal or a 50% restricted ration was low and not significant (0.22). Feed Conversion Ratio for GIFT fish reared in groups or in isolation and fed with a restricted ration [scenarios (ii) and (iii)] were not significantly correlated either. Social interactions between fish, potentially impacting their efficiency, may explain the results. Therefore, selective breeding programs seeking to improve feed efficiency will need to carefully plan the feeding rate and the rearing system used to estimate FCR in order to optimize selection for the targeted production system.


Magnetic Properties of Restacked 2D Spin 1/2 honeycomb RuCl3 Nanosheets.
Spin 1/2 honeycomb materials have gained substantial interest due to their exotic magnetism and possible application in quantum computing. However, in all current materials out-of-plane interactions are interfering with the in-plane order, hence a true 2D magnetic honeycomb system is still in demand. Here, we report the exfoliation of the magnetic semiconductor α-RuCl3 into the first halide monolayers and the magnetic characterization of the spin 1/2 honeycomb arrangement of turbostratically stacked RuCl3 monolayers. The exfoliation is based on a reductive lithiation/hydration approach, which gives rise to a loss of cooperative magnetism due to the disruption of the spin 1/2 state by electron injection into the layers. The restacked, macroscopic pellets of RuCl3 layers lack symmetry along the stacking direction. After an oxidative treatment, cooperative magnetism similar to the bulk is restored. The oxidized pellets of restacked single layers feature a magnetic transition at TN = 7 K if the field is aligned parallel to the ab-plane, while the magnetic properties differ from bulk α-RuCl3 if the field is aligned perpendicular to the ab-plane. The deliberate introduction of turbostratic disorder to manipulate the magnetic properties of RuCl3 is of interest for research in frustrated magnetism and complex magnetic order as predicted by the Kitaev-Heisenberg model.


Usefulness of Bronchoscopic Rebiopsy of Non-Small Cell Lung Cancer with Acquired Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor.
Background: Approximately 50% of non-small cell lung cancer (NSCLC) patients with acquired resistance to EGFR-TKI harbor the EGFR mutation T790M. The recent development and wide use of third-generation EGFR-TKIs targeting T790M-mutant NSCLCs have increased the importance of rebiopsy after EGFR-TKI failure. We aimed to investigate the advantages of flexible bronchoscopy as a rebiopsy method and the prevalence of and factors affecting the T790M mutation after EGFR-TKI failure. Methods: We investigated 139 patients who had undergone bronchoscopic rebiopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) between Sep 2014 and Jul 2016. Results: Among the 139 patients, bronchoscopic rebiopsy yielded successful pathological diagnoses in 102 (73.4%). Among them, 41 patients with EGFR-mutant lung adenocarcinoma and EGFR-TKI progression were selected for an investigation of T790M mutation prevalence at rebiopsy. The initial EGFR mutations were exon 19 del (56.1%), L858R or L861Q (34.1%), and others (9.8%). The most common rebiopsy method was transbronchial lung biopsy (41.5%), followed by EBUS-TBNA (26.8%) and endobronchial biopsy (19.5%). The median interval to T790M emergence was the longest among cases with exon 19 deletion (14.1 months), followed by exon 21 L858R or L861Q (11.3 months) and other rare EGFR mutations (2.9 months). The T790M mutation was identified in 18 (43.9%) patients, and exon 19 del was the most significant factor affecting T790M mutation development (hazard ratio: 6.875, P = 0.014). Conclusions: Bronchoscopy was more useful than other rebiopsy approaches. The T790M emergence rate was highest in cases with exon 19 deletion, likely as a consequence of long-term EGFR-TKI exposure.


Genome-Wide Analysis of Lung Adenocarcinoma Identifies Novel Prognostic Factors and a Prognostic Score.
Lung adenocarcinoma (LUAD) is the most common histological type of all lung cancers and is associated with genetic and epigenetic aberrations. The tumor, node, and metastasis (TNM) stage is the most authoritative indicator of the clinical outcome in LUAD patients in current clinical practice. In this study, we attempted to identify novel genetic and epigenetic modifications and integrate them as a predictor of the prognosis for LUAD, to supplement the TNM stage with additional information. A dataset of 445 patients with LUAD was obtained from The Cancer Genome Atlas database. Both genetic and epigenetic aberrations were screened for their prognostic impact on overall survival (OS). A prognostic score (PS) integrating all the candidate prognostic factors was then developed and its prognostic value validated. A total of two micro-RNAs, two mRNAs and two DNA methylation sites were identified as prognostic factors associated with OS. The low- and high-risk patient groups, divided by their PS level, showed significantly different OS (p < 0.001) and recurrence-free survival (RFS; p = 0.005). Patients in the early stages (stages I/II) and advanced stages (stages III/IV) of LUAD could be further subdivided by PS into four subgroups. PS remained efficient in stratifying patients into different OS (p < 0.001) and RFS (p = 0.005) when the low- and high-risk subgroups were in the early stages of the disease. However, there was only a significant difference in OS (p = 0.04) but not RFS (p = 0.2), between the low-risk and high-risk subgroups when both were in advanced stages. PS, in combination with the TNM stage, provides additional precision in stratifying patients with significantly different OS and RFS prognoses. Further studies are warranted to assess the efficiency of PS and to explain the effects of the genetic and epigenetic aberrations observed in LUAD.


Is dexmedetomidine superior to midazolam as a premedication in children? A meta-analysis of randomized controlled trials.
In the current published literature, there are controversial results regarding the effectiveness of dexmedetomidine compared with midazolam as premedication in children. The aim of this meta-analysis was to compare the use of dexmedetomidine as a premedication in pediatric patients with that of midazolam. We searched for articles published in English that matched the key words 'dexmedetomidine', 'midazolam', and 'children' in the PubMed, Cochrane Library, Ovid, and Google Scholar databases. Additional studies were identified from the reference lists of the retrieved articles. Only prospective randomized controlled trials (RCTs) that compared the use of dexmedetomidine and midazolam as premedications in children were included. The extraction of data from the articles was performed independently by two authors using a predesigned Excel spreadsheet. The relative risks (RRs), weighted mean differences (WMDs), and their corresponding 95% confidence intervals (95% CIs) were calculated for dichotomous and continuous outcome data using the quality effects model of the MetaXL version 1.3 software. Eleven prospective RCTs (829 children) met our criteria. Compared with midazolam, dexmedetomidine premedication was associated with more satisfactory sedation upon parent separation (eight RCTs [679 children]; RR: 1.25; 95% CI: 1.06, 1.46) and upon mask acceptance (seven RCTs [559 children]; RR: 1.17; 95% CI: 1.01, 1.36). During the postoperative period, premedication with dexmedetomidine lowered the numbers of requests for rescue analgesia (six RCTs [477 children]; RR: 0.55; 95% CI: 0.40, 0.74) and lowered the risks of agitation or delirium (seven RCTs with [466 children]; RR: 0.59; 95% CI: 0.40, 0.88), and shivering (three RCTs [192 children]; RR: 0.33; 95% CI: 0.18, 0.61). However, dexmedetomidine premedication reduced systolic blood pressure (three RCTs [242 children]; WMD: -11.47 mm·Hg(-1) ; 95% CI: -13.95, -8.98), mean blood pressure (three RCTs [202 children]; WMD: -5.66 mm·Hg(-1) ; 95% CI: -8.89, -2.43), and heart rate (six RCTs [444 children]; WMD: -12.71 beat·min(-1) ; 95% CI: -14.80, -10.62), and prolonged the onset of sedation (two RCTs [132 children] WMD: 13.78 min; 95% CI: 11.33, 16.23; I(2) = 0%) relative to midazolam. This meta-analysis demonstrated that dexmedetomidine premedication is superior to midazolam premedication in terms of producing satisfactory sedation upon parent separation and mask acceptance. Dexmedetomidine premedication provides clinical benefits that included reducing the requirements for rescue analgesia and reducing agitation or delirium and shivering during the postoperative period. However, the risks of heart rate and blood pressure decreases, and the prolonged onset of sedation associated with dexmedetomidine should be considered.


Ca(2+)-dependent and Ca(2+)-permeable ion channels in aortic endothelial cells.
We investigated whether osmotic stress would activate specific ion channels in bovine aortic endothelial cells (BAECs). In isotonic medium (290 mosmol/kgH2O), cell-attached patch recordings contained both 165-pS K+ channels activated by depolarization and 40-pS K+ channels activated by 200 nM bradykinin. These inwardly rectifying K+ channels were activated by raising "cytoplasmic" Ca2+ in inside-out patches. BAEC exposed to hypotonic bath (220 mosmol/kg) exhibited a 20% decrease in intracellular K+ content within 5 min. Cell-attached patches revealed biphasic K+ channel activation with hypotonic exposure; initial activation of 165- and 40-pS K+ channels (1-3 min) was followed by a delayed but sustained reactivation of both K+ channels (> 5 min). The delayed reactivation phase was dependent on the presence of external Ca2+ and was attenuated by 10 microM gadolinium. A 28-pS nonselective cation channel (NSCC), which conducted inward Ca2+ current, was also detected during hypotonic exposure. This NSCC was stimulated by hyperpolarization and was blocked by 10 microM gadolinium. In BAEC 1) hypotonic exposure activates Ca(2+)-dependent, 165- and 40-pS K+ channels biphasically; 2) the initial phase is independent of external Ca2+, while the delayed phase requires external Ca2+; and 3) Ca(2+)-permeable, 28-pS NSCCs stimulated by membrane hyperpolarization provide a pathway for external Ca2+ influx.


Cell polarity in the protist-to-animal transition.
A signature feature of the animal kingdom is the presence of epithelia: sheets of polarized cells that both insulate the organism from its environment and mediate interactions with it. Epithelial cells display a marked apico-basal polarity, which is highly conserved across the animal kingdom, both in terms of morphology and of molecular regulators. How did this architecture first evolve? Although the last eukaryotic common ancestor almost certainly possessed a simple form of apico-basal polarity (marked by the presence of one or several flagella at a single cellular pole), comparative genomics and evolutionary cell biology reveal that the polarity regulators of animal epithelial cells have a surprisingly complex and stepwise evolutionary history. Here, we retrace their evolutionary assembly. We suggest that the "polarity network" that polarized animal epithelial cells evolved by integration of initially independent cellular modules that evolved at distinct steps of our evolutionary ancestry. The first module dates back to the last common ancestor of animals and amoebozoans and involved Par1, extracellular matrix proteins, and the integrin-mediated adhesion complex. Other regulators, such as Cdc42, Dlg, Par6 and cadherins evolved in ancient unicellular opisthokonts, and might have first been involved in F-actin remodeling and filopodial dynamics. Finally, the bulk of "polarity proteins" as well as specialized adhesion complexes evolved in the metazoan stem-line, in concert with the newly evolved intercellular junctional belts. Thus, the polarized architecture of epithelia can be understood as a palimpsest of components of distinct histories and ancestral functions, which have become tightly integrated in animal tissues.


The effect of mass on frequency.
Two experiments are described where an apparent decrease in frequency was detected when the optical path was in the vicinity of a mass. In the first experiment the 21-centimeter absorption line from Taurus A was observed near occultation by the sun. In the second experiment the frequency of a portable cesium clock was compared with the frequency of a similar clock which transmits its signals from Cape Fear, North Carolina. A decrease of frequency of the received signals as a function of the distance between the two clocks was apparent. Several relevant observations (the red shift of lines from the sun, the Mossbauer determination of the gravitational red shift, and the cosmological red shif) are discussed in view of the present results. confirmation.


Detection of monosomy 7 in interphase cells of patients with myeloid disorders.
Six patients, five with acute myeloid leukemia (AML) and one with a myelodysplastic syndrome (MDS), were found to have monosomy 7 by conventional cytogenetics at diagnosis. Repetitive DNA sequences from the heterochromatic region of human chromosomes 1 and 7 were used as probes for in situ hybridization experiments on interphase cells of these patients. A double hybridization protocol was used to reveal the particular chromosomes as distinct spots or clusters of signals within interphase nuclei. The chromosome 1 sequence served as an internal control. Simultaneous detection of the sequences showed the presence of two normal number 1 chromosomes and a missing 7 chromosome from individual cells. While cytogenetic preparations showed only -7 metaphases in 3 AML and 1 MDS patients, in situ hybridization of interphase cells showed many normal cells as well as the presence of -7 in fully mature granulocytes. One AML patient studied in remission showed only normal metaphases yet had 9% interphase cells with a missing 7 and relapsed within 3 months. We conclude that examination of interphase cells by in situ hybridization provides clinically useful data since every cell including mature granulocytes can be examined, the lineage of a cell can be determined, and efficacy of differentiation therapy can be evaluated.


Comparative analysis of extreme acid survival in Salmonella typhimurium, Shigella flexneri, and Escherichia coli.
Several members of the family Enterobacteriaceae were examined for differences in extreme acid survival strategies. A surprising degree of variety was found between three related genera. The minimum growth pH of Salmonella typhimurium was shown to be significantly lower (pH 4.0) than that of either Escherichia coli (pH 4.4) or Shigella flexneri (pH 4.8), yet E. coli and S. flexneri both survive exposure to lower pH levels (2 to 2.5) than S. typhimurium (pH 3.0) in complex medium. S. typhimurium and E. coli but not S. flexneri expressed low-pH-inducible log-phase and stationary-phase acid tolerance response (ATR) systems that function in minimal or complex medium to protect cells to pH 3.0. All of the organisms also expressed a pH-independent general stress resistance system that contributed to acid survival during stationary phase. E. coli and S. flexneri possessed several acid survival systems (termed acid resistance [AR]) that were not demonstrable in S. typhimurium. These additional AR systems protected cells to pH 2.5 and below but required supplementation of minimal medium for either induction or function. One acid-inducible AR system required oxidative growth in complex medium for expression but successfully protected cells to pH 2.5 in unsupplemented minimal medium, while two other AR systems important for fermentatively grown cells required the addition of either glutamate or arginine during pH 2.5 acid challenge. The arginine AR system was only observed in E. coli and required stationary-phase induction in acidified complex medium. The product of the adi locus, arginine decarboxylase, was responsible for arginine-based acid survival.


A novel population health approach: Using fish retinoblastoma gene profiles as a surrogate for humans.
Retinoblastoma, a tumor suppressor gene, is frequently mutated in diverse types of human tumors. We have previously shown that two types of fish tumor, eye and liver, also possess mutant Rb genes. Our aim is to determine if the Rb allele status is linked to environmentally-induced cancer and whether this information in fish can be used to predict future phenotype. This is a proof-of-concept investigation to elucidate if fish may act as surrogates in assessing pollution-induced tumor incidence and inform regulatory authorities of potential long-term population health consequences. Marine flatfish, Limanda limanda, that display either normal liver histopathology, liver adenoma or liver hepatocellular carcinoma were analysed for the presence of Rb gene alterations. Several Rb alterations were detected in the fish displaying adenoma and carcinoma, and not in the surrounding normal tissue from the same individuals. The profile is similar to that reported in humans in that they spread across the gene, particularly exons 8-23, and a functionally important region of the protein. This Rb allele data was then used to build statistical classifier sets, linking Rb status with tumor pathology. Further flatfish caught from coastal-water areas of differing contaminant burden around the UK were subsequently analysed for the presence of Rb alterations. Using novel pattern matching statistics of the classifier sets compared with the coastal samples, the coastal fish were considered more similar to the characterised disease phenotype than the normal phenotype. Preliminary data suggests that using a statistical approach, based on classifying sets of histopathologically-defined tumor states, makes it possible to predict the phenotype of wild fish based on the status of the Rb allele. Since the Rb gene is orthologous, fish populations could act as surrogates for human populations in an eco-epidemiological investigation of the combined roles of genetics and environmental exposures in the tumorigenesis process.


Bioenergy definitions and research guidelines.
A model for the functional and observable interrelation among the various components in a physical bioenergy system is presented. The analogy is made between electric circuits and electromagnetic interactions, and contact and noncontact bioenergy transfer. It is postulated that there exists some form of bioenergy that has the capacity to do work and that this energy behaves in a manner similar to electricity in that the physical concepts of electromotive force, current, and impedance have their equivalents in bioenergy. It is further postulated that these analogous components are related by an equivalent to Ohm's and other physical laws of electricity. This is extended to a conjecture that bioenergy healing is the transfer of information from a practitioner to a healee. Research guidelines for bioenergy measurements are presented, including basic measurement practices for electrical and electromagnetic systems through direct measurements and the use of indirect measurement experiments for detecting these or other forms of bioenergy transfer. The research guidelines are divided into 2 sections: those involving direct measurement of the physical electrical properties of a practitioner, in particular the difficulties associated with electrical measurements of extremely low-level signals outside of a Faraday shield or electromagnetic measurements outside of a radio frequency anechoic chamber; and those for conducting experiments in which the effects of bioenergy are being investigated on the healee or other target system without direct measurements of the means for bioenergy transfer.


Skeletal muscle is anabolically unresponsive to an amino acid infusion in pediatric burn patients 6 months postinjury.
To evaluate leg muscle, whole-body muscle, and whole-body nonmuscle protein response to anabolic signaling of amino acids in pediatric burn patients at 6 months after injury. Burn injury is associated with a catabolic state persisting years after the injury. The tissue response to nutritional signaling (eg, amino acids) plays a critical role in tissue protein net balance via coordination of protein synthesis and breakdown mechanisms. A total of 10 patients (7.4 ± 3.8 years; 27.4 ± 14.7 kg) and 5 healthy young males (22 ± 3 years; 76 ± 15 kg) underwent an 8-hour stable isotope infusion study. During the last 3 hours, an amino acid solution (10% Travasol, Clintec Nutrition, Deerfield, IL) was infused. Femoral arterial and venous blood samples and muscle biopsy samples were collected throughout the study. A P value of less than 0.05 was considered statistically different. During amino acid infusion, leg muscle protein synthesis rate significantly increased (P < 0.05) in both groups, however, in the burn group, protein breakdown also increased, although nonsignificantly. As a result, protein net balance remained negative. In the control group, breakdown nonsignificantly decreased resulting in a significant increase (P < 0.05) in muscle protein net balance. Whole-body protein breakdown was significantly higher in the burn patients. In pediatric burn patients at 6 months postinjury, leg muscle protein net deposition is unresponsive to amino acid infusion; and whole-body protein breakdown is significantly higher than in the control group.


Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling.
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.


Remote memory deficits in transient epileptic amnesia.
Transient epileptic amnesia is a form of temporal lobe epilepsy in which sufferers often complain of irretrievable loss of remote memories. We used a broad range of memory tests to clarify the extent and nature of the remote memory deficits in patients with transient epileptic amnesia. Performance on standard tests of anterograde memory was normal. In contrast, there was a severe impairment of memory for autobiographical events extending across the entire lifespan, providing evidence for the occurrence of 'focal retrograde amnesia' in transient epileptic amnesia. There was a milder impairment of personal semantic memory, most pronounced for midlife years. There were limited deficits of public semantic memory for recent decades. These results may reflect subtle structural pathology in the medial temporal lobes or the effects of the propagation of epileptiform activity through the network of brain regions responsible for long-term memory, or a combination of these two mechanisms.


Unusual presentation of postdural puncture headache requiring repeat epidural blood patch in a 4-year-old child.
We present the case of a 4-year-old child who required two epidural blood patches (EBPs) to treat a delayed onset postdural puncture headache (PDPH) caused by lumbar cerebrospinal fluid drain. The first EBP was unsuccessful with 0.41 ml·kg(-1) of blood injected. A second EBP with 0.76 ml·kg(-1) of blood was performed 2 days later with the complete resolution of symptoms. The volume of blood necessary for effective treatment for symptomatic cerebrospinal fluid leaks in children remains controversial, and a repeat EBP may be required for resolution of symptoms.


Toward Evidence-Based Measures of Implementation: Examining the Relationship Between Implementation Outcomes and Client Outcomes.
Developing consistent, valid, and efficient implementation outcome measures is necessary to advance implementation science. However, development of such measures has been limited to date, especially for validating the extent to which such measures are associated with important improvements in client outcomes. This study seeks to address this gap by developing one or more evidence-based measures of implementation (EBMIs; i.e., implementation outcome measure that is predictive of improvements in key client outcomes) for the Adolescent Community Reinforcement Approach (A-CRA), an evidence-based practice (EBP) for adolescent substance use. Data for the current study were collected as part of a large-scale federally funded EBP dissemination and implementation initiative. The multilevel dataset included 65 substance use treatment organizations, 308 clinicians, and 5873 adolescent clients. Adjusted multilevel regression analyses were used to examine the extent to which client-level outcome measures assessed at 6-month follow-up (i.e., substance use, emotional problems) could be predicted by four implementation outcomes: two measures of fidelity (i.e., session exposure, procedure exposure) and two measures of penetration (i.e., absolute client penetration, absolute staff penetration). Adjusting for client substance use at intake, as well as several client characteristics (e.g., age, race, criminal justice involvement), client substance use at follow-up was significantly lower for treatment organizations that had higher procedure exposure (B=-1.227, standard error [SE]=0.583, 95% confidence interval=-2.370, 0.252; p<.05). None of the other three implementation outcome measures were found to predict improvements in client outcomes. The current study provides support for procedure exposure as an organizational-level EBMI for A-CRA. Thus, future efforts focused on implementing A-CRA could be improved by measuring and monitoring the extent to which A-CRA procedures are being delivered to clients. Additionally, given the dearth of studies that have examined the relationship between organizational-level measures of implementation and client outcomes, this article provides a prototype for future research to identify EBMIs for other behavioral treatments.


Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors.
Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity.


Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus-Specific CD8+ T Cells.
Zika virus (ZIKV) constitutes an increasing public health problem. Previous studies have shown that CD8+ T cells play an important role in ZIKV-specific protective immunity. We have previously defined antigenic targets of the ZIKV-specific CD8+ T cell response in humans. In this study, we characterized the quality and phenotypes of these responses by a combined use of flow cytometry and transcriptomic methods, using PBMCs from donors deriving from different geographical locations collected in the convalescent phase of infection. We show that ZIKV-specific CD8+ T cells are characterized by a polyfunctional IFN-γ signature with upregulation of TNF-α, TNF receptors, and related activation markers, such as CD69, as well as a cytotoxic signature characterized by strong upregulation of GZMB and CRTAM. The signature is stable and not influenced by previous dengue virus exposure, geographical location, or time of sample collection postinfection. To our knowledge, this work elucidates the first in-depth characterization of human CD8+ T cells responding to ZIKV infection.


Fission yeast pap1-dependent transcription is negatively regulated by an essential nuclear protein, crm1.
The fission yeast pap1+ gene encodes an AP-1-like transcription factor that contains a leucine zipper motif. We identified a target gene of pap1, the p25 gene. The 5' upstream region of the p25 gene contains an AP-1 site, and by DNase I footprint analysis, we showed that the pap1 protein binds to the AP-1 site as well as to a 14-bp palindrome sequence. p25 is overproduced when the pap1+ gene is overexpressed, whereas p25 is not produced at all in the pap1 deletion mutant. p25 was previously found to be overproduced in strains carrying cold-sensitive crm1 mutations whose gene product is essential for viability and is thought to play an important role in maintenance of a proper chromosomal architecture. Deletion and site-directed mutagenesis of sequences upstream of the p25 gene demonstrated that the AP-1 site as well as the palindrome sequence are crucial for transcriptional activation either by pap1 overproduction or by the cold-sensitive crm1 mutation; pap1+ is apparently negatively regulated by crm1+. Moreover, we found that cold-sensitive crm1 mutations are suppressed by the deletion of pap1+, further indicating a close relationship between crm1+ and pap1+. The crm1 protein is highly conserved; the budding yeast homolog, CRM1, which complements the fission yeast cold-sensitive crm1 mutation, was isolated and found to also be essential for viability. These results suggest the functional importance of chromosome structure on the regulation of gene expression through the pap1 transcription factor.