CCL3L1-CCR5 genotype improves the assessment of AIDS Risk in HIV-1-infected individuals.
Whether vexing clinical decision-making dilemmas can be partly addressed by recent advances in genomics is unclear. For example, when to initiate highly active antiretroviral therapy (HAART) during HIV-1 infection remains a clinical dilemma. This decision relies heavily on assessing AIDS risk based on the CD4+ T cell count and plasma viral load. However, the trajectories of these two laboratory markers are influenced, in part, by polymorphisms in CCR5, the major HIV coreceptor, and the gene copy number of CCL3L1, a potent CCR5 ligand and HIV-suppressive chemokine. Therefore, we determined whether accounting for both genetic and laboratory markers provided an improved means of assessing AIDS risk. In a prospective, single-site, ethnically-mixed cohort of 1,132 HIV-positive subjects, we determined the AIDS risk conveyed by the laboratory and genetic markers separately and in combination. Subjects were assigned to a low, moderate or high genetic risk group (GRG) based on variations in CCL3L1 and CCR5. The predictive value of the CCL3L1-CCR5 GRGs, as estimated by likelihood ratios, was equivalent to that of the laboratory markers. GRG status also predicted AIDS development when the laboratory markers conveyed a contrary risk. Additionally, in two separate and large groups of HIV+ subjects from a natural history cohort, the results from additive risk-scoring systems and classification and regression tree (CART) analysis revealed that the laboratory and CCL3L1-CCR5 genetic markers together provided more prognostic information than either marker alone. Furthermore, GRGs independently predicted the time interval from seroconversion to CD4+ cell count thresholds used to guide HAART initiation. The combination of the laboratory and genetic markers captures a broader spectrum of AIDS risk than either marker alone. By tracking a unique aspect of AIDS risk distinct from that captured by the laboratory parameters, CCL3L1-CCR5 genotypes may have utility in HIV clinical management. These findings illustrate how genomic information might be applied to achieve practical benefits of personalized medicine.


Using Mobile Phone Data Collection Tool, Surveda, for Noncommunicable Disease Surveillance in Five Low- and Middle-income Countries.
The Noncommunicable Disease (NCD) Mobile Phone Survey, a component of the Bloomberg Philanthropies Data for Health Initiative, determines the prevalence of NCDs and their associated risk factors and demonstrates the use of mobile phone administered surveys to supplement periodic national household surveys. The NCD Mobile Phone Survey uses Surveda to administer the survey; Surveda is an open-source, multi-modal software specifically developed for the project. The objective of the paper is to describe Surveda, review data collection methods used in participating countries and discuss how Surveda and similar approaches can improve public health surveillance. Surveda features full-service survey design and implementation through a web application and collects data via Short Messaging Service (SMS), Interactive Voice Response (IVR) and/or mobile web. Surveda's survey design process employs five steps: creating a project, creating questionnaires, designing and starting a survey, monitoring survey progress, and exporting survey results. The NCD Mobile Phone Survey has been successfully conducted in five countries, Zambia (2017), Philippines (2018), Morocco (2019), Malawi (2019), and Sri Lanka (2019), with a total of 23,682 interviews completed. This approach to data collection demonstrates that mobile phone surveys can supplement face-to-face data collection methods. Furthermore, Surveda offers major advantages including automated mode-switch, question randomization and comparison features. Accurate and timely survey data informs a country's abilities to make targeted policy decisions while prioritizing limited resources. The high acceptance of Surveda demonstrates that the use of mobile phones for surveillance can deliver accurate and timely data collection.


The complete amino acid sequence confirms the presence of pseudoazurin in Thiosphaera pantotropha.
The complete amino acid sequence, obtained by direct protein sequencing, of the pseudoazurin from Thiosphaera pantotropha is reported. It shows sequence identities varying from 46 to 66% with previously sequenced pseudoazurins. Previously identified conserved residues with key functions in pseudoazurins are found in the protein from T. pantotropha with the exception of glycine-39, the carbonyl group of which has been considered as a ligand to the copper, which is replaced by a serine residue. Electrospray-ionization MS (ESI-MS) has shown that pseudoazurin from T. pantotropha often contains two polypeptide species differing in molecular mass by 16 Da, presumably owing to oxidation of a methionine residue to a sulphoxide derivative. These two species have different endoproteinase Arg-C digestion patterns. Conditions for ESI-MS were identified that permitted either the retention or the loss of the single copper ion associated with the pseudoazurin. The aberrant tendency of T. pantotropha pseudoazurin to form a disulphide-bridged dimer on SDS/PAGE under some conditions is described.


Computer simulations show that Neanderthal facial morphology represents adaptation to cold and high energy demands, but not heavy biting.
Three adaptive hypotheses have been forwarded to explain the distinctive Neanderthal face: (i) an improved ability to accommodate high anterior bite forces, (ii) more effective conditioning of cold and/or dry air and, (iii) adaptation to facilitate greater ventilatory demands. We test these hypotheses using three-dimensional models of Neanderthals, modern humans, and a close outgroup (Homo heidelbergensis), applying finite-element analysis (FEA) and computational fluid dynamics (CFD). This is the most comprehensive application of either approach applied to date and the first to include both. FEA reveals few differences between H. heidelbergensis, modern humans, and Neanderthals in their capacities to sustain high anterior tooth loadings. CFD shows that the nasal cavities of Neanderthals and especially modern humans condition air more efficiently than does that of H. heidelbergensis, suggesting that both evolved to better withstand cold and/or dry climates than less derived Homo We further find that Neanderthals could move considerably more air through the nasal pathway than could H. heidelbergensis or modern humans, consistent with the propositions that, relative to our outgroup Homo, Neanderthal facial morphology evolved to reflect improved capacities to better condition cold, dry air, and, to move greater air volumes in response to higher energetic requirements.


Prevalence and clinical characteristics of human respiratory syncytial virus in Chinese adults with acute respiratory tract infection.
Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illnesses worldwide. Although the prevalence and clinical manifestations of the two subtypes, RSV-A and RSV-B, have been studied in some detail in infants and young children, they have not been determined in adults. To evaluate the prevalence of the RSV subtypes and disease severity between RSV-A and RSV-B infections in adults, nasal and throat swabs that were collected from patients ≥15 years old who sought medical care for acute respiratory infections at the Fever Clinic of the Peking Union Medical College Hospital in Beijing, China between May 2005 and April 2010. The samples were tested for RSV infection using PCR and sequencing analysis. RSV was detected in 95 (1%) of the adult patients, of whom 53 (55.8%) were positive for RSV-A and 42 (44.2%) for RSV-B. The incidence of RSV infections increased with age (χ(2) = 37.17, P = 1.66E-07). Demographic data and clinical manifestations of RSV-A were similar to those of RSV-B. Although RSV-A and RSV-B co-circulated during the 2005-2006 and 2008-2009 seasons, RSV-A was predominant in the 2006-2008 seasons, whereas RSV-B was predominant in the 2009-2010 season. Upper respiratory tract infections were diagnosed in most RSV-infected patients (n = 80, 84.2%), and three patients suffered from pulmonary infection. This is the first study to provide data on the prevalence and clinical manifestations of RSV subgroups among Chinese adults with fever and acute illness, over five successive epidemic seasons.


History and physical examination of hip injuries in elderly adults.
Hip fracture is the most common injury occurring to elderly people and is associated with restrictions of the activities of the patients themselves. The discovery of a hip fracture can be the beginning of a complex journey of care, from initial diagnosis, through operational procedures to rehabilitation. The patient's history and physical examination form the basis of the diagnosis and monitoring of elderly patients with hip problems and dictate the appropriate treatment strategy to be implemented. The aim of this study is to discuss the different diagnoses of hip pain in a case study of an elderly woman who initially complained of pain in her right knee following a fall at home. It shows that musculoskeletal physical examination determined the management of the hip fracture that was found to be present. In addition, the aim of this article is to review diagnostic tests such as radiographs and recommend appropriate management and treatment of hip fractures in elderly patients.


Enterovirus d68. A focused review and clinical highlights from the 2014 U.S. Outbreak.
Enterovirus D68 (EV-D68), a member of the Picornaviridae family, was first identified in 1962 and is part of a group of small, nonenveloped RNA viruses. As a family, these viruses are among the most common causes of disease among humans. However, outbreaks of disease attributable to EV-D68 have been rarely reported in the previous 4 decades. Reports from a few localized outbreaks since 2008 describe severe lower respiratory tract infection in children. In the late summer of 2014, EV-D68 caused a geographically widespread outbreak of respiratory disease of unprecedented magnitude in the United States. The Centers for Disease Control and Prevention was first notified of increased respiratory viral activity by Children's Mercy Hospitals (CMH) in Kansas City, Missouri, and EV-D68 was identified in 50% of nasopharyngeal specimens initially tested. Between mid-August and December 18, 2014, confirmed cases of lower respiratory tract infection caused by EV-D68 were reported in 1,152 people in 49 states and the District of Columbia. A focused review of EV-D68 respiratory disease and clinical highlights from the 2014 U.S. outbreak are presented here.


Adherence of neutrophils to canine cardiac myocytes in vitro is dependent on intercellular adhesion molecule-1.
The adhesiveness of isolated canine cardiac myocytes for neutrophils is greatly increased by stimulation with cytokines such as tumor necrosis factor alpha (TNF alpha). Since this adhesion is significantly inhibited by an anti-CD18 MAb, experiments were performed to test the hypothesis that the newly expressed adhesion molecule on the cardiac myocytes was intercellular adhesion molecule-1 (ICAM-1). A newly developed MAb, CL18/6, was found to exhibit the functional and binding characteristics with canine neutrophils and canine jugular vein endothelial cells expected of an antibody recognizing ICAM-1. MAb CL18/6 also bound to isolated cardiac myocytes after stimulation of the myocytes with cytokines, and it blocked by greater than 90% the adhesion of neutrophils to stimulated myocytes. A partial cDNA clone for canine ICAM-1 was isolated, and ICAM-1 mRNA was found to be increased in both endothelial cells and cardiac myocytes after cytokine stimulation. Cytokines that both increased the CL18/6-inhibitable adhesion of neutrophils to myocytes and induced expression of ICAM-1 were IL-1 beta, TNF alpha, and LPS. These results are consistent with the conclusion that canine endothelial cells and cardiac myocytes express ICAM-1 in response to cytokine stimulation, and that ICAM-1 functions as an adhesive molecule for neutrophils on both cell types.


Long-Range Augmented Reality with Dynamic Occlusion Rendering.
Proper occlusion based rendering is very important to achieve realism in all indoor and outdoor Augmented Reality (AR) applications. This paper addresses the problem of fast and accurate dynamic occlusion reasoning by real objects in the scene for large scale outdoor AR applications. Conceptually, proper occlusion reasoning requires an estimate of depth for every point in augmented scene which is technically hard to achieve for outdoor scenarios, especially in the presence of moving objects. We propose a method to detect and automatically infer the depth for real objects in the scene without explicit detailed scene modeling and depth sensing (e.g. without using sensors such as 3D-LiDAR). Specifically, we employ instance segmentation of color image data to detect real dynamic objects in the scene and use either a top-down terrain elevation model or deep learning based monocular depth estimation model to infer their metric distance from the camera for proper occlusion reasoning in real time. The realized solution is implemented in a low latency real-time framework for video-see-though AR and is directly extendable to optical-see-through AR. We minimize latency in depth reasoning and occlusion rendering by doing semantic object tracking and prediction in video frames.


Site-specific grafting on titanium surfaces with hybrid temporin antibacterial peptides.
Relying on a membrane-disturbing mechanism of action and not on any intracellular target, antimicrobial peptides (AMP) are attractive compounds to be grafted on the surface of implantable materials such as silicone catheters or titanium surgical implants. AMP sequences often display numerous reactive functions (e.g. amine, carboxylic acid) on their side chains and straightforward conjugation chemistries could lead to uncontrolled covalent grafting, random orientation, and non-homogenous density. To achieve an easy and site specific covalent attachment of unprotected peptides on titanium surfaces, we designed hybrid silylated biomolecules based on the temporin-SHa amphipathic helical antimicrobial sequence. With the grafting reaction being chemoselective, we designed five analogues displaying the silane anchoring function at the N-ter, C-ter or at different positions inside the sequence to get an accurate control of the orientation. Grafting density calculations were performed by XPS and the influence of the orientation of the peptide on the surface was clearly demonstrated by the measure of antimicrobial activity. Temporin amphipathic helices are described to permeabilize the bacterial membrane by interacting in a parallel orientation with it. Our results move in the direction of this mechanism as the selective grafting of hybrid temporin 2 through a lysine placed at the center of the peptide sequence, resulted in better biofilm growth inhibition of E. coli and S. epidermis than substrates in which temporins were grafted via their C- or N-terminus.


Low Prevalence of Pfcrt Resistance Alleles among Patients with Uncomplicated Falciparum Malaria in Niger Six Years after Chloroquine Withdrawal.
Chloroquine (CQ) resistance is widespread in Africa, but few data are available for Niger. Pfcrt haplotypes (aa 56-118) and ex vivo responses to CQ and amodiaquine were characterized for 26 isolates collected in South Niger from children under 15 years of age suffering from uncomplicated falciparum malaria, six years after the introduction of artemisinin-based combinations and the withdrawal of CQ. The wild-type Pfcrt haplotype CVMNK was found in 22 of the 26 isolates, with CVIET sequences observed in only three of the samples. We also describe for the first time a new CVINT haplotype. The ex vivo responses were better for CVMNK than for CVIET parasites. Pfcrt sequence data were compared with those obtained for 26 additional parasitized blood samples collected in Gabon, from an area of CQ resistance used as a control. Our findings suggest that there has been a significant decline in CQ-resistant genotypes since the previous estimates for Niger were obtained. No such decline in molecular resistance to CQ was observed in the subset of samples collected in similar conditions from Gabon. These results have important implications for public health and support the policy implemented in Niger since 2005, which aims to increase the efficacy and availability of antimalarial drugs whilst controlling the spread of resistance.


International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading.
Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.


Extra-team connections for knowledge transfer between staff teams.
As organizations implement novel health promotion programs across multiple sites, they face great challenges related to knowledge management. Staff social networks may be a useful medium for transferring program-related knowledge in multi-site implementation efforts. To study this potential, we focused on the role of extra-team connections (ties between staff members based in different site teams) as potential channels for knowledge sharing. Data come from a cross-sectional study of after-school child-care staff implementing a health promotion program at 20 urban sites of the Young Men's Christian Association of Greater Boston. We conducted a sociometric social network analysis and attempted a census of 91 program staff members. We surveyed 80 individuals, and included 73 coordinators and general staff, who lead and support implementation, respectively, in this study. A multiple linear regression model demonstrated a positive relationship between extra-team connections (beta = 3.41, P < 0.0001) and skill receipt, a measure of knowledge transfer. We also found that intra-team connections (within-team ties between staff members) were also positively related to skill receipt. Connections between teams appear to support knowledge transfer in this network, but likely require greater active facilitation, perhaps via organizational changes. Further research on extra-team connections and knowledge transfer in low-resource, high turnover environments is needed.


Comparative genomic hybridization analysis detects frequent, often high-level, overrepresentation of DNA sequences at 3q, 5p, 7p, and 8q in human non-small cell lung carcinomas.
Comparative genomic hybridization analysis was used to identify chromosomal imbalances in 20 non-small cell lung carcinoma (NSCLC) biopsies and cell lines. The chromosome arms most often overrepresented were 3q (85%), 5p (70%), 7p (65%), and 8q (65%), which were observed at high copy numbers in many cases. Other common overrepresented sites were 1q, 2p, and 20p. DNA sequence amplification was often observed, with the most frequent site being 3q26 (six cases). Other recurrent sites of amplification included 8q24, 3q13, 3q28-qter, 7q11.2, 8p11-12, 12p12, and 19q13.1-13.2. The most frequent underrepresented segment was 3p21 (50%); other recurrent sites of autosomal loss included 8p21-pter, 15q11.2-13, 5q11.2-15, 9p, 13q12-14, 17p, and 18q21-qter. These regions of copy number decreases are also common sites of allelic loss, further implicating these sites as locations of tumor suppressor genes. Although some of the overrepresented segments harbor known or suspected oncogenes/growth-regulatory genes, we have identified 3q and 5p as new sites that are very frequently overrepresented in NSCLC. These findings could represent entry points for the identification of novel amplified DNA sequences that may contribute to the development or progression of NSCLC.


Coenzyme Q10 Attenuates High Glucose-Induced Endothelial Progenitor Cell Dysfunction through AMP-Activated Protein Kinase Pathways.
Coenzyme Q10 (CoQ10), an antiapoptosis enzyme, is stored in the mitochondria of cells. We investigated whether CoQ10 can attenuate high glucose-induced endothelial progenitor cell (EPC) apoptosis and clarified its mechanism. EPCs were incubated with normal glucose (5 mM) or high glucose (25 mM) environment for 3 days, followed by treatment with CoQ10 (10 μM) for 24 hr. Cell proliferation, nitric oxide (NO) production, and JC-1 assay were examined. The specific signal pathways of AMP-activated protein kinase (AMPK), eNOS/Akt, and heme oxygenase-1 (HO-1) were also assessed. High glucose reduced EPC functional activities, including proliferation and migration. Additionally, Akt/eNOS activity and NO production were downregulated in high glucose-stimulated EPCs. Administration of CoQ10 ameliorated high glucose-induced EPC apoptosis, including downregulation of caspase 3, upregulation of Bcl-2, and increase in mitochondrial membrane potential. Furthermore, treatment with CoQ10 reduced reactive oxygen species, enhanced eNOS/Akt activity, and increased HO-1 expression in high glucose-treated EPCs. These effects were negated by administration of AMPK inhibitor. Transplantation of CoQ10-treated EPCs under high glucose conditions into ischemic hindlimbs improved blood flow recovery. CoQ10 reduced high glucose-induced EPC apoptosis and dysfunction through upregulation of eNOS, HO-1 through the AMPK pathway. Our findings provide a potential treatment strategy targeting dysfunctional EPC in diabetic patients.


Inhibition and response to error in remitted major depression.
Depression is a common illness which tends to have a relapsing progression. Revealing vulnerability factors is an important step towards improved treatment and prevention. Previous studies of individuals in remission indicate that inhibitory control is more strongly impaired than other cognitive functions. Studies have mostly used Stroop tasks; it is unclear how this population performs on other measures of inhibition. Abnormal reactions to errors may also promote depression relapse, but this has rarely been studied in remitted depression. We used a Stop Signal task and Stroop inhibition task to investigate inhibitory function and post-error reaction time adjustments in 54 individuals with a history of depression and 185 never-depressed controls. Inhibitory processing was slower among the remitted depressed individuals on the Stop Signal task, but no difference was found in Stroop inhibition. The groups were not different on post-error adjustments. This finding extends the understanding of inhibitory deficiency in this population and offers insight into trait markers of depression.


African American Recruitment in Early Heart Failure Palliative Care Trials: Outcomes and Comparison With the ENABLE CHF-PC Randomized Trial.
Palliative care trial recruitment of African Americans (AAs) is a formidable research challenge. Examine AA clinical trial recruitment and enrollment in a palliative care randomized controlled trial (RCT) for heart failure (HF) patients and compare patient baseline characteristics to other HF palliative care RCTs. This is a descriptive analysis the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends: Comprehensive Heartcare for Patients and Caregivers) RCT using bivariate statistics to compare racial and patient characteristics and differences through recruitment stages. We then compared the baseline sample characteristics among three palliative HF trials. Of 785 patients screened, 566 eligible patients with NYHA classification III-IV were approached; 461 were enrolled and 415 randomized (AA = 226). African Americans were more likely to consent than Caucasians (55%; P FDR = .001), were younger (62.7 + 8; P FDR = .03), had a lower ejection fraction (39.1 + 15.4; PFDR = .03), were more likely to be single (P FDR = .001), and lack an advanced directive (16.4%; P FDR < .001). AAs reported higher goal setting (3.3 + 1.3; P FDR = .007), care coordination (2.8 + 1.3; P FDR = .001) and used more "denial" coping strategies (0.8 + 1; P FDR = .001). Compared to two recent HF RCTs, the ENABLE CHF-PC sample had a higher proportion of AAs and higher baseline KCCQ clinical summary scores. ENABLE CHF-PC has the highest reported recruitment rate and proportion of AAs in a palliative clinical trial to date. Community-based recruitment partnerships, recruiter training, ongoing communication with recruiters and clinician co-investigators, and recruiter racial concordance likely contributed to successful recruitment of AAs. These important insights provide guidance for design of future HF palliative RCTs. ClinicalTrials.gov Identifier: NCT02505425.


The pediatrics milestones: initial evidence for their use as learning road maps for residents.
As the next step in competency-based medical education, the Pediatrics Milestone Project seeks to provide a learner-centered approach to training and assessment. To help accomplish this goal, this study sought to determine how pediatric residents understand, interpret, and respond to the Pediatrics Milestones. Cognitive interviews with 48 pediatric residents from all training levels at 2 training programs were conducted. Each participant reviewed one Pediatrics Milestone document (PMD). Eight total Pediatrics Milestones, chosen for their range of complexity, length, competency domain, and primary author, were included in this study. Six residents, 2 from each year of residency training, reviewed each PMD. Interviews were transcribed and coded using inductive methods, and codes were grouped into themes that emerged. Four major themes emerged through coding and analysis: 1) the participants' degree of understanding of the PMDs is sufficient, often deep; 2) the etiology of participants' understanding is rooted in their experiences; 3) there are qualities of the PMD that may contribute to or detract from understanding; and 4) participants apply their understanding by noting the PMD describes a developmental progression that can provide a road map for learning. Additionally, we learned that residents are generally comfortable being placed in the middle of a series of developmental milestones. Two minor themes focusing on interest and practicality were also identified. This study provides initial evidence for the Pediatrics Milestones as learner-centered documents that can be used for orientation, education, formative feedback, and, ultimately, assessment.


Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia.
Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function.


Self-injurious behavior: a review of the behavior and biology of self-mutilation.
The authors describe the clinical characteristics of self-injurious behavior, giving special emphasis to self-injurious behavior occurring among individuals with character disorders. They review data suggesting the involvement of serotonergic, dopaminergic, and opiate neurotransmitter systems in the expression of self-injurious behavior. Self-injurious behavior occurs among mentally retarded individuals, psychotic patients, prison populations, and individuals with severe character disorders. Although theoretical psychological models of self-injurious behavior are helpful in understanding the patient's experience of self-injury, no generally useful therapeutic approach has yet evolved from these models. Data derived from animal models and treatment studies suggest the involvement of opiatergic and dopaminergic mechanisms in self-injury among the mentally retarded. Serotonergic influences on self-injurious behavior may be present in varying forms of this behavior. The scientific literature on the benefits of pharmacological agents for mentally retarded individuals is beset with a number of problems. Support is emerging, however, for the use of lithium and carbamazepine with self-injuring mentally retarded patients, and some behavioral interventions appear to be successful for mentally retarded individuals. Self-injuring patients with borderline personality disorder may benefit from milieu treatment. Although no form of treatment has yet been demonstrated to be of general benefit, the literature suggests that therapeutic trials with dopamine antagonists, serotonin reuptake inhibitors, and opiate antagonists may be of value.


Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis.
Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis. To determine whether AjA can modulate fibrogenesis in murine models of scleroderma. Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment. AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist. AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.


Prevalence and outcomes of frailty in unplanned hospital admissions: a systematic review and meta-analysis of hospital-wide and general (internal) medicine cohorts.
Guidelines recommend routine frailty screening for all hospitalised older adults to inform care decisions, based mainly on studies in elective or speciality-specific settings. However, most hospital bed days are accounted for by acute non-elective admissions, in which the prevalence and prognostic value of frailty might differ, and uptake of screening is limited. We therefore did a systematic review and meta-analysis of frailty prevalence and outcomes in unplanned hospital admissions. We searched MEDLINE, EMBASE and CINAHL up to 31/01/2023 and included observational studies using validated frailty measures in adult hospital-wide or general medicine admissions. Summary data on the prevalence of frailty and associated outcomes, measurement tools, study setting (hospital-wide vs general medicine), and design (prospective vs retrospective) were extracted and risk of bias assessed (modified Joanna Briggs Institute checklists). Unadjusted relative risks (RR; moderate/severe frailty vs no/mild) for mortality (within one year), length of stay (LOS), discharge destination and readmission were calculated and pooled, where appropriate, using random-effects models. PROSPERO CRD42021235663. Among 45 cohorts (median/SD age = 80/5 years; n = 39,041,266 admissions, n = 22 measurement tools) moderate/severe frailty ranged from 14.3% to 79.6% overall (and in the 26 cohorts with low-moderate risk of bias) with considerable heterogeneity between studies (phet < 0.001) preventing pooling of results but with rates <25% in only 3 cohorts. Moderate/severe vs no/mild frailty was associated with increased mortality (n = 19 cohorts; RR range = 1.08-3.70), more consistently among cohorts using clinically administered tools (n = 11; RR range = 1.63-3.70; phet = 0.08; pooled RR = 2.53, 95% CI = 2.15-2.97) vs cohorts using (retrospective) administrative coding data (n = 8; RR range = 1.08-3.02; phet < 0.001). Clinically administered tools also predicted increasing mortality across the full range of frailty severity in each of the six cohorts that allowed ordinal analysis (all p < 0.05). Moderate/severe vs no/mild frailty was also associated with a LOS >8 days (RR range = 2.14-3.04; n = 6) and discharge to a location other than home (RR range = 1.97-2.82; n = 4) but was inconsistently related to 30-day readmission (RR range = 0.83-1.94; n = 12). Associations remained clinically significant after adjustment for age, sex and comorbidity where reported. Frailty is common in older patients with acute, non-elective hospital admission and remains predictive of mortality, LOS and discharge home with more severe frailty associated with greater risk, justifying more widespread implementation of screening using clinically administered tools. None.


Threshold selection criteria for quantification of lumbosacral cerebrospinal fluid and root volumes from MRI.
The high variability of CSF volumes partly explains the inconsistency of anesthetic effects, but may also be due to image analysis itself. In this study, criteria for threshold selection are anatomically defined. T2 MR images (n = 7 cases) were analyzed using 3-dimentional software. Maximal-minimal thresholds were selected in standardized blocks of 50 slices of the dural sac ending caudally at the L5-S1 intervertebral space (caudal blocks) and middle L3 (rostral blocks). Maximal CSF thresholds: threshold value was increased until at least one voxel in a CSF area appeared unlabeled and decreased until that voxel was labeled again: this final threshold was selected. Minimal root thresholds: thresholds values that selected cauda equina root area but not adjacent gray voxels in the CSF-root interface were chosen. Significant differences were found between caudal and rostral thresholds. No significant differences were found between expert and nonexpert observers. Average max/min thresholds were around 1.30 but max/min CSF volumes were around 1.15. Great interindividual CSF volume variability was detected (max/min volumes 1.6-2.7). The estimation of a close range of CSF volumes which probably contains the real CSF volume value can be standardized and calculated prior to certain intrathecal procedures.


Bioaccumulation of hexachlorobutadiene in pumpkin seedlings after waterborne exposure.
Hexachlorobutadiene (HCBD) has been listed as a persistent organic pollutant (POP) in the Stockholm Convention, and is now drawing more and more research interest. However, the understanding of its bioaccumulation, especially in plants, is still very limited. In this work, the behavior of HCBD in aqueous solution and pumpkin seedlings was studied through in-lab hydroponic exposure experiments. It was found that 69% of HCBD volatilized from water to the atmosphere after one day of exposure, and only 1% remained in the solution after four days. This high volatility might be the main cause of the low HCBD levels in aqueous environments. Although a great amount of HCBD volatilized into the atmosphere, only a small proportion of airborne HCBD was captured by the leaves and stems of the blank pumpkin seedling controls. The translocation of HCBD from the leaves to the bottom roots, as well as its release from the roots into the water, was detected. For the exposure groups, the pumpkin seedlings absorbed HCBD from both the hydroponic solution and the air via the roots and leaves, respectively. The concentration of HCBD in the exposed pumpkin roots linearly increased with the continuous addition of HCBD into the exposure system. Upward translocation from the roots to the leaves and downward translocation from the leaves to the roots existed simultaneously in the exposed pumpkin seedlings. However, the concentrations of HCBD in the leaves, stems and roots in the exposure group were much higher than those of the blank plant controls, suggesting little contribution from the airborne HCBD in the hydroponically exposed pumpkin seedlings. The lipid content did not show obvious effects on the bioaccumulation and biodistribution of HCBD in the pumpkin seedlings, indicating that the translocation of HCBD within the pumpkin seedlings might be an active process. This study provided new findings on the environmental behavior of HCBD, which will be helpful for understanding the exposure risks.


Ultrasound assessment of thyroid gland volume in diabetic patients without overt thyroid disease.
Diabetes mellitus and thyroid disease are known to mutually influence each other. Thyroid disease can worsen glycaemic control in diabetes, and patients with diabetes mellitus have increased incidence of thyroid disorders such as increase in size, compared to the normal population. The aim of the study was to sonographically assess thyroid gland volume in Nigerian adult diabetic patients and compare with apparently healthy adults (controls). The study setting was the Department of Radiology, University of Benin Teaching Hospital (UBTH) Nigeria. The thyroid gland in 120 diabetic subjects and equal number of apparently healthy controls was scanned with a 5-12 MHz linear transducer of a SONOACE X4 Machine. Thyroid gland volume was assessed. Statistical analysis was done with Statistical Package for the Social Sciences (SPSS) version 17 (SPSS Inc, Chicago, IL, USA). Diabetics had significantly increased thyroid volume compared to age matched male and female control subjects (11.5 ± 5.2 cm3 vs 7.4 ± 1.9 cm3; P< 0.001 for males) and (9.9 ± 6.2 cm3 vs 7.1 ± 3.4 cm3; P< 0.001 for females) respectively. Gender did not significantly influence thyroid volume among diabetics. Diabetics have higher thyroid gland dimensions, compared to apparently healthy subjects. Gland proliferation from circulating insulin may play a role. This is not influenced by gender.


Topical miconazole nitrate ointment in the treatment of diaper dermatitis complicated by candidiasis.
Diaper dermatitis (DD) complicated by candidiasis is a common problem in diaper-wearing infants and children. We report a double-blind, vehicle-controlled, parallel-group study evaluating the efficacy and safety of a low concentration of miconazole nitrate in a zinc oxide/petrolatum ointment for the treatment of DD complicated by candidiasis. Patients (N=330) who had DD with a severity score of 3 or higher were enrolled. Those patients with a baseline potassium hydroxide (KOH) preparation and a baseline culture specimen that both tested positive for Candida were retained for efficacy analysis (n=236). Miconazole nitrate 0.25% ointment or a zinc oxide/petrolatum vehicle control were applied to all clinically affected areas of patients with DD for 7 days at each diaper change and after bathing. A follow-up test-of-cure visit was conducted at day 14. Among the patients completing the study, the overall rate of cure (clinical cure plus microbiologic cure) was 23% for the miconazole nitrate group and 10% for the vehicle control group (P=.005); the rate of clinical cure (complete rash clearance, DD severity score=0 at day 14) was 38% for the miconazole nitrate group and 11% for the vehicle control group (P<.001); and the rate of microbiologic cure (no culture growth of Candida) was 50% for the miconazole nitrate group and 23% for the vehicle control group. The vehicle control resulted in mild improvement at day 3 but little or no subsequent improvement. The discontinuation rate due to clinical failure was substantially lower for the miconazole nitrate group (4%) than the vehicle control group (47%). The mean DD severity index score for the miconazole nitrate group was significantly lower from day 3 through day 14 compared with that of the vehicle control group (P<.001). Adverse events were assessed as either unlikely to be related to study medication or unrelated to study medication. By including only those patients with microbiologically confirmed Candida infection, the study population may not be fully indicative of patients treated for DD in routine clinical practice. Our data show that miconazole nitrate 0.25% ointment was well tolerated and significantly more effective than the zinc oxide/petrolatum vehicle control for treatment of DD complicated by candidiasis.


Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination.
The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity. We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications. In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d-dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms. Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.


Integrative network analysis unveils convergent molecular pathways in Parkinson's disease and diabetes.
Shared dysregulated pathways may contribute to Parkinson's disease and type 2 diabetes, chronic diseases that afflict millions of people worldwide. Despite the evidence provided by epidemiological and gene profiling studies, the molecular and functional networks implicated in both diseases, have not been fully explored. In this study, we used an integrated network approach to investigate the extent to which Parkinson's disease and type 2 diabetes are linked at the molecular level. Using a random walk algorithm within the human functional linkage network we identified a molecular cluster of 478 neighboring genes closely associated with confirmed Parkinson's disease and type 2 diabetes genes. Biological and functional analysis identified the protein serine-threonine kinase activity, MAPK cascade, activation of the immune response, and insulin receptor and lipid signaling as convergent pathways. Integration of results from microarrays studies identified a blood signature comprising seven genes whose expression is dysregulated in Parkinson's disease and type 2 diabetes. Among this group of genes, is the amyloid precursor protein (APP), previously associated with neurodegeneration and insulin regulation. Quantification of RNA from whole blood of 192 samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Prognostic Biomarker Study (PROBE), revealed that expression of APP is significantly upregulated in Parkinson's disease patients compared to healthy controls. Assessment of biomarker performance revealed that expression of APP could distinguish Parkinson's disease from healthy individuals with a diagnostic accuracy of 80% in both cohorts of patients. These results provide the first evidence that Parkinson's disease and diabetes are strongly linked at the molecular level and that shared molecular networks provide an additional source for identifying highly sensitive biomarkers. Further, these results suggest for the first time that increased expression of APP in blood may modulate the neurodegenerative phenotype in type 2 diabetes patients.


Inhibition of Mitochondrial Fission Protein Reduced Mechanical Allodynia and Suppressed Spinal Mitochondrial Superoxide Induced by Perineural Human Immunodeficiency Virus gp120 in Rats.
Mitochondria play an important role in many cellular and physiologic functions. Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis. The most common complaint of human immunodeficiency virus (HIV)-sensory neuropathy is pain on the soles in patients with HIV, but the exact molecular mechanisms of HIV neuropathic pain are not clear. In the present study, we investigated the role of mitochondrial dynamin-related protein 1 (Drp1, a GTPase that mediates mitochondrial fission) in the perineural HIV coat glycoprotein gp120-induced neuropathic pain state. Neuropathic pain was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. Mechanical threshold was tested using von Frey filaments. The mechanical threshold response was assessed over time using the area under curves. Intrathecal administration of antisense oligodeoxynucleotide (ODN) against Drp1, mitochondrial division inhibitor-1 (mdivi-1), or phenyl-N-tert-butylnitrone (a reactive oxygen species scavenger) was given. The expression of spinal Drp1 was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. Intrathecal administration of either antisense ODN against Drp1 or mdivi-1 decreased mechanical allodynia (a sensation of pain evoked by nonpainful stimuli) in the gp120 model. Intrathecal ODN or mdivi-1 did not change basic mechanical threshold in sham surgery rats. Intrathecal Drp1 antisense ODN decreased the spinal expression of increased Drp1 protein induced by peripheral gp120 application. Intrathecal phenyl-N-tert-butylnitrone reduced mechanical allodynia. Furthermore, both intrathecal Drp1 antisense ODN and mdivi-1 reversed the upregulation of mitochondrial superoxide in the spinal dorsal horn in the gp120 neuropathic pain state. These data suggest that mitochondrial division plays a substantial role in the HIV gp120-related neuropathic pain state through mitochondrial reactive oxygen species and provides evidence for a novel approach to treating chronic pain in patients with HIV.


Handshape monitoring: Evaluation of linguistic and perceptual factors in the processing of American Sign Language.
We investigated the relevance of linguistic and perceptual factors to sign processing by comparing hearing individuals and deaf signers as they performed a handshape monitoring task, a sign-language analogue to the phoneme-monitoring paradigms used in many spoken-language studies. Each subject saw a series of brief video clips, each of which showed either an ASL sign or a phonologically possible but non-lexical "non-sign," and responded when the viewed action was formed with a particular handshape. Stimuli varied with respect to the factors of Lexicality, handshape Markedness (Battison, 1978), and Type, defined according to whether the action is performed with one or two hands and for two-handed stimuli, whether or not the action is symmetrical.Deaf signers performed faster and more accurately than hearing non-signers, and effects related to handshape Markedness and stimulus Type were observed in both groups. However, no effects or interactions related to Lexicality were seen. A further analysis restricted to the deaf group indicated that these results were not dependent upon subjects' age of acquisition of ASL. This work provides new insights into the processes by which the handshape component of sign forms is recognized in a sign language, the role of language experience, and the extent to which these processes may or may not be considered specifically linguistic.


The diagnosis and treatment of aplastic anemia: a review.
Aplastic anemia is a rare disorder characterized by suppression of bone marrow function resulting in progressive pancytopenia. A trigger-related abnormal T cell response facilitated by some genetic predisposition has been postulated as the pathogenetic mechanism leading to the overproduction of bone marrow-inhibiting cytokines. Immuno-mediated pathogenesis is confirmed by the response to immunosuppressive treatment (IST) (cyclosporin A+ATG), which represents the first-choice therapy for patients <40 years when a matched sibling donor (MSD) is not available for transplant. MSD hematopoietic stem cell transplantation (HSCT) is associated with cure in ~90 % of patients. IST up-front provides an overall survival (OS) rate of above 90 %, but a response rate of about 60 %. Front-line matched unrelated donor (MUD) appears to be a viable option in children with similar OS and event-free survival to that in MSD HSCT. MUD HSCT post-IST failure proved to be a very good rescue strategy. Haploidentical donors/cord blood transplants or alternative immunosuppressive therapies, such as alemtuzumab, may represent valid tools for resistant/relapsing cases. New promising strategies, such as eltrombopag, are now under investigation. Patients should be offered an accurate diagnostic work-up in order to rule out other underlying disorders, primarily constitutional marrow failures, which may require different approaches.


Harnessing Ion-Binding Sites for GPCR Pharmacology.
Endogenous ions play important roles in the function and pharmacology of G-protein coupled receptors (GPCRs). Historically the evidence for ionic modulation of GPCR function dates to 1973 with studies of opioid receptors, where it was demonstrated that physiologic concentrations of sodium allosterically attenuated agonist binding. This Na+-selective effect was distinct from effects of other monovalent and divalent cations, with the latter usually counteracting sodium's negative allosteric modulation of binding. Since then, numerous studies documenting the effects of mono- and divalent ions on GPCR function have been published. While ions can act selectively and nonselectively at many sites in different receptors, the discovery of the conserved sodium ion site in class A GPCR structures in 2012 revealed the unique nature of Na+ site, which has emerged as a near-universal site for allosteric modulation of class A GPCR structure and function. In this review, we synthesize and highlight recent advances in the functional, biophysical, and structural characterization of ions bound to GPCRs. Taken together, these findings provide a molecular understanding of the unique roles of Na+ and other ions as GPCR allosteric modulators. We will also discuss how this knowledge can be applied to the redesign of receptors and ligand probes for desired functional and pharmacological profiles. SIGNIFICANCE STATEMENT: The function and pharmacology of GPCRs strongly depend on the presence of mono and divalent ions in experimental assays and in living organisms. Recent insights into the molecular mechanism of this ion-dependent allosterism from structural, biophysical, biochemical, and computational studies provide quantitative understandings of the pharmacological effects of drugs in vitro and in vivo and open new avenues for the rational design of chemical probes and drug candidates with improved properties.


Solvation in protein (un)folding of melittin tetramer-monomer transition.
Protein structural integrity and flexibility are intimately tied to solvation. Here, we examine the effect that changes in bulk and local solvent properties have on protein structure and stability. We observe the change in solvation of an unfolding of the protein model, melittin, in the presence of a denaturant, trifluoroethanol. The peptide system displays a well defined transition in that the tetramer unfolds without disrupting the secondary or tertiary structure. In the absence of local structural perturbation, we are able to reveal exclusively the role of solvation dynamics in protein structure stabilization and the (un)folding pathway. A sudden retardation in solvent dynamics, which is coupled to the change in protein structure, is observed at a critical trifluoroethanol concentration. The large amplitude conformational changes are regulated by the local solvent hydrophobicity and bulk solvent viscosity.


Contact dependent reproducible hypomania induced by deep brain stimulation in Parkinson's disease: clinical, anatomical and functional imaging study.
Hypomanic symptoms depending on anatomical location of contacts are reported in patients with Parkinson's disease (PD) treated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, the underlying cortical and subcortical dysfunction is debated. In this study, five PD patients implanted with DBS-STN who presented with reversible and reproducible hypomanic symptoms after stimulation of specific 'manic' contacts were investigated. Hypomanic symptoms were assessed using the Bech and Rafaelsen Mania Scale (MAS). Three dimensional anatomical location of 'euthymic' and 'manic' contacts, after matching the postoperative CT scan with the preoperative stereotactic MRI, and a H(2)(15)O positron emission tomography (PET) study testing 'euthymic' and 'manic' contacts, were performed. Under 'euthymic' conditions, MAS score (mean±SD) was 0.6±0.5 compared with 7.8±3.1 under 'manic' conditions. Nine of 10 'manic' contacts were located in the substantia nigra, mainly in its ventral part. PET showed that hypomania was associated with strong asymmetrical cerebral activation involving preferentially the right hemisphere and was mediated by activation of the anterior cingulate and medial prefrontal cortex. The present study demonstrates the role of the subcortical structures in the genesis of hypomania in PD patients treated with DBS and stresses the involvement of the substantia nigra.


Depression and Identity: Are Self-Constructions Negative or Conflictual?
Negative self-views have proved to be a consistent marker of vulnerability for depression. However, recent research has shown that a particular kind of cognitive conflict, implicative dilemma, is highly prevalent in depression. In this study, the relevance of these conflicts is assessed as compared to the cognitive model of depression of a negative view of the self. In so doing, 161 patients with major depression and 110 controls were assessed to explore negative self-construing (self-ideal discrepancy) and conflicts (implicative dilemmas), as well as severity of symptoms. Results showed specificity for the clinical group indicating a pattern of mixed positive and negative self-descriptions with a high rate of conflict. Regression analysis lent support to the conflict hypothesis in relation to clinically relevant indicators such as symptom severity, global functioning. However, self-ideal discrepancy was a stronger predictor of group membership. The findings showed the relevance of cognitive conflicts to compliment the well-consolidated theory of negative self-views. Clinical implications for designing interventions are discussed.


The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation.
Multiple endocrine neoplasia type 1 is an autosomal dominant tumor syndrome. Manifestations include neoplasms of the parathyroid glands, enteropancreatic neuroendocrine cells, and the anterior pituitary gland. The MEN1 tumor suppressor gene encodes menin, a 610 amino acid nuclear protein without sequence homology to other proteins. To elucidate menin function, we used immunoprecipitation to identify interacting proteins. The NF-kappaB proteins p50, p52 and p65 were found to interact specifically and directly with menin in vitro and in vivo. The region of NF-kappaB proteins sufficient for binding to menin is the N-terminus. Furthermore, amino acids 305-381 of menin are essential for this binding. Menin represses p65-mediated transcriptional activation on NF-kappaB sites in a dose-dependent and specific manner. Also, PMA (phorbol 12-myristate 13-acetate)-stimulated NF-kappaB activation is suppressed by menin. These observations suggest that menin's ability to interact with NF-kappaB proteins and its modulation of NF-kappaB transactivation contribute to menin's tumor suppressor function.


Structural basis for the endoribonuclease activity of the type III-A CRISPR-associated protein Csm6.
Prokaryotic CRISPR-Cas systems provide an RNA-guided mechanism for genome defense against mobile genetic elements such as viruses and plasmids. In type III-A CRISPR-Cas systems, the RNA-guided multisubunit Csm effector complex targets both single-stranded RNAs and double-stranded DNAs. In addition to the Csm complex, efficient anti-plasmid immunity mediated by type III-A systems also requires the CRISPR-associated protein Csm6. Here we report the crystal structure of Csm6 from Thermus thermophilus and show that the protein is a ssRNA-specific endoribonuclease. The structure reveals a dimeric architecture generated by interactions involving the N-terminal CARF and C-terminal HEPN domains. HEPN domain dimerization leads to the formation of a composite ribonuclease active site. Consistently, mutations of invariant active site residues impair catalytic activity in vitro. We further show that the ribonuclease activity of Csm6 is conserved across orthologs, suggesting that it plays an important functional role in CRISPR-Cas systems. The dimer interface of the CARF domains features a conserved electropositive pocket that may function as a ligand-binding site for allosteric control of ribonuclease activity. Altogether, our work suggests that Csm6 proteins provide an auxiliary RNA-targeting interference mechanism in type III-A CRISPR-Cas systems that operates in conjunction with the RNA- and DNA-targeting endonuclease activities of the Csm effector complex.


The 'Hikikomori' syndrome: worldwide prevalence and co-occurring major psychiatric disorders: a systematic review and meta-analysis protocol.
The 'Hikikomori' syndrome (HS) consists of prolonged and severe social withdrawal. It has been studied first in Japan and recently has increasingly drawn the attention of researchers and clinicians all over the world. It is unclear whether it exists in other cultural contexts than Asia. The existing systematic reviews did not provide a quantitative synthesis on its prevalence. In addition, a summary of the co-occurring rates of psychiatric disorders is lacking. To provide a more comprehensive understanding of the clinical picture, it seems important to investigate which psychiatric disorders listed in the classification systems are most frequently associated with this psychological condition affecting young people. This paper describes a systematic review and meta-analysis protocol summarising worldwide prevalence of the HS in general population and clinical samples with psychiatric disorders. The review will also assess the co-occurrence between HS and each psychiatric disorder defined by any version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) in any clinical samples with psychiatric disorders. A systematic review will be conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies will be included if they use youth aged 12-35 years, recruited from general population or population with psychiatric disorders, if they use international criteria to diagnose HS. No restriction about design or language will be applied. The search will be conducted during the first week of November 2019 by two independent reviewers through the databases Scopus, PubMed, PsycINFO, Web of Science, by examining study references, by looking for conference proceedings/dissertations/theses, by contacting study corresponding authors. Random-effect meta-analysis will be performed by computing effect sizes as logit event rates. Study quality will be assessed through the Newcastle-Ottawa Scale. The current review does not require ethics approval. The results will be disseminated through conference presentations and publications in peer-reviewed journals. CRD 42018098747.


A possible contributor to the higher degree of girls reporting psychological symptoms compared with boys in grade nine?
It is a recurrent finding that adolescent girls report psychological symptoms in a higher degree compared with boys. The explanations for this difference vary, but the psychosocial school environment has never been a focus in these explanations. The aim of this study was to analyse whether psychosocial factors at school were associated with a high degree of psychological symptoms among boys and girls in grade nine, with a special focus on sexual harassment. The study was based on a cross-sectional study including 336 pupils (175 girls and 161 boys) in grade nine (about 15 years old), who answered an extensive questionnaire. The non-response rate was negligible (<1%). Logistic regression analysis was used to analyse whether school-related factors (teacher support, classmate support, sexual harassment), body image, and parental support were associated with a high degree of psychological symptoms. Sexual harassment at school was associated with a high degree of psychological symptoms among girls. Sexual harassment must be acknowledged as a negative psychosocial school environmental factor of importance for the high degree of psychological ill-health symptoms among girls compared with boys.


Breastfeeding and the risk of hospitalization for respiratory disease in infancy: a meta-analysis.
To examine breastfeeding and the risk of hospitalization for lower respiratory tract disease in healthy full-term infants with access to modern medical care. MEDLINE, personal communication with researchers, the OVID databases, Dissertation Abstracts Online, and BIOSIS. The titles, abstracts, and text of studies from developed countries were explored for breastfeeding exposure measures and lower respiratory tract disease hospitalization rates. For summary statistics, we required 3 inclusion criteria: (1) a feeding contrast of a minimum of 2 months of exclusive breastfeeding (no formula supplementation) vs no breastfeeding and (2) study populations that excluded sick, low birth weight or premature infants and (3) reflected affluent regions; 27% of studies met these criteria. We abstracted data from all relevant reports. Data from all primary material (33 studies) indicated a protective association between breastfeeding and the risk of respiratory disease hospitalization. Nine studies met all inclusion criteria, and 7 cohort studies were pooled. The feeding contrasts in these 7 studies were 4 or more months of exclusive breastfeeding vs no breastfeeding. The summary relative risk (95% confidence interval) was 0.28 (0.14-0.54), using a random-effects model. This effect remained stable and statistically significant after adjusting for the effects of smoking or socioeconomic status. Among generally healthy infants in developed nations, more than a tripling in severe respiratory tract illnesses resulting in hospitalizations was noted for infants who were not breastfed compared with those who were exclusively breastfed for 4 months.


Mesoscopic-microscopic spatial stochastic simulation with automatic system partitioning.
The reaction-diffusion master equation (RDME) is a model that allows for efficient on-lattice simulation of spatially resolved stochastic chemical kinetics. Compared to off-lattice hard-sphere simulations with Brownian dynamics or Green's function reaction dynamics, the RDME can be orders of magnitude faster if the lattice spacing can be chosen coarse enough. However, strongly diffusion-controlled reactions mandate a very fine mesh resolution for acceptable accuracy. It is common that reactions in the same model differ in their degree of diffusion control and therefore require different degrees of mesh resolution. This renders mesoscopic simulation inefficient for systems with multiscale properties. Mesoscopic-microscopic hybrid methods address this problem by resolving the most challenging reactions with a microscale, off-lattice simulation. However, all methods to date require manual partitioning of a system, effectively limiting their usefulness as "black-box" simulation codes. In this paper, we propose a hybrid simulation algorithm with automatic system partitioning based on indirect a priori error estimates. We demonstrate the accuracy and efficiency of the method on models of diffusion-controlled networks in 3D.


Multisensory cues capture spatial attention regardless of perceptual load.
We compared the ability of auditory, visual, and audiovisual (bimodal) exogenous cues to capture visuo-spatial attention under conditions of no load versus high perceptual load. Participants had to discriminate the elevation (up vs. down) of visual targets preceded by either unimodal or bimodal cues under conditions of high perceptual load (in which they had to monitor a rapidly presented central stream of visual letters for occasionally presented target digits) or no perceptual load (in which the central stream was replaced by a fixation point). The results of 3 experiments showed that all 3 cues captured visuo-spatial attention in the no-load condition. By contrast, only the bimodal cues captured visuo-spatial attention in the high-load condition, indicating for the first time that multisensory integration can play a key role in disengaging spatial attention from a concurrent perceptually demanding stimulus.


Bioinspired, nanoscale approaches in contemporary bioanalytics (Review).
The genesis for this topical review stems from the interdisciplinary Biointerfaces International conference 2016 (BI 2016) in Zurich, Switzerland, wherein the need for advances in analytical tools was both expressed and addressed. Pushing the limits of detection for characterizing individual components, such as single proteins, single drug-delivery vehicles, or probing single living cells in a more natural environment, will contribute to the understanding of the complex biomolecular systems central to a number of applications including medical diagnostics, tissue engineering, and drug screening and delivery. Accordingly, the authors begin with an overview of single nanoparticle analytics highlighting two emerging techniques and how they compare with existing techniques. The first is based on single particle tracking of nanoparticles tethered to a mobile supported lipid bilayer, enabling the simultaneous characterization of both size and composition of individual nanoparticles. The second technique is based on probing variations in the ionic conduction across nanoscale apertures for detection of not only nanoparticles but also membrane-tethered proteins, thereby allowing a multiparameter characterization of individual nanoscopic objects, addressing their size, shape, charge, and dipole moment. Subsequently, the authors lead into an example of an area of application that stands to benefit from such advances in bioanalytics, namely, the development of biomimetic lipid- and polymer-based assemblies as stimuli-responsive artificial organelles and nanocarriers designed to optimize delivery of next generation high-molecular-weight biological drugs. This in turn motivates the need for additional advanced techniques for investigating the cellular response to drug delivery, and so the review returns again to bioanalytics, in this case single-cell analysis, while highlighting a technique capable of probing and manipulating the content of individual living cells via fluidic force microscopy. In presenting a concerted movement in the field of bioinspired bioanalytics, positioned in the context of drug delivery, while also noting the critical role of surface modifications, it is the authors' aim to evaluate progress in the field of single component bioanalytics and to emphasize the impact of initiating and maintaining a fruitful dialogue among scientists, together with clinicians and industry, to guide future directions in this area and to steer innovation to successful translation.


A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice.
Autoimmune regulator (Aire) has a unique expression pattern in thymic medullary epithelial cells (mTECs), in which it plays a critical role in the activation of tissue-specific antigens. The expression of Aire in mTECs is activated by receptor activator of nuclear factor κB (RANK) signaling; however, the molecular mechanism behind this activation is unknown. Here, we characterize a conserved noncoding sequence 1 (CNS1) containing two NF-κB binding sites upstream of the Aire coding region. We show that CNS1-deficient mice lack thymic expression of Aire and share several features of Aire-knockout mice, including downregulation of Aire-dependent genes, impaired terminal differentiation of the mTEC population, and reduced production of thymic Treg cells. In addition, we show that CNS1 is indispensable for RANK-induced Aire expression and that CNS1 is activated by NF-κB pathway complexes containing RelA. Together, our results indicate that CNS1 is a critical link between RANK signaling, NF-κB activation, and thymic expression of Aire.


Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study.
Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function. Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID.


[Fatigue at various muscular lengths in myotonic dystrophy].
In myotonic dystrophy alteration in membrane excitability characterizes, in addition to the dystrophic process, modifications of contractile function detectable after fatigue. To verify in which extent sarcolemmal activation or contractility mechanisms are involved in fatigue, some electrophysiological and dynamometer parameters have been studied in tibialis anterior of 5 myotonic dystrophy patients. Evaluation has been performed basally and after protocol consisting of intermittent isometric voluntary contractions lasting 15', at two different muscle lengths, optimal and short. Administration at several recovery times of 20 and 50 Hz tetanizing sequences shows how processes distal to membrane excitability are mainly responsible for fatigue at optimal length, while relative potentiation of excitability preserves the muscle from excessive force loss at short length.


New evidence for Cu-decorated binary-oxides mediating bacterial inactivation/mineralization in aerobic media.
Binary oxide semiconductors TiO2-ZrO2 and Cu-decorated TiO2-ZrO2 (TiO2-ZrO2-Cu) uniform films were sputtered on polyester (PES). These films were irradiated under low intensity solar simulated light and led to bacterial inactivation in aerobic and anaerobic media as evaluated by CFU-plate counting. But bacterial mineralization was only induced by TiO2-ZrO2-Cu in aerobic media. The highly oxidative radicals generated on the films surface under light were identified by the use of appropriate scavengers. The hole generated on the TiO2-ZrO2 films is shown to be the main specie leading to bacterial inactivation. TiO2-ZrO2 and Cu-decorated TiO2-ZrO2 films release Zr and Ti <1ppb and Cu 4.6ppb/cm(2) as determined by inductively coupled plasma mass spectrometry (ICP-MS) This level is far below the citotoxicity permitted level allowed for mammalian cells suggesting that bacterial disinfection proceeds through an oligodynamic effect. By Fourier transform attenuated infrared spectroscopy (ATR-FTIR) the systematic shift of the predominating νs(CH2) vibrational-rotational peak making up most of the bacterial cell-wall content in C was monitored. Based on this evidence a mechanism suggested leading to CH bond stretching followed by cell lysis and cell death. Bacterial inactivation cycling was observed on TiO2-ZrO2-Cu showing the stability of these films leading to bacterial inactivation.


Misdelivery at the Nuclear Pore Complex-Stopping a Virus Dead in Its Tracks.
Many viruses deliver their genomes into the host cell's nucleus before they replicate. While onco-retroviruses and papillomaviruses tether their genomes to host chromatin upon mitotic breakdown of the nuclear envelope, lentiviruses, such as human immunodeficiency virus, adenoviruses, herpesviruses, parvoviruses, influenza viruses, hepatitis B virus, polyomaviruses, and baculoviruses deliver their genomes into the nucleus of post-mitotic cells. This poses the significant challenge of slipping a DNA or RNA genome past the nuclear pore complex (NPC) embedded in the nuclear envelope. Quantitative fluorescence imaging is shedding new light on this process, with recent data implicating misdelivery of viral genomes at nuclear pores as a bottleneck to virus replication. Here, we infer NPC functions for nuclear import of viral genomes from cell biology experiments and explore potential causes of misdelivery, including improper virus docking at NPCs, incomplete translocation, virus-induced stress and innate immunity reactions. We conclude by discussing consequences of viral genome misdelivery for viruses and host cells, and lay out future questions to enhance our understanding of this phenomenon. Further studies into viral genome misdelivery may reveal unexpected aspects about NPC structure and function, as well as aid in developing strategies for controlling viral infections to improve human health.


Microinjection techniques for studying mitosis in the Drosophila melanogaster syncytial embryo.
This protocol describes the use of the Drosophila melanogaster syncytial embryo for studying mitosis. Drosophila has useful genetics with a sequenced genome, and it can be easily maintained and manipulated. Many mitotic mutants exist, and transgenic flies expressing functional fluorescently (e.g. GFP) - tagged mitotic proteins have been and are being generated. Targeted gene expression is possible using the GAL4/UAS system. The Drosophila early embryo carries out multiple mitoses very rapidly (cell cycle duration, asymptotically equal to 10 min). It is well suited for imaging mitosis, because during cycles 10-13, nuclei divide rapidly and synchronously without intervening cytokinesis at the surface of the embryo in a single monolayer just underneath the cortex. These rapidly dividing nuclei probably use the same mitotic machinery as other cells, but they are optimized for speed; the checkpoint is generally believed to not be stringent, allowing the study of mitotic proteins whose absence would cause cell cycle arrest in cells with a strong checkpoint. Embryos expressing GFP labeled proteins or microinjected with fluorescently labeled proteins can be easily imaged to follow live dynamics (Fig. 1). In addition, embryos can be microinjected with function-blocking antibodies or inhibitors of specific proteins to study the effect of the loss or perturbation of their function. These reagents can diffuse throughout the embryo, reaching many spindles to produce a gradient of concentration of inhibitor, which in turn results in a gradient of defects comparable to an allelic series of mutants. Ideally, if the target protein is fluorescently labeled, the gradient of inhibition can be directly visualized. It is assumed that the strongest phenotype is comparable to the null phenotype, although it is hard to formally exclude the possibility that the antibodies may have dominant effects in rare instances, so rigorous controls and cautious interpretation must be applied. Further away from the injection site, protein function is only partially lost allowing other functions of the target protein to become evident.


Acetabular fractures: what radiologists should know and how 3D CT can aid classification.
Correct recognition, description, and classification of acetabular fractures is essential for efficient patient triage and treatment. Acetabular fractures may result from high-energy trauma or low-energy trauma in the elderly. The most widely used acetabular fracture classification system among radiologists and orthopedic surgeons is the system of Judet and Letournel, which includes five elementary (or elemental) and five associated fractures. The elementary fractures are anterior wall, posterior wall, anterior column, posterior column, and transverse. The associated fractures are all combinations or partial combinations of the elementary fractures and include transverse with posterior wall, T-shaped, associated both column, anterior column or wall with posterior hemitransverse, and posterior column with posterior wall. The most unique fracture is the associated both column fracture, which completely dissociates the acetabular articular surface from the sciatic buttress. Accurate categorization of acetabular fractures is challenging because of the complex three-dimensional (3D) anatomy of the pelvis, the rarity of certain acetabular fracture variants, and confusing nomenclature. Comparing a 3D image of the fractured acetabulum with a standard diagram containing the 10 Judet and Letournel categories of acetabular fracture and using a flowchart algorithm are effective ways of arriving at the correct fracture classification. Online supplemental material is available for this article.


Methodology of constructive technology assessment in health care.
Technologies in health care are evolving quickly, with new findings in the area of biotechnological and genetic research being published regularly. A health technology assessment (HTA) is often used to answer the question of whether the new technology should be implemented into clinical practice. International evidence confirms that the results of HTA research sometimes have limited impact on practical implementation and on coverage decisions; the study design is commonly based on the paradigm of stability of both the technology and the environment, which is often not the case. Constructive technology assessment (CTA) was first described in the 1980s. In addition to the traditional HTA elements, this approach also takes into account the technology dynamics by emphasizing sociodynamic processes. With a CTA approach, comprehensive assessment can be combined with an intentional influence in a favorable direction to improve quality. In this study, the methodological aspects mainly concerning the diagnostic use of CTA are explained. The methodology will be illustrated using the controlled introduction of a new technology, called microarray analysis, into the clinical practice of breast cancer treatment as a case study. Attention is paid to the operationalization of the phases of development and implementation and the research methods most appropriate for CTA. In addition to HTA, CTA can be used as a complementary approach, especially in technologies that are introduced in an early stage of development in a controlled way.


Low sensitivity of acoustic breathing mode frequency in Co nanocrystals upon change in nanocrystallinity.
Cobalt nanocrystals (NCs) with narrow size distribution and polycrystalline structure in their native form are synthesized in reverse micelles. After annealing at 350 °C, these NCs are transformed into single crystalline phase with hexagonal close-packed structure. The vibrational dynamics of NCs differing by their nanocrystallinity is studied by femtosecond pump-probe spectroscopy. By recording the differential reflectivity signal in the native and annealed Co NCs, the frequency of their fundamental breathing acoustic mode can be measured in the time domain. A small decrease of the breathing mode frequency is observed in single crystalline Co NCs compared to that measured in polycrystals, indicating low sensitivity of their fundamental radial mode upon change in crystallinity. This result is in agreement with predictions from calculations using the resonant ultrasound approach.


Twice-daily intramuscular ceforanide therapy of Staphylococcus aureus endocarditis in parenteral drug abusers.
Twice-daily intramuscular ceforanide therapy of Staphylococcus aureus endocarditis in parenteral drug abusers was compared in a randomized prospective trial with intravenous cephapirin therapy. Dosage regimens were ceforanide, 1 g every 12 h, and cephapirin, 2 g every 4 h. Mean minimal inhibitory and bactericidal concentrations of ceforanide for S. aureus treated with ceforanide were 0.78 and 1.56 microgram/ml compared to cephapirin for patient isolates of 0.08 and 0.14 microgram/ml, respectively. Serum killing levels with ceforanide were 1:5.7 and 1:1.5 at peak and trough levels, compared to 1:134 (peak) and 1:4.2 (trough) with cephapirin. Despite this apparent in vitro advantage of cephapirin, patients treated with ceforanide did as well as those with cephapirin. Of 16 ceforanide-treated patients, all responded initially to therapy, and 15 were cured with 28 days of therapy. One patient relapsed at the end of therapy. Of 16 cephapirin-treated patients, 1 was a clinical and microbiological failure, and 3 other relapsed at the end of therapy. In addition, one ceforanide-treated patient and two cephapirin-treated patients developed central nervous system abscesses. These were cured with drainage and continuation of antibiotic therapy. Ceforanide was well tolerated by the intramuscular route. Cost analysis suggests that therapy with intramuscular ceforanide would result in an approximate 70% decrease in drug therapy cost when compared to intravenous cephapirin. Ceforanide appears to be a safe, efficacious, convenient, and relatively inexpensive drug for treating staphylococcal endocarditis in parenteral drug abusers.


Tumor Therapeutics Work as Stress Inducers to Enhance Tumor Sensitivity to Natural Killer (NK) Cell Cytolysis by Up-regulating NKp30 Ligand B7-H6.
Immune cells are believed to participate in initiating anti-tumor effects during regular tumor therapy such as chemotherapy, radiation, hyperthermia, and cytokine injection. One of the mechanisms underlying this process is the expression of so-called stress-inducible immunostimulating ligands. Although the activating receptor NKG2D has been proven to play roles in tumor therapy through targeting its ligands, the role of NKp30, another key activating receptor, is seldom addressed. In this study, we found that the NKp30 ligand B7-H6 was widely expressed in tumor cells and closely correlated to their susceptibility to NK cell lysis. Further studies showed that treatment of tumor cells with almost all standard tumor therapeutics, including chemotherapy (cisplatin, 5-fluorouracil), radiation therapy, non-lethal heat shock, and cytokine therapy (TNF-α), could up-regulate the expression of B7-H6 in tumor cells and enhance tumor sensitivity to NK cell cytolysis. B7-H6 shRNA treatment effectively dampened sensitization of tumor cells to NK-mediated lysis. Our study not only reveals the possibility that tumor therapeutics work as stress inducers to enhance tumor sensitivity to NK cell cytolysis but also suggests that B7-H6 could be a potential target for tumor therapy in the future.


Perceptions of "caring" in nursing education by Pakistani nursing students: an exploratory study.
Caring is considered to be a highly abstract concept. Nurturing a caring attitude in nursing education is important as this is the first place for students to learn about the most significant values and essence of their profession. The aim of the study was to describe the concept of caring from the perspective of nursing students. An exploratory research design was utilised for this study. Eight senior nursing students from one government institute (College of Nursing) in X country were recruited as study participants. Data was generated through in-depth one-to-one interviews and analysed using Creswell's six-step guide for qualitative data analysis. The interviews were tape recorded and a "member check" technique was used. The study results found the themes of caring as a mothering relationship, helping attitude, limit setting, communication, and a source of empowerment and development. The implications of the findings for nursing education, faculty development, and research are described in the study.


Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways.
Cyclin G1 is a p53-responsive gene that is induced in alternative reading frame (ARF)-arrested cells, yet its role in growth control is unclear. We tested its effects on growth and involvement in the ARF-Mdm2-p53 tumor suppressor pathway. We show that cyclin G1 interacts with ARF, Mdm2, and p53 in vitro and in vivo. At high levels, cyclin G1 induces a G(1)-phase arrest in mammalian cells that coincides with p53 activation. Conversely, lower levels of cyclin G1 lack intrinsic growth inhibitory effects yet potentiate ARF-mediated growth arrest. Notably, cyclin G1 is down-regulated by Mdm2 through proteasome-mediated degradation. These data suggest that cyclin G1 is a positive feedback regulator of p53 whose expression is restrained by Mdm2. Interestingly, growth inhibition by cyclin G1 does not require p53 but instead exhibits partial retinoblastoma protein (pRb) dependence. These findings reveal that cyclin G1 has growth inhibitory activity that is mechanistically linked to ARF-p53 and pRb tumor suppressor pathways.


Stability and responsiveness in a self-organized living architecture.
Robustness and adaptability are central to the functioning of biological systems, from gene networks to animal societies. Yet the mechanisms by which living organisms achieve both stability to perturbations and sensitivity to input are poorly understood. Here, we present an integrated study of a living architecture in which army ants interconnect their bodies to span gaps. We demonstrate that these self-assembled bridges are a highly effective means of maintaining traffic flow over unpredictable terrain. The individual-level rules responsible depend only on locally-estimated traffic intensity and the number of neighbours to which ants are attached within the structure. We employ a parameterized computational model to reveal that bridges are tuned to be maximally stable in the face of regular, periodic fluctuations in traffic. However analysis of the model also suggests that interactions among ants give rise to feedback processes that result in bridges being highly responsive to sudden interruptions in traffic. Subsequent field experiments confirm this prediction and thus the dual nature of stability and flexibility in living bridges. Our study demonstrates the importance of robust and adaptive modular architecture to efficient traffic organisation and reveals general principles regarding the regulation of form in biological self-assemblies.


Socio-economic dietary inequalities in UK adults: an updated picture of key food groups and nutrients from national surveillance data.
Socio-economic differences in diet are a potential contributor to health inequalities. The present study provides an up-to-date picture of socio-economic differences in diet in the UK, focusing on the consumption of three food groups and two nutrients of public health concern: fruit and vegetables; red and processed meat; oily fish; saturated fats; non-milk extrinsic sugars (NMES). We analysed data for 1491 adults (age ≥ 19 years) from the National Diet and Nutrition Survey 2008-2011. Socio-economic indicators were household income, occupational social class and highest educational qualification. Covariate-adjusted estimates for intakes of fruit and vegetables, red and processed meat, and both nutrients were estimated using general linear models. Covariate-adjusted OR for oily fish consumption were derived with logistic regression models. We observed consistent socio-economic gradients in the consumption of the three food groups as estimated by all the three indicators. Contrasting highest and lowest levels of each socio-economic indicator, we observed significant differences in intakes for the three food groups and NMES. Depending on the socio-economic indicator, highest socio-economic groups consumed up to 128 g/d more fruit and vegetables, 26 g/d less red and processed meat, and 2·6% points less NMES (P< 0·05 for all). Relative to lowest socio-economic groups, highest socio-economic groups were 2·4 to 4·0 times more likely to eat oily fish. No significant patterns in saturated fat consumption were apparent. In conclusion, socio-economic differences were identified in the consumption of food groups and one nutrient of public health importance. Aligning dietary intakes with public health guidance may require interventions specifically designed to reduce health inequalities.


A Nanopore Sequencing-Based Assay for Rapid Detection of Gene Fusions.
Structural chromosomal rearrangements leading to gene fusions are strong driver mutations in a variety of tumors. Identification of specific gene fusions can be essential for distinguishing benign from malignant conditions and for recognizing specific subtypes of neoplasms that can have different management and prognosis. Rapid identification of gene fusions is particularly critical for patients with acute leukemia who cannot wait more than a few days before initiating treatment and for whom treatment can be dramatically different depending on the leukemia subtype. We have developed an assay for rapid detection of oncogenic gene fusions (within 24 hours) that takes advantage of the long reads and real-time data generation of the Oxford Nanopore MinION sequencing system. By using a modification of the anchored multiplex PCR method for library construction, we confidently identified BCR-ABL1 fusion transcripts, with >100 reads within 15 minutes of sequencing. By using formalin-fixed, paraffin-embedded specimens routinely tested in our clinical molecular laboratory, fusions were successfully identified within 5 hours from acquisition of Illumina-ready libraries and 30 minutes of sequencing initiation, including cases diluted to a tumor fraction of 5%. In conclusion, we have developed a nanopore-based sequencing assay that can decrease turnaround time for detection of fusion oncogenes and may be a valid approach for laboratories with low specimen volume and for cases in need of rapid results.


If we build it, will they come? Issues of engagement with digital health interventions for trauma recovery.
Exposure to traumatic events is extremely common with nearly 75% reported to have experienced one or more traumatic events worldwide. A significant number of those exposed will develop posttraumatic stress disorder (PTSD) along with depression, anxiety, and substance use disorders. Globally, trauma-related mental health disorders are the leading cause of global disability burden, and many of these disorders are caused, or worsened, by exposure to wars, natural and human-caused disasters, and other traumatic events. Significant barriers to treatment exist including logistical, geographical, financial, stigma, and other attitudinal challenges. One opportune approach to overcoming these barriers is the provision of mental health interventions via technology that can be readily standardized for wide dissemination of evidence-based care. However, engagement with technology-based interventions is a concern and limited participation and high attrition rates are common. This may be especially true for trauma survivors who often experience symptoms of avoidance and hyperarousal. Engagement is regarded as an essential component of intervention efficacy and has been demonstrated to be associated with more positive clinical outcomes, yet theoretically based research in this area is sparse. This review focuses on the complex issue of engagement with digital health interventions (DHIs). Specifically, we review the conceptualization and measurement of engagement, predictors of engagement, and importantly, the relationship of engagement with intervention effectiveness. Finally, a theoretically based model of engagement is proposed that considers the unique challenges of trauma recovery. This review is not intended to provide a systematic or exhaustive set of recommendations, rather it is intended to highlight the challenges of engagement research including its definition, measurement, and modeling. Future engagement research that includes valid and reliable measures of engagement will enable consistent exploration of engagement predictors that can then inform methods for increasing engagement and, ultimately, intervention effectiveness.


New hybrid procedures in treating occluded arteriovenous hemodialysis grafts.
The use of arteriovenous graft is indicated in patients if the subcutaneous venous bed is exhausted or unsuitable for arteriovenous fistula creation. The leading cause of failure of a prosthetic arteriovenous hemodialysis-access graft is venous anastomotic stenosis causing thrombosis of the graft. A number of surgical techniques and endovascular tools have been used to treat this stenosis and thrombosis. None have yet proven to be ideal. This study was designed to evaluate the results of hybrid treatment of arteriovenous graft thrombosis associated with venous anastomotic stenosis. Over the period 2013-2014, we treated 16 AVG occlusions. Immediately after the diagnosis of occlusion was made, the patients underwent thrombectomy using a Fogarty catheter. After thrombectomy, a diagnostic fistulogram was performed and if VAG stenosis was confirmed, it was treated with balloon angioplasty and stent graft introduction. Lesions were dilated to reduce the stenosis in the treated area to less than 25%. Primary patency after 12 months was 32.8%. Primary assisted patency was 44.7%, secondary patency was 47.6%. Restenosis of the stent graft was seen in two patients. Recurring AVG occlusion was observed in four patients. The average number of interventions to maintain AVG patency was 1.18 per patient/1 year of dialysis. Treatment of AVG thrombosis due to VAG stenosis by hybrid procedure proved to be effective and improved secondary patency.