Treatments for people who use anabolic androgenic steroids: a scoping review.
A growing body of evidence suggests that anabolic androgenic steroids (AAS) are used globally by a diverse population with varying motivations. Evidence has increased greatly in recent years to support understanding of this form of substance use and the associated health harms, but there remains little evidence regarding interventions to support cessation and treat the consequences of use. In this scoping review, we identify and describe what is known about interventions that aim to support and achieve cessation of AAS, and treat and prevent associated health problems. A comprehensive search strategy was developed in four bibliographic databases, supported by an iterative citation searching process to identify eligible studies. Studies of any psychological or medical treatment interventions delivered in response to non-prescribed use of AAS or an associated harm in any setting were eligible. In total, 109 eligible studies were identified, which included case reports representing a diverse range of disciplines and sources. Studies predominantly focussed on treatments for harms associated with AAS use, with scant evidence on interventions to support cessation of AAS use or responding to dependence. The types of conditions requiring treatment included psychiatric, neuroendocrine, hepatic, kidney, cardiovascular, musculoskeletal and infectious. There was limited evidence of engagement with users or delivery of psychosocial interventions as part of treatment for any condition, and of harm reduction interventions initiated alongside, or following, treatment. Findings were limited throughout by the case report study designs and limited information was provided. This scoping review indicates that while a range of case reports describe treatments provided to AAS users, there is scarce evidence on treating dependence, managing withdrawal, or initiating behaviour change in users in any settings. Evidence is urgently required to support the development of effective services for users and of evidence-based guidance and interventions to respond to users in a range of healthcare settings. More consistent reporting in articles of whether engagement or assessment relating to AAS was initiated, and publication within broader health- or drug-related journals, will support development of the evidence base.


Detection of oncogene mutations in sputum precedes diagnosis of lung cancer.
The Johns Hopkins Lung Project developed an archive of sputum specimens during a randomized trial of lung cancer screening (1974-1982). We identified 15 patients from that trial who later developed adenocarcinoma of the lung. The primary lung carcinomas from 10 of these 15 patients contained either a ras or a p53 gene mutation. Using a polymerase chain reaction-based assay, stored sputum samples obtained prior to clinical diagnosis were examined for the presence of these same oncogene mutations. In 8 of 10 patients, the identical mutation identified in the primary tumor was also detected in at least one sputum sample. The earliest detection of a clonal population of cancer cells in sputum was in a sample obtained more than 1 year prior to clinical diagnosis. These results provide the basis of a novel approach for detection of lung cancer based on the evolving molecular genetics of this disease.


Optimizing engagement with Internet-based health behaviour change interventions: comparison of self-assessment with and without tailored feedback using a mixed methods approach.
Internet-based health behaviour interventions have variable effects on health-related outcomes. Effectiveness may be improved by optimizing the design of interventions. This study examined the specific effect on engagement of providing two different design features - tailoring and self-assessment. Three versions of an Internet-delivered intervention to support the self-care of mild bowel problems were developed that provided (1) self-assessment without tailored feedback, (2) self-assessment with tailored feedback, and (3) generic information only. A qualitative study explored participants' engagement with each version of the intervention (N = 24). A larger quantitative study systematically compared participants' use of the intervention and self-reported engagement using a partial factorial design (n = 178). Findings from the qualitative study suggested that self-assessment without tailored feedback appeared to be less acceptable to participants because it was viewed as offering no personal benefit in the absence of personalized advice. In the quantitative study, self-assessment without tailored feedback was associated with greater dropout than when provided in conjunction with tailored feedback. There were significant group differences in participants' engagement with the intervention and perceptions of the intervention. Self-assessment without tailored feedback was rated as marginally less engaging and was associated with fewer positive perceptions than the generic information condition. The acceptability of self-assessment or monitoring components may be optimized by also providing tailored feedback. Without tailored feedback, these components do not appear to be any more engaging than generic information provision. Statement of contribution What is already known on this subject? Digital interventions can be effective for improving a range of health outcomes and behaviours. There is huge variation in the success of different interventions using different combinations of design features. What does this study add? This study used a systematic experimental design to identify the effect on engagement of providing interactive intervention design features alone and in combination. Intervention engagement was better when self-assessment was provided in conjunction with tailored feedback.


Randomization algorithms in BASIC for experimental design.
Six BASIC programs for randomization of treatments with respect to space and time are presented. Program 1 is used to obtain randomization of several treatments in an equal number of positions for any number of replicates such that identical treatments are not replicated successively in the same position. Program 2 randomly assigns different treatments as specified in a grid of any size either (a) without constraints or (b) so that similar treatments do not occur next to each other either horizontally or vertically, or (c) horizontally, vertically, or diagonally. Program 3 assigns from five to 100 different treatments in equal proportions to a grid of specified size with treatments separated as in Program 2 (c) above. Program 4 randomly assigns any number of different treatments in equal proportions to a Latin square-like grid containing row and column cells with a multiple number of the treatments such that no identical treatments are replicated successively in the same row, column, or both row and column. Program 5 produces Latin squares of letters with unique numbered subscripts randomized. Program 6 makes Greco-Latin squares with an odd number of letters per side. These programs will aid in randomization of treatments within positions and replicates when a degree of uniformity or spacing of treatments is desired in order to increase the power of statistical tests. Examples of program output are discussed for tests with bark beetle pheromone components.


The role of reminding in the effects of spaced repetitions on cued recall: sufficient but not necessary.
Three experiments examined the role of study-phase retrieval (reminding) in the effects of spaced repetitions on cued recall. Remindings were brought under task control to evaluate their effects. Participants studied 2 lists of word pairs containing 3 item types: single items that appeared once in List 2, within-list repetitions that appeared twice in List 2, and between-list repetitions that appeared once in List 1 and once in List 2. Our primary interest was in performance on between-list repetitions. Detection of between-list repetitions was encouraged in an n-back condition by instructing participants to indicate when a presented item was a repetition of any preceding item, including items presented in List 1. In contrast, detection of between-list repetitions was discouraged in a within-list back condition by instructing participants only to indicate repetitions occurring in List 2. Cued recall of between-list repetitions was enhanced when instructions encouraged detection of List 1 presentations. These results accord with those from prior experiments showing a role of study-phase retrieval in effects of spacing repetitions. Past experiments have relied on conditionalized data to draw conclusions, producing the possibility that performance benefits merely reflected effects of item selection. By bringing effects under task control, we avoided that problem. Our results provide evidence that reminding resulting from retrieval of earlier presentations plays a role in the effects of spaced repetitions on cued recall. However, our results also reveal that such retrievals are not necessary to produce an effect of spacing repetitions.


Heterogeneity of psychophysiological stress responses in fibromyalgia syndrome patients.
Dysregulated psychophysiological responses have been observed in patients with fibromyalgia syndrome (FMS), although the results are inconsistent. Surface electromyographic (EMG), systolic and diastolic blood pressure, heart rate (HR), and skin conductance levels (SCLs) were continuously recorded at baseline, and during a series of stress and relaxation tasks in 90 FMS patients and 30 age and sex matched healthy controls (HCs). The patient sample demonstrated lower baseline EMG levels compared to the HCs on all tasks. In contrast, the patients displayed elevated HR and SCL (sympathetic vasomotor and sudomotor indices, respectively) during both stress tasks. A cluster analysis identified four psychophysiological response patterns: 63.3% of HCs showed increased muscle tension and stable cardiovascular responses; 34.8% of FMS patients showed a pattern of increased sympathetic vasomotor reactivity with stable sudomotor and reduced muscular response; 12.2% of FMS patients showed a pattern of increased sympathetic sudomotor reactivity connected with increased sympathetic vasomotor response and reduced muscular response; and, in contrast, 46.7% of FMS patients showed a pattern of parasympathetic vasomotor reactivity and reduced sudomotor as well as muscular response. The identification of low baseline muscle tension in FMS is discrepant with other chronic pain syndromes and suggests that unique psychophysiological features may be associated with FMS. The different psychophysiological response patterns within the patient sample support the heterogeneity of FMS.


Inflammation triggers production of dimethylsphingosine from oligodendrocytes.
Neuropathic pain is a chronic, refractory condition that arises after damage to the nervous system. We previously showed that an increased level of the endogenous metabolite N,N-dimethylsphingosine (DMS) in the central nervous system (CNS) is sufficient to induce neuropathic pain-like behavior in rats. However, several important questions remain. First, it has not yet been demonstrated that DMS is produced in humans and its value as a therapeutic target is therefore unknown. Second, the cell types within the CNS that produce DMS are currently unidentified. Here we provide evidence that DMS is present in human CNS tissue. We show that DMS levels increase in demyelinating lesions isolated from patients with multiple sclerosis, an autoimmune disease in which the majority of patients experience chronic pain. On the basis of these results, we hypothesized that oligodendrocytes may be a cellular source of DMS. We show that human oligodendrocytes produce DMS in culture and that the levels of DMS increase when oligodendrocytes are challenged with agents that damage white matter. These results suggest that damage to oligodendrocytes leads to increased DMS production which in turn drives inflammatory astrocyte responses involved in sensory neuron sensitization. Interruption of this pathway in patients may provide analgesia without the debilitating side effects that are commonly observed with other chronic pain therapies.


Crystal structures of Pseudomonas putida esterase reveal the functional role of residues 187 and 287 in substrate binding and chiral recognition.
A recombinant carboxylesterase (rPPE) from Pseudomonas putida ECU1011 was previously cloned and engineered to give a potential application for resolving chiral α-hydroxy acids including mandelic acids and derivatives. Two variants rPPEW187H and rPPED287A showed a ∼100-fold increase in activity towards rac-2-acetoxy-2-(2'-chlorophenyl) acetate (rac-AcO-CPA), but rPPED287A had a significant decrease in enantioselectivity (E=8.7) compared to rPPEW187H and the wild-type rPPE (rPPEWT) (E>200). Here we report the crystal structures of rPPEWT and rPPEW187H, both by themselves and in complex with the substrate, to elucidate the structural basis of this phenomenon. An inactive mutation of nucleophile residue S159A was introduced to obtain the structure of rPPES159A/W187H complexed with (S)-AcO-CPA. The structural analysis reveals that the side chain of residue Asp287 in rPPEWT would have a potential steric conflict with (S)-AcO-CPA when the substrate binds at the active site of the enzyme. However, the mutation W187H could facilitate the relocation of Asp287, while D287A directly eliminates the hindrance of Asp287, both of which offer sufficient space for the binding and hydrolysis of substrate. Moreover, Asp287 generates one site of the "three-point attachment model" as a hydrogen-bond donor that determines the excellent enantioselectivity of rPPE in chiral recognition, and D287A would obviously destroy the hydrogen bond and result in the low enantioselectivity of rPPED287A.


Comparison of participants and non-participants in patient-reported outcome surveys: the case of Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease - International Study.
The last decade has seen a vast increase in the use of patient-reported outcomes. As patient-reported outcomes are used in order to capture patients' perspectives of their health and illness, it is a prerequisite for accurate patient-reported outcome evaluations to use representative samples. In order to evaluate representativeness, the present study focussed on the comparison between participants and non-participants in the Swedish branch of the international study APPROACH-IS (Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease - International Study), regarding demographic, clinical, and health status characteristics. Eligible patients for APPROACH-IS were identified and selected from SWEDCON, the Swedish registry for congenital heart disease (CHD). Overall, 912 eligible patients were identified, of whom 471 participated, 398 did not participate, and 43 were either unreachable or declined to participate in APPROACH-IS. The participants and non-participants were compared in terms of statistical significance and effect sizes. Significant differences were observed between participants and non-participants for sex, age, primary diagnosis, number of cardiac operations, and fatigue; however, the effect sizes were in general small, except for the difference in primary diagnosis. No differences between the two groups were found in number of catheterisations, implanted device, the distribution of NYHA functional class, or health status and symptoms. This study shows that participants and non-participants are relatively comparable groups, which confirms the representativeness of the participants. The Swedish data from APPROACH-IS can therefore be reliably generalised to the population of adults with CHD in Sweden.


Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation.
Oxidant stress, resulting from an excess of reactive electrophiles produced in the lung by both resident (epithelial and endothelial) and infiltrated leukocytes, is thought to play an obligatory role in tissue injury and abnormal repair. Previously, using a conventional (whole-body) knockout model, we showed that antioxidative gene induction regulated by the transcription factor Nrf2 is critical for mitigating oxidant-induced (hyperoxic) stress, as well as for preventing and resolving tissue injury and inflammation in vivo. However, the contribution to pathogenic acute lung injury (ALI) of the cellular stress produced by resident versus infiltrated leukocytes remains largely undefined in vivo. To address this critical gap in our knowledge, we generated mice with a conditional deletion of Nrf2 specifically in Clara cells, subjected these mice to hyperoxic insult, and allowed them to recover. We report that a deficiency of Nrf2 in airway epithelia alone is sufficient to contribute to the development and progression of ALI. When exposed to hyperoxia, mice lacking Nrf2 in Clara cells showed exacerbated lung injury, accompanied by greater levels of cell death and epithelial sloughing than in their wild-type littermates. In addition, we found that an Nrf2 deficiency in Clara cells is associated with a persistent inflammatory response and epithelial sloughing in the lungs during recovery from sublethal hyperoxic insult. Our results demonstrate (for the first time, to the best of our knowledge) that Nrf2 signaling in Clara cells is critical for conferring protection from hyperoxic lung injury and for resolving inflammation during the repair process.


Understanding the Life Histories of Pregnant-Involved Young Aboriginal Women With Substance Use Experiences in Three Canadian Cities.
Despite attention paid to substance use during pregnancy, understandings of young Aboriginal women's experiences based on their perspectives have been virtually absent in the published literature. This study's objective was to understand the life experiences of pregnant-involved young Aboriginal women with alcohol and drugs. Semi-structured interviews to gather life histories were conducted with 23 young Aboriginal women who had experiences with pregnancy, and alcohol and drug use. Transcribed interviews were analyzed for themes to describe the social and historical contexts of women's experiences and their self-representations. The findings detail women's strategies for survival, inner strength, and capacities for love, healing, and resilience. Themes included the following: intersectional identities, life histories of trauma (abuse, violence, and neglect; intergenerational trauma; separations and connections), the ever-presence of alcohol and drugs, and the highs and lows of pregnancy and mothering. The findings have implications for guiding policy and interventions for supporting women and their families.


Preparation of isolated rat liver mitochondria for electron microscopy.
A comparative study of the fixation of isolated rat liver mitochondria was undertaken. If the criterion is adopted that after processing, the mitochondria should resemble as closely as possible rat liver mitochondria in situ, the procedure found to produce such preservation was that of fixation in suspension in veronal-buffered 2% potassium permanganate. Fixation in osmium tetroxide produced variable results, while mitochondria fixed in glutaraldehyde were contracted. We suggest that in cases where fixation procedures modify the morphological appearance of mitochondria, the significance of such changes must be treated with caution.


Evidence for the involvement of presynaptic alpha-2 adrenoceptors in the regulation of norepinephrine metabolism in the rat brain.
In an attempt to evaluate the possible functional role of alpha-2 adrenoceptors located on noradrenergic nerve endings in the regulation of cerebral norepinephrine metabolism, we have measured the effects of clonidine and idazoxan on cerebral free 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (an index of norepinephrine turnover) in the rat after surgical and experimental manipulations that allow an exclusive interaction of the alpha-2 adrenergic agents with presynaptic alpha-2 autoreceptors. The possible contribution of distant (to cell bodies) transsynaptic feedback mechanisms triggered by stimulation of postsynaptic alpha-2 adrenoceptors and of somatodendritic alpha-2 autoreceptor-mediated regulatory mechanisms was eliminated by a local infusion of tetrodotoxin (50 ng) into the ascending noradrenergic bundle followed by electrical stimulation (at a frequency of 8 Hz) of this pathway distally to the neurotoxin injection site in chloral hydrate-anesthetized rats. Under these conditions, systemic injection of idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.) provoked an increase and a decrease, respectively, in free DOPEG levels in the hypothalamus, cerebral cortex and medial septum which were similar to those measured in naive rats. Moreover, in these animals the effect of idazoxan (1 mg/kg i.p.) was surmounted by a large dose of clonidine (0.3 mg/kg i.p.). The possible contribution of feedback mechanisms triggered by activation of postsynaptic alpha-2 adrenoceptors and mediated via local (to terminals) circuits (or a putative humoral agent released postsynaptically) was eliminated subsequently by a local injection of ibotenic acid in noradrenergic projection areas. Systemic administration of idazoxan (20 mg/kg i.p.) to ibotenate-lesioned rats elicited an increase in septal- and hypothalamic-free DOPEG levels comparable to that found in sham-operated rats. The effectiveness of the lesion was attested by a massive neuronal depopulation in the lesioned areas. Finally, ibotenic acid-induced destruction of noradrenergic target cells and local infusion of tetrodotoxin into followed by electrical stimulation of the ascending noradrenergic pathways were combined. Under these conditions, idazoxan still increased hypothalamic- and septal-free DOPEG levels, the extent of this alteration being similar to that found in normal rats. Altogether, these results suggest that irrespective of their low density, presynaptic alpha-2 autoreceptors play a cardinal role in the regulation of central nervous system norepinephrine metabolism.


Pirate primates in uncharted waters: lymphocyte transfers in unrelated, MHC-matched macaques.
An HIV vaccine remains elusive despite the concerted efforts of investigators and clinicians over the past two decades. Animal models are regularly used to obtain new insights on disease pathogenesis and have become invaluable tools in the translation of treatments from basic research laboratories to the clinic. Vaccination of macaques with live, attenuated simian immunodeficiency virus is currently the most effective method of garnering protection against subsequent pathogenic SIV challenge. However, immunization of humans with live, attenuated HIV is not feasible due to safety concerns. Therefore, clues to an effective and safe vaccine against HIV may be found by studying immune correlates of protection in the live, attenuated, vaccinated macaque model. Previous studies have identified the immune correlates of protection against Friend retrovirus in live, attenuated vaccinated mice using allogeneic adoptive transfers. Similar experiments in macaques have thus far been hindered due to the vast genetic diversity found within outbred populations. Here we review the current state of SIV adoptive transfer research and present a novel macaque model that allows for allogeneic adoptive transfers.


Actual causes of death in the United States, 2000.
Modifiable behavioral risk factors are leading causes of mortality in the United States. Quantifying these will provide insight into the effects of recent trends and the implications of missed prevention opportunities. To identify and quantify the leading causes of mortality in the United States. Comprehensive MEDLINE search of English-language articles that identified epidemiological, clinical, and laboratory studies linking risk behaviors and mortality. The search was initially restricted to articles published during or after 1990, but we later included relevant articles published in 1980 to December 31, 2002. Prevalence and relative risk were identified during the literature search. We used 2000 mortality data reported to the Centers for Disease Control and Prevention to identify the causes and number of deaths. The estimates of cause of death were computed by multiplying estimates of the cause-attributable fraction of preventable deaths with the total mortality data. Actual causes of death. The leading causes of death in 2000 were tobacco (435 000 deaths; 18.1% of total US deaths), poor diet and physical inactivity (365 000 deaths; 15.2%) [corrected], and alcohol consumption (85 000 deaths; 3.5%). Other actual causes of death were microbial agents (75 000), toxic agents (55 000), motor vehicle crashes (43 000), incidents involving firearms (29 000), sexual behaviors (20 000), and illicit use of drugs (17 000). These analyses show that smoking remains the leading cause of mortality. However, poor diet and physical inactivity may soon overtake tobacco as the leading cause of death. These findings, along with escalating health care costs and aging population, argue persuasively that the need to establish a more preventive orientation in the US health care and public health systems has become more urgent.


Genetic variation in GOLM1 and prefrontal cortical volume in Alzheimer's disease.
Replications of the association between APOE-ε4 allele load and regional brain atrophy in Alzheimer's disease (AD) patients hold promise for future studies testing relationships between other disease risk gene variants and brain structure. A polymorphism, rs10868366, in the Golgi phosphoprotein 2 gene, GOLM1, was recently identified as an AD risk factor in a genome-wide association study. In a subset of the same AD cohort, we used voxel-based morphometry to test for association between the disease risk genotype and reduced regional gray matter (GM) volume in AD patients (n = 72). A mean 14% reduction in GM volume was observed in the left frontal gyrus with the higher risk GG genotype. A similar association was observed in an independent, dataset of nondemented subjects (n = 278), although with a smaller effect (1%). This replicated association with GM structural variation suggests that GOLM1 polymorphisms may be related to cognitive phenotypes. The greater effect size in AD patients also suggests that the GG genotype could be a risk factor for the expression of cognitive deficits in AD.


Quantification of intratumoral collagen and elastin fibers within hepatocellular carcinoma tissues finds correlations with clinico-patho-radiological features.
Emerging evidence suggests a promising role for tumor stromal factors in characterizing patients with various types of malignancies, including hepatocellular carcinoma (HCC). We quantified the amount of collagen and elastin fibers in HCC samples with the aim of clarifying the clinico-patho-radiological significance of fiber deposition in HCC. We computed the amount of collagen and elastin fibers using digital image analysis of whole-slide images of Elastica van Gieson-stained tissues from 156 surgically resected HCCs. Furthermore, we assessed the correlations between the fiber content of HCC samples and clinical, pathological, and radiological features, including immunohistochemistry-based molecular subtypes and immunosubtypes. The intratumoral area ratio of collagen in HCC tissues (median 3.4%, range 0.1-22.2%) was more than threefold that of elastin (median 0.9%, range 0.1-9.0%); there was a strong positive correlation between the amounts of collagen and elastin. Higher levels of combined collagen and elastin were significantly associated with the confluent multinodular macroscopic tumor type, the absence of a fibrous capsule, intratumoral steatosis, scirrhous tumor stroma, dense inflammatory-cell infiltrates, and the biliary/stem cell markers-positive HCC subtype. The associations of higher collagen levels with radiological findings, including heterogeneous enhancement and persistent enhancement on dynamic computed tomography, were significant. In contrast, the associations of radiological findings with elastin fibers were not significant. Intratumoral fibrous stroma in HCC comprised septum-like and perisinusoidal fibrosis; these two forms represented distinct distribution patterns of fibers and fibroblasts. Quantitative analysis suggested that stromal fiber-rich HCCs likely represent a distinct clinico-patho-radiological entity.


Molecular pathogenesis of Parkinson disease: insights from genetic studies.
Over the past few years, genetic findings have changed our views on the molecular pathogenesis of Parkinson disease (PD), as mutations in a growing number of genes have been found to cause monogenic forms of the disorder. These mutations cause neuronal dysfunction and neurodegeneration either by a toxic gain of function, as in the case of the dominant forms of monogenic PD caused by mutations in the genes for alpha-synuclein or LRRK2, or by a loss of an intrinsic protective function, as is likely for the recessive PD genes parkin (PRKN), PINK1 and DJ-1. Evidence is emerging that at least some of the pathways uncovered in the rare monogenic forms of PD may play a direct role in the aetiology of the common sporadic disorder and that variants of the respective genes contribute to the risk of developing the disease. These findings will allow the search for new treatment strategies that focus on the underlying molecular pathophysiology, rather than simply on ameliorating symptoms.


Evaluation of a New Model of Care for People with Complications of Diabetic Retinopathy: The EMERALD Study.
The increasing diabetes prevalence and advent of new treatments for its major visual-threatening complications (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]), which require frequent life-long follow-up, have increased hospital demands markedly. Subsequent delays in patient's evaluation and treatment are causing sight loss. Strategies to increase capacity are needed urgently. The retinopathy (EMERALD) study tested diagnostic accuracy, acceptability, and costs of a new health care pathway for people with previously treated DME or PDR. Prospective, multicenter, case-referent, cross-sectional, diagnostic accuracy study undertaken in 13 hospitals in the United Kingdom. Adults with type 1 or 2 diabetes previously successfully treated DME or PDR who, at the time of enrollment, had active or inactive disease. A new health care pathway entailing multimodal imaging (spectral-domain OCT for DME, and 7-field Early Treatment Diabetic Retinopathy Study [ETDRS] and ultra-widefield [UWF] fundus images for PDR) interpreted by trained nonmedical staff (ophthalmic graders) to detect reactivation of disease was compared with the current standard care (face-to-face examination by ophthalmologists). Primary outcome: sensitivity of the new pathway. specificity; agreement between pathways; costs; acceptability; proportions requiring subsequent ophthalmologist assessment, unable to undergo imaging, and with inadequate images or indeterminate findings. The new pathway showed sensitivity of 97% (95% confidence interval [CI], 92%-99%) and specificity of 31% (95% CI, 23%-40%) to detect DME. For PDR, sensitivity and specificity using 7-field ETDRS images (85% [95% CI, 77%-91%] and 48% [95% CI, 41%-56%], respectively) or UWF images (83% [95% CI, 75%-89%] and 54% [95% CI, 46%-61%], respectively) were comparable. For detection of high-risk PDR, sensitivity and specificity were higher when using UWF images (87% [95% CI, 78%-93%] and 49% [95% CI, 42%-56%], respectively, for UWF versus 80% [95% CI, 69-88%] and 40% [95% CI, 34%-47%], respectively, for 7-field ETDRS images). Participants preferred ophthalmologists' assessments; in their absence, they preferred immediate feedback by graders, maintaining periodic ophthalmologist evaluations. When compared with the current standard of care, the new pathway could save £1390 per 100 DME visits and between £461 and £1189 per 100 PDR visits. The new pathway has acceptable sensitivity and would release resources. Users' suggestions should guide implementation.


Cell surface receptor FPR2 promotes antitumor host defense by limiting M2 polarization of macrophages.
FPR2 (Fpr2 in mouse) is a G-protein-coupled receptor interacting with bacterial and host-derived chemotactic agonists. Fpr2 supports innate and adaptive immune responses as illustrated by the reduction in severity of allergic airway inflammation in Fpr2-KO mice, due to impaired trafficking of antigen-presenting dendritic cells (DC). The aim of this study is to examine the role of Fpr2 in host antitumor responses. We found that Fpr2-KO mice bearing subcutaneously implanted Lewis lung carcinoma (LLC) cells exhibited significantly shortened survival than normal mice due to more rapidly growing tumors. In contrast, in Fpr2-transgenic mice overexpressing Fpr2, subcutaneously implanted LLC tumors grew more slowly than those in wild-type (WT) littermates. Investigation of tumor tissues revealed an increased number of macrophages associated with tumors grown in Fpr2-KO mice. Macrophages derived from Fpr2-KO mice showed a more potent chemotactic response to LLC-derived supernatant (LLC Sup), which could be neutralized by an anti-CCL2 antibody. The increased chemotaxis of Fpr2-KO mouse macrophages in response to LLC Sup was due to their higher level expression of CCR4, a chemokine receptor that also recognizes the ligand CCL2. Furthermore, macrophages from Fpr2-KO mice acquired an M2 phenotype after stimulation with LLC Sup. These results suggest that Fpr2 plays an important role in host defense against implanted LLC by sustaining macrophages in an M1 phenotype with more potent antitumor activities.


Beyond Screen Time: A Synergistic Approach to a More Comprehensive Assessment of Family Media Exposure During Early Childhood.
Digital media availability has surged over the past decade. Because of a lack of comprehensive measurement tools, this rapid growth in access to digital media is accompanied by a scarcity of research examining the family media context and sociocognitive outcomes. There is also little cross-cultural research in families with young children. Modern media are mobile, interactive, and often short in duration, making them difficult to remember when caregivers respond to surveys about media use. The Comprehensive Assessment of Family Media Exposure (CAFE) Consortium has developed a novel tool to measure household media use through a web-based questionnaire, time-use diary, and passive-sensing app installed on family mobile devices. The goal of developing a comprehensive assessment of family media exposure was to take into account the contextual factors of media use and improve upon the limitations of existing self-report measures, while creating a consistent, scalable, and cost-effective tool. The CAFE tool captures the content and context of early media exposure and addresses the limitations of prior media measurement approaches. Preliminary data collected using this measure have been integrated into a shared visualization platform. In this perspective article, we take a tools-of-the-trade approach (Oakes, 2010) to describe four challenges associated with measuring household media exposure in families with young children: measuring attitudes and practices; capturing content and context; measuring short bursts of mobile device usage; and integrating data to capture the complexity of household media usage. We illustrate how each of these challenges can be addressed with preliminary data collected with the CAFE tool and visualized on our dashboard. We conclude with future directions including plans to test reliability, validity, and generalizability of these measures.


Molecular rationale for antibody-mediated targeting of the hantavirus fusion glycoprotein.
The intricate lattice of Gn and Gc glycoprotein spike complexes on the hantavirus envelope facilitates host-cell entry and is the primary target of the neutralizing antibody-mediated immune response. Through study of a neutralizing monoclonal antibody termed mAb P-4G2, which neutralizes the zoonotic pathogen Puumala virus (PUUV), we provide a molecular-level basis for antibody-mediated targeting of the hantaviral glycoprotein lattice. Crystallographic analysis demonstrates that P-4G2 binds to a multi-domain site on PUUV Gc and may preclude fusogenic rearrangements of the glycoprotein that are required for host-cell entry. Furthermore, cryo-electron microscopy of PUUV-like particles in the presence of P-4G2 reveals a lattice-independent configuration of the Gc, demonstrating that P-4G2 perturbs the (Gn-Gc)4 lattice. This work provides a structure-based blueprint for rationalizing antibody-mediated targeting of hantaviruses.


Demonstrating Brain-Level Interactions Between Visuospatial Attentional Demands and Working Memory Load While Driving Using Functional Near-Infrared Spectroscopy.
Driving is a complex task concurrently drawing on multiple cognitive resources. Yet, there is a lack of studies investigating interactions at the brain-level among different driving subtasks in dual-tasking. This study investigates how visuospatial attentional demands related to increased driving difficulty interacts with different working memory load (WML) levels at the brain level. Using multichannel whole-head high density functional near-infrared spectroscopy (fNIRS) brain activation measurements, we aimed to predict driving difficulty level, both separate for each WML level and with a combined model. Participants drove for approximately 60 min on a highway with concurrent traffic in a virtual reality driving simulator. In half of the time, the course led through a construction site with reduced lane width, increasing visuospatial attentional demands. Concurrently, participants performed a modified version of the n-back task with five different WML levels (from 0-back up to 4-back), forcing them to continuously update, memorize, and recall the sequence of the previous 'n' speed signs and adjust their speed accordingly. Using multivariate logistic ridge regression, we were able to correctly predict driving difficulty in 75.0% of the signal samples (1.955 Hz sampling rate) across 15 participants in an out-of-sample cross-validation of classifiers trained on fNIRS data separately for each WML level. There was a significant effect of the WML level on the driving difficulty prediction accuracies [range 62.2-87.1%; χ2(4) = 19.9, p < 0.001, Kruskal-Wallis H test] with highest prediction rates at intermediate WML levels. On the contrary, training one classifier on fNIRS data across all WML levels severely degraded prediction performance (mean accuracy of 46.8%). Activation changes in the bilateral dorsal frontal (putative BA46), bilateral inferior parietal (putative BA39), and left superior parietal (putative BA7) areas were most predictive to increased driving difficulty. These discriminative patterns diminished at higher WML levels indicating that visuospatial attentional demands and WML involve interacting underlying brain processes. The changing pattern of driving difficulty related brain areas across WML levels could indicate potential changes in the multitasking strategy with level of WML demand, in line with the multiple resource theory.


Microbial flora of odontogenic abscesses in pet guinea pigs.
Abscesses of odontogenic origin in guinea pigs pose a serious health problem and need to be treated with a combination of surgical and medical therapy. The aim of this prospective study was to describe the microbial flora of odontogenic abscesses associated with osteomyelitis in 24 pet guinea pigs, to perform antibiotic sensitivity testing, and to make recommendations for practitioners on the antibiotics of first choice. Inclusion criteria for the study included the animal being diagnosed with an odontogenic abscess which underwent surgery and was not pre-treated with an antibiotic. Inclusion criteria matched for 24 guinea pigs. Samples (pus, capsule and affected tooth/bone) for bacteriological examination were collected under sterile conditions during the surgical procedure. The most commonly isolated bacteria from abscesses of odontogenic origin were Bacteroides fragilis in 12.8 per cent (6/47) of cases, Pasteurella multocida in 10.6 per cent (5/47) and Peptostreptococcus anaerobius in 8.5 per cent (4/47). Aerobic bacterial species only were isolated in 29.2 per cent (7/24) of cases, anaerobic bacteria only were isolated in 33.3 per cent (8/24), and mixed infection with anaerobic and aerobic bacterial species was seen in 37.5 per cent (9/24). Aerobes (n=20) were sensitive to enrofloxacin and marbofloxacin in 100 per cent of samples, benzylpenicillin potassium (penicillin G, PNCG) in 90 per cent, cephalotin in 85 per cent, amoxicillin-clavulanate in 75 per cent, doxycycline in 70 per cent, gentamicin in 65 per cent and trimethoprim-sulfamethoxazole in 55 per cent. Anaerobes (n=27) were sensitive to amoxicillin-clavulanate in 100 per cent of cases, clindamycin in 96.3 per cent, metronidazole in 92.6 per cent, PNCG in 92.6 per cent and cephalotin in 74.1 per cent. As guinea pigs are strictly herbivorous animals, based on the results of this study the recommended antibiotic treatment for odontogenic abscesses is a combination of fluoroquinolones and metronidazole.


Nogo-A-deficient Transgenic Rats Show Deficits in Higher Cognitive Functions, Decreased Anxiety, and Altered Circadian Activity Patterns.
Decreased levels of Nogo-A-dependent signaling have been shown to affect behavior and cognitive functions. In Nogo-A knockout and knockdown laboratory rodents, behavioral alterations were observed, possibly corresponding with human neuropsychiatric diseases of neurodevelopmental origin, particularly schizophrenia. This study offers further insight into behavioral manifestations of Nogo-A knockdown in laboratory rats, focusing on spatial and non-spatial cognition, anxiety levels, circadian rhythmicity, and activity patterns. Demonstrated is an impairment of cognitive functions and behavioral flexibility in a spatial active avoidance task, while non-spatial memory in a step-through avoidance task was spared. No signs of anhedonia, typical for schizophrenic patients, were observed in the animals. Some measures indicated lower anxiety levels in the Nogo-A-deficient group. Circadian rhythmicity in locomotor activity was preserved in the Nogo-A knockout rats and their circadian period (tau) did not differ from controls. However, daily activity patterns were slightly altered in the knockdown animals. We conclude that a reduction of Nogo-A levels induces changes in CNS development, manifested as subtle alterations in cognitive functions, emotionality, and activity patterns.


Engineering enzymatic assembly lines to produce new antibiotics.
Numerous important therapeutic agents, including widely-used antibiotics, anti-cancer drugs, immunosuppressants, agrochemicals and other valuable compounds, are produced by microorganisms. Many of these are biosynthesised by modular enzymatic assembly line polyketide synthases, non-ribosomal peptide synthetases, and hybrids thereof. To alter the backbone structure of these valuable but difficult to modify compounds, the respective enzymatic machineries can be engineered to create even more valuable molecules with improved properties and/or to bypass resistance mechanisms. In the past, many attempts to achieve assembly line pathway engineering failed or led to enzymes with compromised activity. Recently our understanding of assembly line structural biology, including an appreciation of the conformational changes that occur during the catalytic cycle, have improved hugely. This has proven to be a driving force for new approaches and several recent examples have demonstrated the production of new-to-nature molecules, including anti-infectives. We discuss the developments of the last few years and highlight selected, illuminating examples of assembly line engineering.


Lidocaine converts acute vagally associated atrial fibrillation to sinus rhythm in German Shepherd dogs with inherited arrhythmias.
Lidocaine is most frequently used to treat ventricular arrhythmias. However, lidocaine may have an antiarrhythmic effect for certain supraventricular arrhythmias. We hypothesized that lidocaine would be effective in converting experimentally induced atrial fibrillation (AF) to sinus rhythm and that a decrease in the dominant frequency (DF) and an increase in the organization as judged by the spectral entropy (SE) would occur over the course of the conversion. Seven German Shepherd (GS) Dogs. Dogs were anesthetized with fentanyl and pentobarbital. AF was induced with standard pacing protocols while left and right atrial monophasic action potentials (MAP) were recorded. The power spectra from the MAP recordings were analyzed to determine DF and SE during treatment with boluses of 2 mg/kg lidocaine. Lidocaine converted AF to sinus rhythm in all dogs and all episodes (n = 19). Conversion time was 27-87 seconds. After atropine, sustained AF was not induced; however, 5 episodes of atrial tachycardia resulted, and 3 were converted with lidocaine. Frequency domain analysis of 12 conversion sequences showed that left and right DF of the MAP signals decreased from the time of injection to conversion to sinus rhythm (P < .001). Mean SE indicated a gradient between the left and right atria (P = .003) that did not change during conversion. Vagally associated AF in GS dogs is terminated with lidocaine. Lidocaine is likely an effective treatment in clinical dogs with vagally associated AF.


Gbetagamma interferes with Ca2+-dependent binding of synaptotagmin to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex.
Presynaptic inhibitory G protein-coupled receptors (GPCRs) can decrease neurotransmission by inducing interaction of Gbetagamma with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. We have shown that this action of Gbetagamma requires the carboxyl terminus of the 25-kDa synaptosome-associated protein (SNAP25) and is downstream of the well known inhibition of Ca2+ entry through voltage-gated calcium channels. We propose a mechanism in which Gbetagamma and synaptotagmin compete for binding to the SNARE complex. Here, we characterized the Gbetagamma interaction sites on syntaxin1A and SNAP25 and demonstrated an overlap of the Gbetagamma- and synaptotagmin I -binding regions on each member of the SNARE complex. Synaptotagmin competes in a Ca2+-sensitive manner with binding of Gbetagamma to SNAP25, syntaxin1A, and the assembled SNARE complex. We predict, based on these findings, that at high intracellular Ca2+ concentrations, Ca2+-synaptotagmin I can displace Gbetagamma binding and the Gbetagamma-dependent inhibition of exocytosis can be blocked. We tested this hypothesis in giant synapses of the lamprey spinal cord, where 5-HT works via Gbetagamma to inhibit neurotransmission (Blackmer et al., 2001). We showed that increased presynaptic Ca2+ suppresses the 5-HT- and Gbetagamma-dependent inhibition of exocytosis. We suggest that this effect may be due to Ca2+-dependent competition between Gbetagamma and synaptotagmin I for SNARE binding. This type of dynamic regulation may represent a novel mechanism for modifying transmitter release in a graded manner based on the history of action potentials that increase intracellular Ca2+ concentrations and of inhibitory signals through G(i)-coupled GPCRs.


The effectiveness of salicylic acid plasters compared with 'usual' scalpel debridement of corns: a randomised controlled trial.
Corns are a common foot problem and surveys have indicated that between 14-48% of people suffer from them. Many of these will seek podiatry treatment, however there is little evidence to indicate which current treatments provide long term resolution. This study compared 'usual' treatment (enucleation with a scalpel) with the application of 40% salicylic acid plasters to corns to investigate which is the most effective in terms of clinical, economic and patient-centred outcomes. A parallel-group randomised controlled trial was carried out in two centres where adults who presented with one or more corns and who met the inclusion criteria were allocated to either 'usual' scalpel debridement or corn plaster treatment. All participants had measurements of corn size, pain using a 100 mm visual analogue scale (VAS) and health-related quality of life (EQ-5D) measures by an independent podiatrist, blind to treatment allocation at baseline, 3, 6, 9 and 12 months. 202 participants were randomised to receive scalpel debridement or corn plaster treatment (101 in each group). At 3 months 34% (32/95) of corns had completely resolved in the corn plaster group compared with 21% (20/94) in the scalpel group (p = 0.044), and 83% (79/95) had reduced in size in the corn plaster group compared with 56% (53/94) in the scalpel group (p < 0.001). At 12 months, time to corn recurrence was longer in the corn plaster group (p < 0.001). Pain from the corns was significantly lower in the corn plaster group at 3 months (p < 0.001) and EQ-5D scores changed (improved), from baseline, by 0.09 (SD ±0.31) and 0.01 (SD ±0.25) points in the corn plaster and scalpel groups respectively (p = 0.056). By month 12, EQ-5D scores had changed by 0.12 and -0.05 in the corn plaster and scalpel groups respectively (p = 0.005). The EQ-5D, VAS scores and the four domains of the Foot Disability Scale were similar in both groups at 3 and 12 months. The economic analysis indicated that corn plasters were a cost effective intervention. The use of corn plasters was associated with a higher proportion of resolved corns, a prolonged time to corn recurrence, less pain and reduced corn size over the first 6 months in comparison with 'usual' scalpel treatment and this intervention was cost effective. Used under supervision of a podiatrist on appropriate patients, corn plasters offer an effective alternative to scalpel debridement.


The influence of age, comorbidity and frailty on treatment with surgery and systemic therapy in older women with operable triple negative breast cancer (TNBC) in England: A population-based cohort study.
Surgery and chemotherapy use were studied among older women with early stage triple negative breast cancer (TNBC) in a population-based cohort. Women aged ≥50 years with unilateral early (stage 1-3a) TNBC diagnosed in 2014-2017 were identified from English cancer registration data. Information on surgery and chemotherapy was from linked Hospital Episode Statistics and Systemic Anti-Cancer Therapy datasets, respectively. Logistic regression was used to investigate the influences of patient age, comorbidity and frailty on uptake of surgery and chemotherapy. There were 7094 women with early stage TNBC. Overall rate of surgery was 94%, which only decreased among women aged ≥85 years (74%) and among the most frail. Among the 6681 women receiving surgery, 16% had neoadjuvant and 42% had adjuvant chemotherapy; the use of both decreased with age. More comorbidities and greater frailty were associated with lower rates of chemotherapy. There were differences in the uptake of chemotherapy across geographical regions and in the neoadjuvant and adjuvant chemotherapy regimens between age groups. Majority of older women with early TNBC had surgery, although some physically fit older women did not. Chemotherapy use varied by age and fitness.


Right ventricular assessment in patients presenting for lung transplantation.
Chronic pulmonary disease is associated with varying degrees of cardiac dysfunction. Because of the potentially predominant effect of severe lung disease on right ventricular (RV) size and function, a reliable method to assess RV mechanics before and after lung transplantation may provide information of long-term significance and/or prognosis. Conventional invasive and non-invasive imaging methods have a number of limitations in evaluating RV function. Ultrafast computed tomographic (ultrafast CT) scanning has been shown to provide quantitative assessment of RV and left ventricular (LV) function in individuals with and without cardiac disease. Twenty-two patients presenting during evaluation for possible lung transplantation with end-stage pulmonary disease formed the basis of this study. There were 14 patients with chronic obstructive pulmonary disease and 8 with pulmonary fibrosis. Conventional transthoracic echocardiography and ultrafast CT were used for the assessment of RV and LV function. All patients had invasive assessment of right-sided hemodynamics and pulmonary function studies performed within 7-10 days of cardiac imaging. A qualitative assessment of RV size or function was possible in all but two patients by echocardiogram, but in 45%, the echocardiographic examination was described as suboptimal. In contrast, a quantitative assessment of ventricular volumes and systolic function was obtained in all patients by ultrafast CT. Pulmonary function parameters or hemodynamic measurements obtained during cardiac catheterization did not correlate with any assessment of RV function. We concluded that (1) ultrafast CT provides measurement of the RV and LV cavity dimension and systolic function; (2) invasive right-sided hemodynamics or pulmonary function studies do not predict RV function; and (3) echocardiography does not uniformly provide assessment of RV function in patients with chronic pulmonary disease.


Predictors of hospital mortality in the elderly undergoing percutaneous coronary intervention for acute coronary syndromes and stable angina.
The percentage of elderly treated with percutaneous coronary intervention (PCI) has been increasing year by year. Little is known about predictors of hospital mortality in elderly undergoing PCI for acute coronary syndromes (ACS) and stable angina. Between 2005 and 2008 a total of 47,407 consecutive patients undergoing PCI were prospectively enrolled into the PCI-Registry of the EHS Programme. For the present analysis patients were divided into four categories: ACS patients ≥ 75 (n=4,943) and < 75 years (n=19,446), and patients with stable angina ≥ 75 (n=3,393) and < 75 years (n=19,625). A multiple logistic regression analysis was conducted to detect independent predictors of mortality in patients ≥ 75 years undergoing PCI. In addition, differences in clinical characteristics, procedural details and in-hospital outcomes between the subgroups were evaluated. Patients ≥ 75 years had more co-morbidities, and more severe coronary pathology. The use of guideline-recommended adjunctive therapy and procedural success was high in all groups. The incidence of in-hospital death was highest in ACS patients ≥ 75 years (5.2%) and < 75 years (1.7%), followed by patients with stable angina ≥ 75 (0.5%) and < 75 years (0.2%). Haemodynamic instability and acute ST-elevation myocardial infarction were the strongest determinants of hospital mortality among patients ≥ 75 years with ACS, whereas interventional complications were the most meaningful predictors of death in older patients undergoing elective PCI. Patients ≥ 75 years undergoing PCI face a relatively low risk of hospital death. However, complication rates were significantly higher compared to younger patients, strongly influenced by clinical, angiographic and interventional variables.


Surfactant protein D concentrations in serum and bronchoalveolar lavage fluid from young healthy horses on pasture and in a barn environment.
To evaluate surfactant protein D (SP-D) concentrations in serum and bronchoalveolar lavage fluid (BALF) from young healthy horses on pasture or housed in a typical barn. 20 young healthy horses. Horses were randomly assigned to 1 of 2 groups (pasture, n = 10; barn, 10), and serum and BALF samples were collected for SP-D determination at baseline (all horses on pasture) and 2 weeks and 4 weeks after the barn group of horses was relocated from the pasture to the barn. Other evaluations included physical and tracheoscopic examinations. Findings were compared within and between groups. Physical and tracheoscopic examinations, CBC, and serum biochemical analysis did not reveal evidence of respiratory disease, and no significant differences were present within and between groups. Serum SP-D concentrations did not significantly differ within and between groups, but BALF SP-D concentrations were significantly lower for the barn group at 2 weeks but not at 4 weeks, compared with baseline. The BALF SP-D concentration-to-BALF total protein concentration ratio was < 1.5 and did not significantly differ within and between groups. A mild decrease was evident in the concentration of SP-D in the BALF collected from young healthy horses after 2 weeks of exposure to a barn environment. The clinical importance of this finding remains to be determined.


Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update.
The aim of this work is to provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC) without driver alterations. A guideline update for patients with stage IV NSCLC with driver alterations will be published separately. The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel made updated recommendations based on a systematic review of randomized controlled trials from December 2015 to 2019. This guideline update reflects changes in evidence since the previous guideline update. Five randomized controlled trials provide the evidence base. Additional literature suggested by the Expert Panel is discussed. Recommendations apply to patients without driver alterations in epidermal growth factor receptor or ALK. For patients with high programmed death ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%) and non-squamous cell carcinoma (non-SCC), the Expert Panel recommends single-agent pembrolizumab. Additional treatment options include pembrolizumab/carboplatin/pemetrexed, atezolizumab/carboplatin/paclitaxel/bevacizumab, or atezolizumab/carboplatin/nab-paclitaxel. For most patients with non-SCC and either negative (0%) or low positive (1% to 49%) PD-L1, the Expert Panel recommends pembrolizumab/carboplatin/pemetrexed. Additional options are atezolizumab/carboplatin/nab-paclitaxel, atezolizumab/carboplatin/paclitaxel/bevacizumab, platinum-based two-drug combination chemotherapy, or non-platinum-based two-drug therapy. Single-agent pembrolizumab is an option for low positive PD-L1. For patients with high PD-L1 expression (TPS ≥ 50%) and SCC, the Expert Panel recommends single-agent pembrolizumab. An additional treatment option is pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel). For most patients with SCC and either negative (0%) or low positive PD-L1 (TPS 1% to 49%), the Expert Panel recommends pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel) or chemotherapy. Single-agent pembrolizumab is an option in select cases of low positive PD-L1. Recommendations are conditional on the basis of histology, PD-L1 status, and/or the presence or absence of contraindications. Additional information is available at www.asco.org/lung-cancer-guidelines.


Subclinical hypocalcaemia follows specific time-related and severity patterns in post-partum Holstein cows.
Hypocalcaemia is a common metabolic disorder of post-parturient dairy cows; enhancement of our knowledge regarding Ca dynamics would improve cow health and welfare. This study investigated the presence of time- and severity-related subclinical hypocalcaemia (SCHCa) patterns in Holstein cows after calving and their association with diseases during the first week of lactation. A total of 938 cows from nine herds were blood sampled on days 1, 2, 4 and 8 post-partum, and serum Ca concentration was measured with atomic absorption. Subclinical ketosis (serum β-hydroxybutyrate≥1.2 mmol/L) and cases of retained foetal membranes, metritis (MET), mastitis, ketosis and displaced abomasum (DA) were recorded. Using receiver operating characteristic (ROC) analysis, the SCHCa cut-off was identified at serum Ca ≤ 2.09 mmol/L. Hierarchical and two-step cluster analysis classified cows to seven clusters based on test day cow Ca records and overall SCHCa status. Two clusters (NORM and HIGH) included 318 normocalcaemic cows and five clusters (SCH-1 to -5) those that were at least once subclinically hypocalcaemic (n = 620). A second ROC analysis was performed in order to distinguish mild from severe cases of SCHCa in these 620 cows; this cut-off was identified at 1.93 mmol/L. The associated risk of disease with Ca clustership was assessed with generalized linear mixed models. Overall incidence of SCHCa was 66.1%. Clusters SCH-1 and SCH-2 included cows with short-term SCHCa of day 1 and day 2, respectively, while SCH-3 included cows with severe and prolonged SCHCa extending to day 4 and beyond. Clusters SCH-4 and SCH-5 included cows with delayed SCHCa, which culminated on days 4 and 8, respectively. Compared to NORM cows in HIGH had lower risk of MET and no cases of DA. Cows in SCH-3 had higher risk of being diagnosed with retained foetal membranes, DA or any disease during the study period. Cows in SCH-5 had higher risk of being diagnosed with ketosis, subclinical ketosis or any disease. In conclusion, there are multiple normocalcaemic and hypocalcaemic patterns that are differently associated with disease risk.


Role of formulation composition in folate receptor-targeted liposomal doxorubicin delivery to acute myelogenous leukemia cells.
Targeted drug delivery has the potential to improve the efficacy of a therapeutic agent while reducing its side effects. The folate receptor type beta (FR-beta) is a cell surface marker selectively expressed in the leukemic cells of approximately 70% of acute myeloid leukemia (AML) patients. Upregulation of FR-beta may also be selectively induced in AML cells by treatment with all-trans-retinoic acid (ATRA). In this study, the role of formulation composition in FR-targeted liposomal doxorubicin (DOX) delivery to AML cells was investigated. Liposomal formulations with a variable percentage of folate-polyethylene glycol distearoyl phosphatidylethanolamine (f-PEG-DSPE) were synthesized and evaluated for FR-beta-targeted DOX delivery in MV4-11 AML cells in vitro and for their pharmacokinetic properties in vivo. The formulation containing 0.5 mol % f-PEG-DSPE exhibited the highest efficiency of cellular uptake and in vitro cytotoxicity, as well as a long systemic circulation time in mice. In MV4-11 cells, the binding and cytotoxicity of FR-targeted liposomal DOX based on this formulation was also enhanced by ATRA-induced FR-beta upregulation.


Effects of hepatocyte growth factor on viability and biotransformation functions of hepatocytes in gel entrapped and monolayer culture.
An extracorporeal bioartificial liver device must maintain viability and differentiated function of hepatocytes cultivated at high cell density. Growth factors, such as hepatocyte growth factor, found in high concentrations in the plasma of patients with fulminant hepatic failure, have the potential to promote hepatocyte dedifferentiation and thus, decrease function. We tested the hypothesis that hepatocyte growth factor would improve viable cell density and decrease biotransformation functions of liver cells in monolayer culture and in hepatocytes entrapped in collagen cylindrical gel "noodles" as found in the extracorporeal bioartificial liver. In vitro, controlled study. University research laboratory. Adult Sprague Dawley Rats. Hepatocytes were harvested by a two-step collagenase technique. Harvested hepatocytes were plated onto type 1 collagen coated plates or entrapped in type 1 collagen cylindrical gels and cultured in different concentrations of hepatocyte growth factor. Interval measurements of 3H-thymidine incorporation, albumin synthesis, biotransformation functions, and viability were made. In monolayer culture, the addition of hepatocyte growth factor caused a dramatic increase in 3H-thymidine incorporation. This increase was accompanied by a decrease in the appearance of the lidocaine metabolite, monoethyglycinexylidide. Albumin production was unchanged. In cylindrical gel entrapment cultures, hepatocyte growth factor caused a significant increase in 2-day viability but had no effect on the metabolite appearance of lidocaine or 4-methyl umbelliferone or albumin production. Hepatocyte growth factor induces dedifferentiation of hepatocytes in monolayer culture. Collagen matrix entrapment appears to abrogate this effect and improve liver cell viability. There may be reciprocal regulation of hepatocyte reproductive and differentiated functions, such as biotransformation, which can be influenced by the entrapment of hepatocytes in an extracellular type 1 collagen matrix.


Enzymes in Human Milk.
Milk proteins are a complex and diverse source of biological activities. Beyond their function, intact milk proteins also act as carriers of encrypted functional sequences that, when released as peptides, exert biological functions, including antimicrobial and immunomodulatory activity, which could contribute to the infant's competitive success. Research has now revealed that the release of these functional peptides begins within the mammary gland itself. A complex array of proteases produced in mother's milk has been shown to be active in the milk, releasing these peptides. Moreover, our recent research demonstrates that these milk proteases continue to digest milk proteins within the infant's stomach, possibly even to a larger extent than the infant's own proteases. As the neonate has relatively low digestive capacity, the activity of milk proteases in the infant may provide important assistance to digesting milk proteins. The coordinated release of these encrypted sequences is accomplished by selective proteolytic action provided by an array of native milk proteases and infant-produced enzymes. The task for scientists is now to discover the selective advantages of this protein-protease-based peptide release system.


A Brief Primer on the Concept of the Neuroweapon for U.S. Military Medical Personnel.
The malevolent application of neuroscience is an emerging threat to the U.S. military. At present, U.S. military medical personnel are not capable of adequately diagnosing or treating the injuries and illnesses that may result from exposure to potential neuroweapons. This fact was illustrated in 2016 when U.S. diplomats serving in Havana, Cuba reported hearing strange noises accompanied by a constellation of unexplained health effects. Similar incidents have been reported in China and Russia. Although various hypotheses have been put forward to explain these symptoms, none of them have been verified. The reported symptoms were analogous to the physiological responses that have been produced in the laboratory by exposing volunteers to pulsed microwave energy. However, these incidents of undetermined origin demonstrate that widespread neurological illness can be disruptive to U.S. government operations and that it is currently not possible to identify the cause, determine the correct treatment, or ascribe attribution to potential neuroweapon use in an overseas setting. Since it is likely that Special Operations medical personnel will be among the first to respond to neuroweapon attacks in the deployed environment, it is essential that they be made aware of this emerging threat and that efforts be made to incorporate potential directed energy neuroweapons and other neuroweapon configurations into future Chemical, Biological, Radiological, Nuclear, and high yield Explosives (CBRN-E) training modules. The intention of this article is to introduce the concept of the neuroweapon to military medical personnel and to provide a brief review of the relevant literature.


Life histories of Antarctic incirrate octopods (Cephalopoda: Octopoda).
As a general trend in the life history of marine organisms, species inhabiting cold waters have reduced growth rates and increased lifespans. Studies based on egg sizes and brooding times of deep-sea and polar octopods support this hypothesis, but empirical data on growth are still scarce. To test the hypothesis that octopods inhabiting cold waters (< 3°C) live longer than temperate and warm water species, this study investigated size-at-age, maturation and growth rates in incirrate Antarctic octopods. Octopod age was estimated via the interpretation and quantification of beak growth increments, which in shallow water octopods have been validated to be formed on a daily basis. Specimens from the families Megaleledonidae (Adelieledone spp., Pareledone spp. and Megaleledone setebos) and Enteroctopodidae (Muusoctopus rigbyae) were collected on the shelf and slope regions off the Antarctic Peninsula during a cruise in 2012. Examined specimens included early juveniles to animals in advanced maturity. The total number of growth increments ranged from 192-599 in Pareledone aequipapillae (body mass [BM] 2-109 g), 182-431 in Pareledone charcoti (BM 5-124 g), 98-906 in M. setebos (BM 10-6000 g) and 207-425 in M. rigbyae (BM 24-256 g). After the cruise, eleven specimens of P. charcoti were kept alive in captivity for more than 12 months and these animals had 219-364 growth increments, suggesting that increment formation in this species takes longer than one day. The complex population structure (size, age and maturity range) of the specimens that were captured during a relatively short time, the number of beak increments quantified, and the preliminary validation observations indicate that Antarctic octopods do not deposit increments daily, and may have lifespans exceeding 3 years. These findings corroborate the general trend that cold water molluscs have a longer lifespan than their warm water relatives.


Development of contrast agents targeted to macrophage scavenger receptors for MRI of vascular inflammation.
Atherosclerosis is a leading cause of death in the U.S. Because there is a potential to prevent coronary and arterial disease through early diagnosis, there is a need for methods to image arteries in the subclinical stage as well as clinical stage using various noninvasive techniques, including magnetic resonance imaging (MRI). We describe a development of a novel MRI contrast agent targeted to plaques that will allow imaging of lesion formation. The contrast agent is directed to macrophages, one of the earliest components of developing plaques. Macrophages are labeled through the macrophage scavenger receptor A, a macrophage specific cell surface protein, using an MRI contrast agent derived from scavenger receptor ligands. We have synthesized and characterized these contrast agents with a range of relaxivities. In vitro studies show that the targeted contrast agent accumulates in macrophages, and solution studies indicate that micromolar concentrations are sufficient to produce contrast in an MR image. Cell toxicity and initial biodistribution studies indicate low toxicity, no detectable retention in normal blood vessels, and rapid clearance from blood. The promising performance of this contrast agent targeted toward vascular inflammation opens doors to tracking of other inflammatory diseases such as tumor immunotherapy and transplant acceptance using MRI.


Prediction of acute renal failure after birth asphyxia.
Twenty-one babies of 34-41 weeks' gestational age with birth asphyxia (5 minute Apgar score less than or equal to 5 or umbilical artery pH less than or equal to 7.2) were studied during the first two days of life to find out whether the urinary excretion of tubular markers of renal function is of value in the early diagnosis of acute renal failure. Urinary retinol binding protein, myoglobin, and N-acetyl-beta-D-glucosaminidase (NAG), expressed as a ratio with urinary creatinine, were measured and excretion profiles repeated at 3-6 days in 15 infants and at 7-14 days in 11 infants. Plasma creatinine concentration, creatinine clearance, plasma myoglobin concentration, and fractional sodium excretion were measured where possible in asphyxiated infants. Control data were obtained from 50 healthy infants: 28 gave urine samples alone, 17 urine and blood, and five blood alone. Normal urinary values were derived from 17, 25, and three infants, respectively, for the three time periods. The number of control samples was limited for ethical reasons. Four asphyxiated infants had acute renal failure (group 1), four had tubular dysfunction without glomerular disturbance (group 2) and 13 had normal renal function (group 3). Group 1 were clearly identified by greatly increased urinary retinol binding protein (greater than 27,000 micrograms/mmol creatinine) and myoglobin (greater than 1500 micrograms/mmol creatinine) excretion measured in the first two days of life. In control infants the range of excretion of retinol binding protein within the same time period was 3 to 967 micrograms/mmol creatinine and urinary myoglobin was undetectable. Excretion of NAG failed to discriminate between groups 1 and 2. Acute renal failure occurred only in infants who had heavy myoglobinaemia. Tubular dysfunction in group 2 was transient and not accompanied by plasma electrolyte disturbances. We conclude that measurement of urinary excretion of retinol binding protein or myoglobin after birth is helpful in the early diagnosis of acute renal failure.


The Prognostic Impact of Tumor Border Configuration, Tumor Budding and Tumor Stroma Ratio in Colorectal Carcinoma.
Tumor border configuration, tumor budding and tumor stroma ratio are reliable histopathological parameters that play a central role in the invasion-metastasis cascade. This study aimed to investigate the prognostic impact of these parameters and a new combined score in colorectal cancer. A cohort of 103 colorectal cancer surgical specimens was retrospectively evaluated for tumor border configuration, tumor budding and tumor stroma ratio using H&E sections. A combined risk score was then constructed to divide cases into low risk-tumors and high risk-tumors. Infiltrating tumor border, high tumor budding, low tumor stroma ratio and high combined risk score were associated with positive lymph node involvement, presence of metastasis, high tumor grade, lymphovascular invasion, poor overall survival and short recurrence-free survival. Infiltrating tumor border, high tumor budding and high combined risk score were associated with advanced T stage. High tumor budding, and low tumor stroma ratio were associated with perineural invasion. Infiltrating tumor border was associated with increased tumor size and conventional adenocarcinoma, high tumor budding and low tumor stroma ratio. Low tumor stroma ratio was associated with high tumor budding. On multivariate survival analysis, tumor stroma ratio was found to be an independent predictor for overall survival and recurrence-free survival. Tumor border configuration, tumor budding, tumor stroma ratio and the newly constructed combined risk score are potential predictors of outcome in colorectal cancer patients, suggesting that their incorporation in the routine histopathological evaluation could be useful in determining the prognosis of colorectal cancer cases.


Gold-nanoparticle-assisted random lasing from powdered GaN.
We demonstrate Au-nanoparticle-assisted random lasing from a powdered GaN sample. In the presence of Au nanoparticles on GaN powder surfaces, several lasing lines are observed in photoexcited luminescence spectra near the center of the GaN band-edge emission peak. The random lasing is considered to arise from a decrease in the lasing threshold due to the suppression of crystal defect loss by surface plasmon excitation on Au. From spatially resolved lasing emission spectra and their FT analysis results, the formation of random lasing cavities at different spatial positions is confirmed. The size of the random lasing spot is determined to be larger than that of the scattered light speckle of the pumping source on a thin powdered GaN sample.


De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.
Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.


White butterflies as solar photovoltaic concentrators.
Man's harvesting of photovoltaic energy requires the deployment of extensive arrays of solar panels. To improve both the gathering of thermal and photovoltaic energy from the sun we have examined the concept of biomimicry in white butterflies of the family Pieridae. We tested the hypothesis that the V-shaped posture of basking white butterflies mimics the V-trough concentrator which is designed to increase solar input to photovoltaic cells. These solar concentrators improve harvesting efficiency but are both heavy and bulky, severely limiting their deployment. Here, we show that the attachment of butterfly wings to a solar cell increases its output power by 42.3%, proving that the wings are indeed highly reflective. Importantly, and relative to current concentrators, the wings improve the power to weight ratio of the overall structure 17-fold, vastly expanding their potential application. Moreover, a single mono-layer of scale cells removed from the butterflies' wings maintained this high reflectivity showing that a single layer of scale cell-like structures can also form a useful coating. As predicted, the wings increased the temperature of the butterflies' thorax dramatically, showing that the V-shaped basking posture of white butterflies has indeed evolved to increase the temperature of their flight muscles prior to take-off.


Socio-demographic characteristics associated with cigarettes smoking, drug abuse and alcohol drinking among male medical university students in Iran.
Substance abuse is one of the most complicated social problems. Understanding socio-demographic characteristics of those who abuse substances could help deal with this problem more efficiently. The main objective of this study was to determine socio-demographic characteristics associated with alcohol drinking, cigarettes smoking and drug abuse among a sample of male medical university students in Iran. This cross-sectional study was conducted in 2014 among 425 male medical college students randomly selected with the proportional to size among different faculties in Isfahan and Kermanshah medical universities in Iran. A self-report written questionnaire was applied to collect data. Data were analyzed by the SPSS-20. Mean age of the respondents was 19.9 yr (ranging from 18 to 22 yr). About 19.4%, 3.9%, and 10.1% of the respondents had history of cigarette smoking, drug use, and alcohol drinking during the past three months, respectively. Logistic regression showed that mother's educational level, living place, economic status, and parents' divorce were the most influential predictive factors on substance abuse. Considering the high prevalence of substance abuse (especially smoking and alcohol drinking), it seems essential to design educational interventions to prevent substance abuse, paying attention to predictive factors mentioned above, among college students.


Cost-effectiveness model of cytomegalovirus management strategies in renal transplantation. Comparing valaciclovir prophylaxis with current practice.
Cytomegalovirus (CMV) disease may occur following renal transplantation and has been shown to have health and cost consequences in this setting. To compare the cost effectiveness of different CMV management strategies for renal transplant patients: prophylaxis with (i) oral valaciclovir or (ii) intravenous ganciclovir; viral testing for CMV followed by (iii) pre-emptive therapy with intravenous ganciclovir or (iv) adjustment of immunosuppression and intensive monitoring; or (v) waiting to treat when CMV disease develops. A decision-tree model was constructed that included the different management strategies for the donor seropositive/recipient seronegative (D+R-) population. Clinical outcomes for the D+R- population came from clinical trials. Treatment algorithms and costs for CMV syndrome and tissue invasive disease were developed from published literature and UK physician interviews. One- and 2-way sensitivity analyses were performed. UK National Health Service. Prophylaxis with either oral valaciclovir or intravenous ganciclovir dominated (lower costs and fewer cases of CMV disease) the pre-emptive treatment and wait-and-treat strategies. The cost per patient was from 157 Pounds to 438 Pounds higher with oral valaciclovir prophylaxis compared with intravenous ganciclovir prophylaxis and the incremental cost per case of CMV disease avoided with valaciclovir prophylaxis ranged from 2243 Pounds to 8111 Pounds (1996 values). These results are sensitive to the efficacy of intravenous ganciclovir prophylaxis and CMV management costs. For D+R- renal transplant patients, prophylaxis is the dominant (more effective and less costly) management strategy compared with pre-emptive and wait-and-treat strategies. The cost per patient with oral valaciclovir prophylaxis compared with intravenous ganciclovir prophylaxis is slightly higher in our base case scenario, but may be lower under reasonable alternative assumptions.


Potency and penetration of telavancin in staphylococcal biofilms.
Due to the emergence of staphylococcal biofilm infections, the need for advanced antibiotics is crucial. The aim of this investigation was to evaluate the potency and penetration of telavancin against staphylococcal biofilms using two different biofilm models. Multiple staphylococcal strains, including meticillin-sensitive Staphylococcus aureus ATCC 29213, vancomycin-intermediate S. aureus ATCC 700787, heterogeneously vancomycin-intermediate S. aureus ATCC 700698 and meticillin-sensitive Staphylococcus epidermidis ATCC 12228, were grown and treated in drip-flow reactors to determine log reductions due to telavancin treatment. After 3 days of biofilm growth and 24 h of treatment, mean log reductions for telavancin ranged from 1.65 to 2.17 depending on the bacterial strain tested. Penetration was evaluated qualitatively using confocal scanning laser microscopy to image the infiltration of fluorescently labelled antibiotic into a staphylococcal biofilm grown in a flow cell. Fluorescently labelled telavancin rapidly penetrated the biofilms with no alteration in the biofilm structure.


Evaluation of cholinesterase inhibitory and antioxidant activities of wild and cultivated samples of sage (Salvia fruticosa) by activity-guided fractionation.
In European folk medicine, Salvia species have traditionally been used to enhance memory. In our previous study of 55 Salvia taxa, we explored significant anticholinesterase activity of cultivated S. fruticosa. In this study, we compared the inhibitory activity of dichloromethane, ethyl acetate, and ethanol extracts of 3 wild-grown samples and 1 cultivated sample of S. fruticosa against acetylcholinesterase and butyrylcholinesterase enzymes (which are associated with pathogenesis of Alzheimer's disease) by using the spectrophotometric Ellman method. Antioxidant activities were assessed by determining 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity, iron-chelating capacity, and ferric-reducing antioxidant power. The dichloromethane extract of the cultivated sample was then subjected to fractionation by using open column chromatography and medium-pressure liquid chromatography to obtain the most active fraction by activity-guided fractionation. All fractions and subfractions were tested in the same manner, and inactive subfractions were discarded. The essential oil of the cultivated sample was analyzed by gas chromatography-mass spectrometry.


Blood monoamine metabolism in Huntington's disease.
In 25 patients with Huntington's disease (HD), the mean blood concentration of serotonin (5-HT) and percentage of plasma free tryptophan were significantly increased while plasma concentrations of total and protein-bound tryptophan were significantly decreased. The pattern of changes in tryptophan concentrations was related to clinical severity but not to 5-HT levels. Platelet monoamine oxidase (MAO) activity was significantly increased in patients with HD; kinetic and marker enzyme studies suggested an increased enzyme concentration. Offspring at risk for HD also had elevated platelet MAO activity but normal concentrations of blood 5-HT and plasma tryptophan. In ten patients, plasma epinephrine concentrations were significantly increased; plasma dopamine and norepinephrine concentrations were positively related to MAO activity. The finding of peripheral neurotransmitter abnormalities in HD raises the question of an interaction between CNS and peripheral processes or a systemic disorder of neurotransmitter metabolism.


NMR dynamics investigation of ligand-induced changes of main and side-chain arginine N-H's in human phosphomevalonate kinase.
Phosphomevalonate kinase (PMK) catalyzes phosphoryl transfer from adenosine triphosphate (ATP) to mevalonate 5-phosphate (M5P) on the pathway for synthesizing cholesterol and other isoprenoids. To permit this reaction, its substrates must be brought proximal, which would result in a significant and repulsive buildup of negative charge. To facilitate this difficult task, PMK contains 17 arginines and eight lysines. However, the way in which this charge neutralization and binding is achieved, from a structural and dynamics perspective, is not known. More broadly, the role of arginine side-chain dynamics in binding of charged substrates has not been experimentally defined for any protein to date. Herein we report a characterization of changes to the dynamical state of the arginine side chains in PMK due to binding of its highly charged substrates, ATP and M5P. These studies were facilitated by the use of arginine-selective labeling to eliminate spectral overlap. Model-free analysis indicated that while substrate binding has little effect on the arginine backbone dynamics, binding of either substrate leads to significant rigidification of the arginine side chains throughout the protein, even those that are >8 A from the binding site. Such a global rigidification of arginine side chains is unprecedented and suggests that there are long-range electrostatic interactions of sufficient strength to restrict the motion of arginine side chains on the picosecond-to-nanosecond time scale. It will be interesting to see whether such effects are general for arginine residues in proteins that bind highly charged substrates, once additional studies of arginine side-chain dynamics are reported.


Organic Matter Type Defines the Composition of Active Microbial Communities Originating From Anoxic Baltic Sea Sediments.
Carbon cycling in anoxic marine sediments is dependent on uncultured microbial communities. Niches of heterotrophic microorganisms are defined by organic matter (OM) type and the different phases in OM degradation. We investigated how OM type defines microbial communities originating from organic-rich, anoxic sediments from the Baltic Sea. We compared changes in the sediment microbial community, after incubation with different stable isotope labeled OM types [i.e., particulate algal organic matter (PAOM), protein, and acetate], by using DNA stable isotope probing (DNA-SIP). Incorporation of 13C and/or 15N label was predominantly detected in members of the phyla Planctomycetes and Chloroflexi, which also formed the majority (>50%) of the original sediment community. While these phylum-level lineages incorporated label from all OM types, phylogenetic analyses revealed a niche separation at the order level. Members of the MSBL9 (Planctomycetes), the Anaerolineales (Chloroflexi), and the class Bathyarchaeota, were identified as initial degraders of carbohydrate-rich OM, while other uncultured orders, like the CCM11a and Phycisphaerales (Planctomycetes), Dehalococcoidia, and JG30-KF-CM66 (Chloroflexi), incorporated label also from protein and acetate. Our study highlights the importance of initial fermentation of complex carbon pools in shaping anoxic sediment microbial communities and reveals niche specialization at the order level for the most important initial degraders in anoxic sediments.


[Applying toothpaste and mouthwash BLUEM in complex oral care in patients with coronary heart disease].
For patients with coronary heart disease oral hygiene and treatment of oral mucosa inflammatory changes and periodontal disease are of vital importance. Dental status assessment in 110 patients hospitalized in cardiology department revealed that they all suffered from periodontal disease, diseases of teeth and oral mucosa. In 100% of cases it was necessary to improve oral hygiene. Inclusion in everyday hygienic oral care of toothpaste and mouthwash Bluem reduced the severity of inflammatory changes and improved the hygienic condition of the oral cavity.


Right-angle slot waveguide bends with high bending efficiency.
Two right-angle bends for nanoscale slot waveguides with high bending efficiency based on a corner mirror and different resonant cavities are presented, one with a triangular cavity and the other with a square cavity. Through two-dimensional parametric scanning of the position of the mirror and the dimension of the cavity, a maximum bending efficiency calculated using mode overlap integral (MOI) of 94.3% is achieved for the bend with the triangular cavity and 93.1% is achieved for the bend with the square cavity. Although they both have similar bending performance, the position of the mirror is different between the two cases.


Investigation of the isoplanatic patch and wavefront aberration along the pupillary axis compared to the line of sight in the eye.
Conventional optical systems usually provide best image quality on axis, while showing unavoidable gradual decrease in image quality towards the periphery of the field. The optical system of the human eye is not an exception. Within a limiting boundary the image quality can be considered invariant with field angle, and this region is known as the isoplanatic patch. We investigate the isoplanatic patch of eight healthy eyes and measure the wavefront aberration along the pupillary axis compared to the line of sight. The results are used to discuss methods of ocular aberration correction in wide-field retinal imaging with particular application to multi-conjugate adaptive optics systems.


Breed comparisons of Angus, Brahman, Hereford, Pinzgauer, Sahiwal, and Tarentaise for weight, weight adjusted for condition score, height, and body condition score.
Data from topcross cows (n = 468) from six breeds of sire (Angus, Brahman, Hereford, Pinzgauer, Sahiwal, Tarentaise) and two breeds of dam (Angus and Hereford) of Cycle III of the Germplasm Evaluation (GPE) program at the U.S. Meat Animal Research Center (MARC) comprising cow weight (CW, n = 9,012), height (CH, n = 9,010), and condition score (CS, n = 8,991) recorded in four seasons per year from 2 to 6 yr of age were used to estimate breed-group differences. The mixed models included cow age, season of measurement and their interactions, year of birth, pregnancy-lactation code (PL), and breed group as fixed effects for CW and CS. Analyses of weight adjusted for condition score included CS as a linear covariate. Model for CH excluded PL. Random effects were additive genetic and permanent environmental effects. Differences among breed-groups were significant for all traits for different ages and were maintained across ages, with few interchanges in ranking through maturity. Cows with Sahiwal sires were lightest (392 to 479 kg), whereas Hereford-Angus (HA) reciprocal-cross cows were shortest (119 to 123 cm) at each age. Cows with Brahman sires were heaviest and tallest among breed groups at all ages, exceeding HA cows by 19 to 24 kg and 9 to 10 cm, respectively. Cows with Pinzgauer and Tarentaise sires were intermediate for weight and height and interchanged ranking across ages. Differences in weight due to differences in condition seemed to be of small magnitude because adjustment for condition score did not affect rankings of breed groups across ages. Important changes for mature size of cows can be achieved by breed substitution with the breeds of sires used in this study.


Development of a Food Group-Based Diet Score and Its Association with Bone Mineral Density in the Elderly: The Rotterdam Study.
No diet score exists that summarizes the features of a diet that is optimal for bone mineral density (BMD) in the elderly. Our aims were (a) to develop a BMD-Diet Score reflecting a diet that may be beneficial for BMD based on the existing literature, and (b) to examine the association of the BMD-Diet Score and the Healthy Diet Indicator, a score based on guidelines of the World Health Organization, with BMD in Dutch elderly participating in a prospective cohort study, the Rotterdam Study (n = 5144). Baseline dietary intake, assessed using a food frequency questionnaire, was categorized into food groups. Food groups that were consistently associated with BMD in the literature were included in the BMD-Diet Score. BMD was measured repeatedly and was assessed using dual energy X-ray absorptiometry. The BMD-Diet Score considered intake of vegetables, fruits, fish, whole grains, legumes/beans and dairy products as "high-BMD" components and meat and confectionary as "low-BMD" components. After adjustment, the BMD-Diet Score was positively associated with BMD (β (95% confidence interval) = 0.009 (0.005, 0.012) g/cm(2) per standard deviation). This effect size was approximately three times as large as has been observed for the Healthy Diet Indicator. The food groups included in our BMD-Diet Score could be considered in the development of future dietary guidelines for healthy ageing.


The human brain somatostatin interactome: SST binds selectively to P-type family ATPases.
Somatostatin (SST) is a cyclic peptide that is understood to inhibit the release of hormones and neurotransmitters from a variety of cells by binding to one of five canonical G protein-coupled SST receptors (SSTR1 to SSTR5). Recently, SST was also observed to interact with the amyloid beta (Aβ) peptide and affect its aggregation kinetics, raising the possibility that it may bind other brain proteins. Here we report on an SST interactome analysis that made use of human brain extracts as biological source material and incorporated advanced mass spectrometry workflows for the relative quantitation of SST binding proteins. The analysis revealed SST to predominantly bind several members of the P-type family of ATPases. Subsequent validation experiments confirmed an interaction between SST and the sodium-potassium pump (Na+/K+-ATPase) and identified a tryptophan residue within SST as critical for binding. Functional analyses in three different cell lines indicated that SST might negatively modulate the K+ uptake rate of the Na+/K+-ATPase.


Pumping-induced drawdown and stream depletion in a leaky aquifer system.
The impact of ground water pumping on nearby streams is often estimated using analytic models of the interconnected stream-aquifer system. A common assumption of these models is that the pumped aquifer is underlain by an impermeable formation. A new semianalytic solution for drawdown and stream depletion has been developed that does not require this assumption. This solution shows that pumping-induced flow (leakage) through an underlying aquitard can be an important recharge mechanism in many stream-aquifer systems. The relative importance of this source of recharge increases with the distance between the pumping well and the stream. The distance at which leakage becomes the primary component of the pumping-induced recharge depends on the specific properties of the aquifer, aquitard, and streambed. Even when the aquitard is orders of magnitude less transmissive than the aquifer, leakage can be an important recharge mechanism because of the large surface area over which it occurs. Failure to consider aquitard leakage can lead to large overestimations of both the drawdown produced by pumping and the contribution of stream depletion to the pumping-induced recharge. The ramifications for water resources management and water rights adjudication can be significant. A hypothetical example helps illustrate these points and demonstrates that more attention should be given to estimating the properties of aquitards underlying stream-aquifer systems. The solution presented here should serve as a relatively simple but versatile tool for practical assessments of pumping-induced stream-aquifer interactions. However, this solution should not be used for such assessments without site-specific data that indicate pumping has induced leakage through the aquitard.