Manganese and acute paranoid psychosis: a case report.
Manganese regulates many enzymes and is essential for normal development and body function. Chronic manganese intoxication has an insidious and progressive course and usually starts with complaints of headache, fatigue, sleep disturbances, irritability and emotional instability. Later, several organ systems may be affected and, due to neurotoxicity, an atypical parkinsonian syndrome may emerge. With regard to neuropsychiatry, an array of symptoms may develop up to 30 years after intoxication, of which gait and speech abnormalities, cognitive and motor slowing, mood changes and hallucinations are the most common. Psychotic phenomena are rarely reported. We describe the case of a 49-year-old Caucasian man working as a welder who was referred to our facility for evaluation of acute paranoid psychotic behavior. Our patient's medical history made no mention of any somatic complaints or psychiatric symptoms, and he had been involved in a professional career as a metalworker. On magnetic resonance imaging scanning of his brain, a bilateral hyperdensity of the globus pallidus, suggestive for manganese intoxication, was found. His manganese serum level was 52 to 97 nmol/L (range: 7 to 20 nmol/L). A diagnosis of organic psychotic disorder due to manganese overexposure was made. His psychotic symptoms disappeared within two weeks of treatment with low-dose risperidone. At three months later, serum manganese was decreased to slightly elevated levels and the magnetic resonance imaging T1 signal intensity was reduced. No signs of Parkinsonism were found and a definite diagnosis of manganese-induced apathy syndrome was made. Although neuropsychiatric and neurological symptoms caused by (chronic) manganese exposure have been reported frequently in the past, in the present day the disorder is rarely diagnosed. In this report we stress that manganese intoxication can still occur, in our case in a confined-space welder, and may present clinically with a paranoid psychotic state that necessitates a rapid diagnostic procedure in order to avoid the permanent structural brain damage that may occur with chronic exposure.


Abortion Access for Incarcerated People: Incidence of Abortion and Policies at U.S. Prisons and Jails.
To understand abortion incidence among incarcerated people and the relation to prison and jail pregnancy policies. We collected abortion numbers and policy data from convenience sample of 22 state prison systems, all Federal Bureau of Prisons sites, and six county jails that voluntarily reported monthly, aggregate pregnancy outcomes for 12 months in 2016-2017. Sites also completed a baseline survey of institution characteristics and pregnancy policies, including abortion. We reported facility policies and abortion incidence according to state-level abortion characteristics. Only half of state prisons in the study allowed abortion in both the first and second trimesters, and 14% did not allow abortion at all. Of the 19 state prisons permitting abortion, two thirds required the incarcerated woman to pay. Four jails of the six study jails (67%) allowed abortions in the first and second trimesters, and 25% of those required the incarcerated woman to pay for the procedure. The three prisons and two jails that did not allow abortions were in states considered hostile to abortion access. In the state and federal prisons studied, 11 of the 816 pregnancies (1.3%) that ended during the study time period were abortions. Of the 224 pregnancies that ended at study jails, 33 were abortions (15%), with more than half of those (55%) occurring in the first trimester. The abortion ratio (proportion of pregnancies ending in abortion) was 1.4% for prisons and 18% for jails. Although some incarcerated individuals have abortions, many prisons and jails have restrictive policies surrounding abortion, either through self-payment requirements or explicit prohibition. Findings from this study should prompt further inquiry into abortion incidence in these settings and address interventions to ensure incarcerated people, in accordance with legal requirements and health equity, have access to abortion.


Fringe-counting technique used to lock a suspended interferometer.
We implement a digital fringe-counting technique to measure in real time the relative mirror displacement of a suspended Michelson interferometer with modulated optical path length for oscillations much larger than the laser wavelength (λ). This provides the proper error signal for a servo mechanism that reduces the relative displacement within λ/2. The implemented technique does not require extra optics or polarizers and thus can be used for interferometric gravitational wave detectors as a starting procedure to get the system locked.


The phylogenetic roots of human lethal violence.
The psychological, sociological and evolutionary roots of conspecific violence in humans are still debated, despite attracting the attention of intellectuals for over two millennia. Here we propose a conceptual approach towards understanding these roots based on the assumption that aggression in mammals, including humans, has a significant phylogenetic component. By compiling sources of mortality from a comprehensive sample of mammals, we assessed the percentage of deaths due to conspecifics and, using phylogenetic comparative tools, predicted this value for humans. The proportion of human deaths phylogenetically predicted to be caused by interpersonal violence stood at 2%. This value was similar to the one phylogenetically inferred for the evolutionary ancestor of primates and apes, indicating that a certain level of lethal violence arises owing to our position within the phylogeny of mammals. It was also similar to the percentage seen in prehistoric bands and tribes, indicating that we were as lethally violent then as common mammalian evolutionary history would predict. However, the level of lethal violence has changed through human history and can be associated with changes in the socio-political organization of human populations. Our study provides a detailed phylogenetic and historical context against which to compare levels of lethal violence observed throughout our history.


Low-glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials.
The use of diets with low glycemic index (GI) in the management of diabetes is controversial, with contrasting recommendations around the world. We performed a meta-analysis of randomized controlled trials to determine whether low-GI diets, compared with conventional or high-GI diets, improved overall glycemic control in individuals with diabetes, as assessed by reduced HbA(1c) or fructosamine levels. Literature searches identified 14 studies, comprising 356 subjects, that met strict inclusion criteria. All were randomized crossover or parallel experimental design of 12 days' to 12 months' duration (mean 10 weeks) with modification of at least two meals per day. Only 10 studies documented differences in postprandial glycemia on the two types of diet. Low-GI diets reduced HbA(1c) by 0.43% points (CI 0.72-0.13) over and above that produced by high-GI diets. Taking both HbA(1c) and fructosamine data together and adjusting for baseline differences, glycated proteins were reduced 7.4% (8.8-6.0) more on the low-GI diet than on the high-GI diet. This result was stable and changed little if the data were unadjusted for baseline levels or excluded studies of short duration. Systematically taking out each study from the meta-analysis did not change the CIs. Choosing low-GI foods in place of conventional or high-GI foods has a small but clinically useful effect on medium-term glycemic control in patients with diabetes. The incremental benefit is similar to that offered by pharmacological agents that also target postprandial hyperglycemia.


Biological characterization of white line-inducing principle (WLIP) produced by Pseudomonas reactans NCPPB1311.
The biological activities of the lipodepsipeptides (LDP) white line-inducing principle (WLIP), produced by Pseudomonas reactans NCPPB1311, and tolaasin I, produced by R tolaasii NCPPB2192, were compared. Antimicrobial assays showed that both LDP inhibited the growth of fungi-including the cultivated mushrooms Agaricus bisporus, Lentinus edodes, and Pleurotus spp.--chromista, and gram-positive bacteria. Assays of the two LDP on blocks of Agaricus bisporus showed their capacity to alter the mushrooms' pseudo-tissues though WLIP was less active than that of tolaasin I. Contrary to previous studies, tolaasin I was found to inhibit the growth of gram-negative bacteria belonging to the genera Escherichia, Erwinia, Agrobacterium, Pseudomonas, and Xanthomonas. The only gram-negative bacterium affected by WLIP was Erwinia carotovora subsp. carotovora. Both WLIP and tolaasin I caused red blood cell lysis through a colloid-osmotic shock mediated by transmembrane pores; however, the haemolytic activity of WLIP was greater than that of tolaasin I. Transmembrane pores, at a concentration corresponding to 1.5 x C50, showed a radius between 1.5 and 1.7 +/- 0.1 nm for WLIP and 2.1 +/- 0.1 nm for tolaasin I. The antifungal activity of WLIP together with the finding that avirulent morphological variants of P. reactans lack WLIP production suggests that WLIP may play an important role in the interaction of the producing bacterium P. reactans and cultivated mushrooms.


Lithium prevents and ameliorates experimental autoimmune encephalomyelitis.
Experimental autoimmune encephalomyelitis (EAE) models, in animals, many characteristics of multiple sclerosis, for which there is no adequate therapy. We investigated whether lithium, an inhibitor of glycogen synthase kinase-3 (GSK3), can ameliorate EAE in mice. Pretreatment with lithium markedly suppressed the clinical symptoms of EAE induced in mice by myelin oligodendrocyte glycoprotein peptide (MOG35-55) immunization and greatly reduced demyelination, microglia activation, and leukocyte infiltration in the spinal cord. Lithium administered postimmunization, after disease onset, reduced disease severity and facilitated partial recovery. Conversely, in knock-in mice expressing constitutively active GSK3, EAE developed more rapidly and was more severe. In vivo lithium therapy suppressed MOG35-55-reactive effector T cell differentiation, greatly reducing in vitro MOG35-55- stimulated proliferation of mononuclear cells from draining lymph nodes and spleens, and MOG35-55-induced IFN-gamma, IL-6, and IL-17 production by splenocytes isolated from MOG35-55-immunized mice. In relapsing/remitting EAE induced with proteolipid protein peptide139-151, lithium administered after the first clinical episode maintained long-term (90 days after immunization) protection, and after lithium withdrawal the disease rapidly relapsed. These results demonstrate that lithium suppresses EAE and identify GSK3 as a new target for inhibition that may be useful for therapeutic intervention of multiple sclerosis and other autoimmune and inflammatory diseases afflicting the CNS.


The dynamic Z bands of striated muscle cells.
The distribution of proteins in the sarcomeres of skeletal and cardiac muscle gives rise to the striated pattern of these muscles. Sarcomeric protein localization is not, however, permanently fixed. There is dynamic exchange of proteins between a cytosolic pool and the sarcomere, addition of newly synthesized proteins during development and repair, and aberrant redistribution of proteins due to mutations. Recent studies have shown that two groups of proteins that localize in the sarcomere Z band can relocate, in one case to the A band, and in the other to the nucleus.


Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis.
Despite the advent of biological therapies for the treatment of rheumatoid arthritis, there is a compelling need to develop alternative therapeutic targets for nonresponders to existing treatments. Soluble receptors occur naturally in vivo, such as the splice variant of the cell surface receptor for vascular endothelial growth factor (VEGF)--a key regulator of angiogenesis in rheumatoid arthritis. Bioinformatics analyses predict that the majority of human genes undergo alternative splicing, generating proteins--many of which may have regulatory functions. The objective of the present study was to identify alternative splice variants (ASV) from cell surface receptor genes, and to determine whether the novel proteins encoded exert therapeutic activity in an in vivo model of arthritis. To identify novel splice variants, we performed RT-PCR using an mRNA pool representing major human tissue types and tumors. Novel ASV were identified by alignment of each cloned sequence to its respective genomic sequence in comparison with full-length transcripts. To test whether these ASV have biologic activity, we characterized a subset of them for ligand binding, and for efficacy in an animal model of arthritis. The in vivo study was accomplished using adenoviruses expressing secreted ASV. We cloned 60 novel human ASV from 21 genes, encoding cell surface receptors--many of which are known to be important in the regulation of angiogenesis. The ASV were characterized by exon extension, intron retention and alternative exon utilization. Efficient expression and secretion of selected ASV--corresponding to VEGF receptor type 1, VEGF receptor type 2, VEGF receptor type 3, angiopoietin receptor Tie1, Met (receptor for hepatocyte growth factor), colony-stimulating factor 1 receptor, platelet-derived growth factor receptor beta, fibroblast growth factor receptor 1, Kit, and RAGE--was demonstrated, together with binding to their cognate ligands. Importantly, ASV derived from VEGF receptor type 1 and Tie1, and to a lesser extent from VEGF receptor type 2 and fibroblast growth factor receptor 1, reduced clinical signs of arthritis in vivo. The reduction was paralleled by decreased joint inflammation and destruction. The present study shows that unique ASV derived from receptors that play key roles in angiogenesis--namely, VEGF receptor type 1 and, for the first time, Tie1--can markedly reduce arthritis severity. More broadly, our results demonstrate that ASV are a source of novel proteins with therapeutic potential in diseases in which angiogenesis and cellular hyperplasia play a central role, such as rheumatoid arthritis.


Semantic validation of the use of SNOMED CT in HL7 clinical documents.
The HL7 Clinical Document Architecture (CDA) constrains the HL7 Reference Information model (RIM) to specify the format of HL7-compliant clinical documents, dubbed CDA documents. The use of clinical terminologies such as SNOMED CT® further improves interoperability as they provide a shared understanding of concepts used in clinical documents. However, despite the use of the RIM and of shared terminologies such as SNOMED CT®, gaps remain as to how to use both the RIM and SNOMED CT® in HL7 clinical documents. The HL7 implementation guide on Using SNOMED CT in HL7 Version 3 is an effort to close this gap. It is, however, a human-readable document that is not suited for automatic processing. As such, health care professionals designing clinical documents need to ensure validity of documents manually. We represent the CDA using the Ontology Web Language OWL and further use the OWL version of SNOMED CT® to enable the translation of CDA documents to so-called OWL ontologies. We formalize a subset of the constraints in the implementation guide on Using SNOMED CT in HL7 Version 3 as OWL Integrity Constraints and show that we can automatically validate CDA documents using OWL reasoners such as Pellet. Finally, we evaluate our approach via a prototype implementation that plugs in the Open Health Workbench. We present a methodology to automatically check the validity of CDA documents which make reference to SNOMED CT® terminology. The methodology relies on semantic technologies such as OWL. As such it removes the burden from IT health care professionals of having to manually implement such guidelines in systems that use HL7 Version 3 documents.


Neurotrophic factor strategies for the treatment of Alzheimer disease.
Cholinergic neurons in the nucleus basalis of Meynert are reduced early in the course of Alzheimer disease, and the dysfunction of cholinergic neurons is believed to be primarily responsible for cognitive deficits in the disease. Nerve growth factor has a trophic effect on cholinergic neurons and therefore may have some beneficial effects on the cognitive impairment observed in patients with Alzheimer disease. Experimental studies demonstrated that a continuous infusion of nerve growth factor into the cerebroventricle prevents cholinergic neuron atrophy after axotomy or associated with normal aging and ameliorates cognition impairment in these animals. A clinical study in three patients with Alzheimer disease revealed, however, that a long-term intracerebroventricular infusion of nerve growth factor may have certain potentially beneficial effects, but the continuous intracerebroventricular route of administration is also associated with negative side effects that appear to outweigh the positive effects. Several other strategies have been suggested to provide neurotrophic support to cholinergic neurons. In this article, we review the neurotrophic factor strategies for the treatment of Alzheimer disease.


Whole genome sequencing used in an industrial context reveals a Salmonella laboratory cross-contamination.
In 2013, during a routine laboratory analysis performed on food samples, one finished product from a European factory was tested positive for Salmonella Hadar. At the same period, one environmental isolate in the same laboratory was serotyped Salmonella Hadar. Prior to this event, the laboratory performed a proficiency testing involving a sample spiked with NCTC 9877 Salmonella Hadar. The concomitance of Salmonella Hadar detection led to the suspicion of a laboratory cross-contamination between the Salmonella Hadar isolate used in the laboratory proficiency testing and the Salmonella Hadar isolate found on the finished product by the same laboratory. Since the classical phenotypic serotyping method is able to attribute a serotype to Salmonella isolates with a common antigenic formula, but cannot differentiate strains of the same serotype within the subspecies, whole genome sequencing was used to test the laboratory cross-contamination hypothesis. Additionally, 12 Salmonella Hadar from public databases, available until the time of the event, were included in the whole genome sequencing analysis to better understand the genomic diversity of this serotype in Europe. The outcome of the analysis showed a maximum of ten single nucleotide polymorphisms (SNPs) between the isolates coming from the laboratory and the finished product, and thus confirmed the laboratory cross-contamination. These results combined with all additional investigations done at the factory, allowed to release finished product batches produced and thus circumvented unnecessary food waste and economic losses for the factory.


Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer.
The levels of lysophosphatidic acid (LPA) are consistently elevated in the ascites of ovarian cancer patients, suggesting that ovarian cancer cells are exposed to an LPA replete environment. LPA stimulates cell proliferation, cell survival, resistance to cisplatin, production and activation of proteases, invasiveness and production of the neovascularizing factors, vascular endothelial growth factor, and interleukin 8. Although ovarian cancer cells can produce LPA, this may not be the major reason for altered LPA levels in ascites. We have demonstrated that the major mechanism of degradation of LPA by ovarian cancer cells is through a lipid phosphate phosphatase (LPP)-like activity. We demonstrate herein that LPP-1 mRNA is decreased in the majority of ovarian cancers. This is recapitulated in ovarian cancer cell lines, where LPP-1 RNA levels are lower than those in normal ovarian epithelium and immortalized ovarian epithelial cells. Introduction of LPP-1 into ovarian cancer cell lines results in increased LPA hydrolysis, which is associated with a marked inhibition of cell proliferation and colony-forming activity and a marked increase in apoptosis. Thus, the LPA-rich environment of the ovarian cancer cell in vivo and the subsequent effects of cellular pathophysiology may be a consequence of both increased LPA production and decreased LPA metabolism by ovarian cancer cells.


The critical role of the tumor microenvironment in shaping natural killer cell-mediated anti-tumor immunity.
Considerable evidence has been gathered over the last 10 years showing that the tumor microenvironment (TME) is not simply a passive recipient of immune cells, but an active participant in the establishment of immunosuppressive conditions. It is now well documented that hypoxia, within the TME, affects the functions of immune effectors including natural killer (NK) cells by multiple overlapping mechanisms. Indeed, each cell in the TME, irrespective of its transformation status, has the capacity to adapt to the hostile TME and produce immune modulatory signals or mediators affecting the function of immune cells either directly or through the stimulation of other cells present in the tumor site. This observation has led to intense research efforts focused mainly on tumor-derived factors. Notably, it has become increasingly clear that tumor cells secrete a number of environmental factors such as cytokines, growth factors, exosomes, and microRNAs impacting the immune cell response. Moreover, tumor cells in hostile microenvironments may activate their own intrinsic resistance mechanisms, such as autophagy, to escape the effective immune response. Such adaptive mechanisms may also include the ability of tumor cells to modify their metabolism and release several metabolites to impair the function of immune cells. In this review, we summarize the different mechanisms involved in the TME that affect the anti-tumor immune function of NK cells.


Potent Enhancement of HIV-1 Replication by Nef in the Absence of SERINC3 and SERINC5.
It has recently emerged that HIV-1 Nef counteracts the antiviral host proteins SERINC3 and SERINC5. In particular, SERINC5 inhibits the infectivity of progeny virions when incorporated. SERINC3 and SERINC5 are also counteracted by the unrelated murine leukemia virus glycosylated Gag (glycoGag) protein, which possesses a potent Nef-like activity on HIV-1 infectivity. We now report that a minimal glycoGag termed glycoMA can fully substitute for Nef in promoting HIV-1 replication in Jurkat T lymphoid cells, indicating that Nef enhances replication in these cells mainly by counteracting SERINCs. In contrast, the SERINC antagonist glycoMA was unable to substitute for Nef in MOLT-3 T lymphoid cells, in which HIV-1 replication was highly dependent on Nef, and remained so even in the absence of SERINC3 and SERINC5. As in MOLT-3 cells, glycoMA was unable to substitute for Nef in stimulating HIV-1 replication in primary human cells. Although the ability of Nef mutants to promote HIV-1 replication in MOLT-3 cells correlated with the ability to engage endocytic machinery and to downregulate CD4, Nef nevertheless rescued virus replication under conditions where CD4 downregulation did not occur. Taken together, our observations raise the possibility that Nef triggers the endocytosis of a novel antiviral factor that is active against both laboratory-adapted and primary HIV-1 strains.IMPORTANCE The Nef protein of HIV-1 and the unrelated glycoGag protein of a murine leukemia virus similarly prevent the uptake of antiviral host proteins called SERINC3 and SERINC5 into HIV-1 particles, which enhances their infectiousness. We now show that although both SERINC antagonists can in principle similarly enhance HIV-1 replication, glycoGag is unable to substitute for Nef in primary human cells and in a T cell line called MOLT-3. In MOLT-3 cells, Nef remained crucial for HIV-1 replication even in the absence of SERINC3 and SERINC5. The pronounced effect of Nef on HIV-1 spreading in MOLT-3 cells correlated with the ability of Nef to engage cellular endocytic machinery and to downregulate the HIV-1 receptor CD4 but nevertheless persisted in the absence of CD4 downregulation. Collectively, our results provide evidence for a potent novel restriction activity that affects even relatively SERINC-resistant HIV-1 isolates and is counteracted by Nef.


2-Dimensional porphyrin self-assemblies at molecular interfaces.
The heterodimer formed by electrostatic association of zinc(II) meso-tetrakis(N-methylpyridyl)porphyrin (ZnTMPyP) and zinc(II) meso-tetrakis(p-sulfonatophenyl)porphyrin (ZnTPPS) exhibits a strong affinity for the interface between water and 1,2-dichloroethane (DCE). Surface tension measurements using the quasi-elastic light scattering (QELS) technique reveal that the heterodimer adsorption can be described in terms of a Langmuir isotherm with standard Gibbs energy of adsorption of -45.5 kJ mol(-1). The orientation of the heterodimer transition dipole moment, as estimated from light polarization modulated reflectance (LPMR), shows a marked dependence on the bulk concentration of heterodimer. On the other hand, changes in the Galvani potential difference between the two phases have little effect on the heterodimer organization at the water/1,2-dichloroethane interface when the surface coverage is close to maximum. This behavior suggests that the ZnTPPS-ZnTMPyP heterodimer forms an adsorbed layer of aggregated molecules which affects the physical properties of the interface. Indeed, capacitance and surface tension measurements reveal that the dielectric properties of the water/DCE interface are significantly altered in the presence of heterodimer species.


Mortality and length-of-stay outcomes, 1993-2003, in the binational Australian and New Zealand intensive care adult patient database.
Intensive care unit (ICU) outcomes have been the subject of controversy. The objective was to model hospital mortality and ICU length-of-stay time-change of patients recorded in the Australian and New Zealand Intensive Care Society adult patient database. Retrospective, cohort study of prospectively collected data on index patient admissions. Australian and New Zealand ICUs, 1993-2003. The Australian and New Zealand Intensive Care Society adult patient database, which contains data for 223,129 patients. None. Hospital mortality and ICU length of stay were modeled using logistic and linear regression, respectively, with determination (80%) and validation (20%) data sets. Model adequacy was assessed by discrimination (receiver operating characteristic curve area, AZ) and calibration (Hosmer-Lemeshow C) for mortality and R2 for length of stay. Predictor variables included patient demographics, severity score, surgical and ventilation status, ICU categories, and geographical locality. The data set comprised 223,129 patients: Their mean (SD) age was 59.2 (18.9) yrs, 41.7% were female, their mean (SD) Acute Physiology and Chronic Health Evaluation (APACHE) III score was 53 (31), they had 16.1% overall mortality rate, and 45.7% were mechanically ventilated. ICU length of stay was 3.6 (5.6) days. A(Z), C statistic, and R2 for developmental and validation model data sets were 0.88, 17.64 (p = .02), and 0.18; and 0.88, 12.32 (p = .26), and 0.18, respectively. Variables with mortality impact (p < or = .001) were age (odds ratio [OR] 1.023), gender (OR 1.16; males vs. females), APACHE III score (OR 1.06), mechanical ventilation (OR 1.66), and surgical status (elective, OR 0.17; emergency, OR 0.47; compared with nonsurgical). ICU level and locality had significant mortality-time effects. Similar variables were found to predict length of stay. Risk-adjusted mortality declined, during 1993-2003, from 0.19 (95% confidence interval 0.17-0.21) to 0.15 (0.13-0.16) and similarly for ventilated patients: 0.26 (0.24-0.29) to 0.23 (0.21-0.25). Predicted mean ICU length of stay (days) demonstrated minimal overall time-change: 3.4 (2.2) in 1993 to 3.5 (2.7) in 2003, peaking at 3.7 (2.4) in 2000. Overall hospital mortality rate in patients admitted to Australian and New Zealand ICUs decreased 4% over 11 yrs. A similar trend occurred for mechanically ventilated patients. Length of stay changed minimally over this period.


High levels of childhood obesity observed among 3- to 7-year-old New Zealand Pacific children is a public health concern.
This cross-sectional, community-based survey was designed to assess attained growth and body composition of 3- to 7-y-old Pacific children (n = 21 boys and 20 girls) living in Dunedin, New Zealand, and to examine nondietary factors associated with the percentage of body fat. Fat mass, lean tissue mass and the percentage of body fat were measured using dual energy X-ray absorptiometry. One trained anthropometrist also measured height, weight, skinfolds (triceps, subscapular) and circumferences (mid-upper arm, chest, waist, calf). Compared with the National Center for Health Statistics and National Health and Examination Surveys I and II reference data, these Pacific children were tall and heavy for their age with high arm-muscle-area-for-height. Median (quartiles) Z-scores for height and BMI-for-age and arm-muscle-area-for-height were 1.33 (0.60, 2.15), 1.20 (0.74, 4.43) and 1.09 (0.63, 1.85), respectively. Their median (quartile) percentage of body fat was 21.8% (15.0, 35.5) of which 38.5% was located in the trunk. The estimated percentage of children classified as obese ranged from 34 to 49% depending on the criterion used. Over 60% of the children had levels of trunk fat above 1 SD of reported age- and sex-specific Z-scores for New Zealand children. The nondietary factors examined (hours of television viewing and hours playing organized sports, as reported by parents) were not associated with variations in the percentage of body fat, after adjusting for age, sex and birth weight. These extremely high levels of obesity and truncal fat among very young New Zealand children will have major public health implications as these children age.


Modal coupling analysis for integrated optical components in glass and lithium niobate.
Coupling efficiency between the fundamental modes of two different graded-index waveguides, which are fabricated in glass or lithium niobate, is calculated by numerical and variational methods. Analytical results are derived by the variational approach, which supplies a systematic method for studying the influence of modal coupling on the design of integrated optical components.


The relevance of somatosensory auras in refractory temporal lobe epilepsies.
The purpose of this study is to look at the prevalence, characteristics, and prognostic value of somatosensory auras (SSAs) in patients who have undergone temporal lobe epilepsy (TLE) surgery to treat drug-resistant focal epilepsy. We retrospectively reviewed all patients with drug-resistant epilepsy who underwent TLE surgery at Cleveland Clinic between 2005 and 2010 (n = 333) to study the prevalence, characteristics, and prognostic implications of SSA in the context of TLE surgery. Analyses were performed using two seizure outcome definitions: complete seizure freedom and Engel classification. Of the 333 patients, 26 (7.8%) had SSA. Almost half (12 patients) had unilateral sensory symptoms, whereas the rest had bilateral symptoms. Tingling and numbness were the most frequently reported sensations. Compared to their non-SSA counterparts, patients with SSA had the same clinical and imaging characteristics, but had a higher rate of breakthrough seizures (p = 0.03), although most (54%) were still able to achieve Engel class of I (p = 0.02). Based on our results we would encourage detailed presurgical testing, which may include an invasive evaluation to analyze the extent of the epileptogenic zone in patients with SSA and suspected TLE.


Extracellular vesicle integrins act as a nexus for platelet adhesion in cerebral microvessels.
Circulating extracellular vesicles (EVs) regulate signaling pathways via receptor-ligand interactions and content delivery, after attachment or internalization by endothelial cells. However, they originate from diverse cell populations and are heterogeneous in composition. To determine the effects of specific surface molecules, the use of synthetic EV mimetics permits the study of specific EV receptor-ligand interactions. Here, we used endogenous EVs derived from the circulation of rats, as well as ligand-decorated synthetic microparticles (MPs) to examine the role of integrin αvβ3 in platelet adhesion under flow in structurally intact cerebral arteries. At an intraluminal pressure of 50 mmHg and flow rate of 10 µl/min, platelets were delivered to the artery lumen and imaged with whole-field fluorescent microscopy. Under basal conditions very few platelets bound to the endothelium. However, adhesion events were markedly increased following the introduction of arginine-glycine-aspartate (RGD)-labelled synthetic MPs or endogenously-derived EVs from experimental stroke animals carrying excess RGD proteins, including vitronectin, CD40-ligand and thrombospondin-1. These data, which were generated in a dynamic and physiologically relevant system, demonstrate the importance of vesicle-carried RGD ligands in platelet adherence to the cerebrovascular endothelium and highlight the ability of synthetic EVs to isolate and identify key components of the molecular handshake between EVs and their targets.


Multiplex coherent anti-Stokes Raman spectroscopy by use of a nearly degenerate broadband optical parametric oscillator.
Optical parametric oscillators (OPO's) provide low-maintenance solid-state alternatives to dye lasers. We present results from use of a nearly degenerate broadband OPO for multiplex coherent anti-Stokes Raman spectroscopy. The system described is capable of generating spectra that cover a range of approximately 1000 cm(-1).


Inhibition of carbonic anhydrase IX (CA9) sensitizes renal cell carcinoma to ionizing radiation.
While normal kidneys are relatively sensitive to ionizing radiation (IR), renal cell carcinoma (RCC) is considered radioresistant. Carbonic anhydrase IX (CA9), an enzyme that maintains intracellular pH by carbon dioxide dissolution, is upregulated in the majority of RCC, but not in normal kidneys. Since regulation of intracellular pH may enhance radiation effects, we hypothesized that inhibition of CA9 may radiosensitize RCC. Clonogenic survival assay of human clear cell RCC 786-O and murine RCC RAG cells in the presence of a pharmacological CA9 inhibitor or with shRNA-mediated knockdown of CA9 was performed to investigate the response to IR in vitro (single dose or fractionated) and in vivo. Extracellular pH changes were measured in vitro. Treatment with AEBS [4-(2-aminoethyl)benzene sulfonamide], a sulfonamide, was used as a pharmacological inhibitor of the enzymatic activity of CA9. Nude mice bearing subcutaneous xenografts of 786-O cells stably expressing CA9 shRNA or scrambled control were irradiated (6 Gy). Tumor growth was followed longitudinally in the 786-O-bearing mice receiving AEBS (50-200 µg/ml drinking water) or control (vehicle only) which were irradiated (6 Gy) and compared with mice receiving either IR or AEBS alone. In vitro inhibition of CA9 activity or expression significantly sensitized RCC cells to the effects of IR (p<0.05), an effect even more significant when hypofractionated IR was applied. In vivo irradiated xenografts from RCC cells transfected with CA9 shRNA were significantly smaller compared to irradiated xenografts from the scrambled shRNA controls (p<0.05). RCC xenografts from mice treated with AEBS in combination with IR grew significantly slower than all controls (p<0.05). Inhibition of CA9 expression or activity resulted in radiation sensitization of RCC in a preclinical mouse model.


Wnt Ligands Secreted by Subepithelial Mesenchymal Cells Are Essential for the Survival of Intestinal Stem Cells and Gut Homeostasis.
Targeting of Wnt signaling represents a promising anti-cancer therapy. However, the consequences of systemically attenuating the Wnt pathway in an adult organism are unknown. Here, we globally prevent Wnt secretion by genetically ablating Wntless. We find that preventing Wnt signaling in the entire body causes mortality due to impaired intestinal homeostasis. This is caused by the loss of intestinal stem cells. Reconstitution of Wnt/β-catenin signaling via delivery of external Wnt ligands prolongs the survival of intestinal stem cells and reveals the essential role of extra-epithelial Wnt ligands for the renewal of the intestinal epithelium. Wnt2b is a key extra-epithelial Wnt ligand capable of promoting Wnt/β-catenin signaling and intestinal homeostasis. Wnt2b is secreted by subepithelial mesenchymal cells that co-express either Gli1 or Acta2. Subepithelial mesenchymal cells expressing high levels of Wnt2b are predominantly Gli1 positive.


Religiosity and Health: A Holistic Biopsychosocial Perspective.
The resurgence of interest in the influence of religion and spirituality on health is examined within the context of the holistic paradigm and historical connection between nursing and spirituality. While nursing and spirituality often intersect with end-of-life considerations, this article presents findings from studies that demonstrate that religious involvement favors health and longevity across the life course. Examples include protective associations with stress, depression, self-rated health, and infant birth weight. Theoretical and empirical explanations for this relationship are offered, such as social and psychological resources and healthy behaviors. The effects of religion on biological functioning, including allostatic load and telomere length, are also discussed, although this area is understudied. Considerations for the "dark-side" of religious involvement are also offered. Suggestions for nurses wishing to protect and promote the health of their patients using a holistic approach include expanding knowledge of research on religion and health and advocating for patients' spiritual needs by conducting a comprehensive spiritual assessment in primary, secondary, and tertiary clinical settings.


Personal health records: a scoping review.
Electronic personal health record systems (PHRs) support patient centered healthcare by making medical records and other relevant information accessible to patients, thus assisting patients in health self-management. We reviewed the literature on PHRs including design, functionality, implementation, applications, outcomes, and benefits. We found that, because primary care physicians play a key role in patient health, PHRs are likely to be linked to physician electronic medical record systems, so PHR adoption is dependent on growth in electronic medical record adoption. Many PHR systems are physician-oriented, and do not include patient-oriented functionalities. These must be provided to support self-management and disease prevention if improvements in health outcomes are to be expected. Differences in patient motivation to use PHRs exist, but an overall low adoption rate is to be expected, except for the disabled, chronically ill, or caregivers for the elderly. Finally, trials of PHR effectiveness and sustainability for patient self-management are needed.


Comparative study of the molecular species of chloropropanediol diesters and triacylglycerols in milk fat.
In an effort to establish the origin of the fatty acid esters of 3-chloropropanediol, which recently have been isolated in small amounts from goat milk, we compared the molecular species composition of the chlorohydrin diesters and of goat milk triacylglycerols. The chloropropanediol diesters were found to be composed of molecular species containing C10-C18 fatty acids and corresponded closely in carbon number to those calculated for the long chain sn-1,2-diacylglycerol moieties of goat milk triacylglycerols. The molecular species of goat milk total triacylglycerols contained C4-C18 fatty acids. It is suggested that triacylglycerols and chloropropanediol diesters are derived from the same pool of long chain fatty acids. A molecular distillate of bovine milk fat did not contain chloropropanediol diesters, while the available samples of human milk fat were shown to contain alkyldiacylglycerols as the major components of a neutral lipid fraction corresponding in polarity to the chloropropanediol diesters.


16p11.2 Microduplication and associated symptoms: A case study.
The minimal amount known regarding chromosomal microduplications and microdeletions presents a fascinating new direction of research into better understanding misunderstood symptoms and overall genomic influence. Specifically, the 16p11.2 microduplication has been associated with a myriad of possible cognitive, physical, and emotional symptoms. The purpose of this study is to inform the reader of the biological basis of the 16p11.2 microduplication, review sources that suggest a link between the microduplication and clinically relevant diagnoses/sources of impairment, and to better understand the implications and development of symptoms through the illustration of a case example. The case study involves an adolescent African-American female that possesses the 16p11.2 microduplication and focuses on the patient's intellectual and developmental delays, seen through self-report and analysis of her neurocognitive assessment results. Additionally, the patient's associated health complications, such as the development of seizures and a possibly compromised immune system, along with the development of anxiety and depression, are discussed. Implications toward the need for more robust protocol in testing and tracking the effects of this microduplication, such as implementing immunosorbent assay testing at the first sign of associated symptoms, are explored. Limitations are discussed.


National survey of percutaneous coronary intervention during the COVID-19 pandemic in Japan: second report of the Japanese Association of Cardiovascular Intervention and Therapeutics.
Healthcare systems worldwide have been overburdened by the coronavirus disease 2019 (COVID-19) outbreak. Accordingly, hospitals have had to implement strategies to profoundly reorganize activities, which have affected procedures such as primary percutaneous coronary interventions (PCIs). This study aimed to describe changes in PCI practices during the health emergency at the national level. The Japanese Association of Cardiovascular Intervention and Therapeutics performed provided serial surveys of institutions throughout Japan during the pandemic. The data obtained on December, 2020 and February 2021 (during the 2nd wave of pandemic) were compared with the data obtained on August 2020 (1st wave). Primary PCI for STEMI was performed as usual in 99.1%, 98.7%, and 97.5% of institutions in mid-August, mid-December, 2020 and mid-February, 2021, respectively. The COVID-19 screening tests rates in patients were significantly higher during the third wave than during the second wave (54.0% in mid-August, 2020 and 64.6% in mid-February, 2021, P = 0.002). In addition, hospitals reported that personal protective equipment was more available over time (66.4% in mid-August, 2020 and 83.8% in mid-February, 2021, P < 0.001). In conclusion, most institutions surveyed in Japan continued to perform primary PCI as usual for STEMI patients during the second and third waves of the COVID-19 pandemic. In addition, the COVID-19 screening tests were more frequently performed over time.


Microscopic aquatic predators strongly affect infection dynamics of a globally emerged pathogen.
Research on emerging infectious wildlife diseases has placed particular emphasis on host-derived barriers to infection and disease. This focus neglects important extrinsic determinants of the host/pathogen dynamic, where all barriers to infection should be considered when ascertaining the determinants of infectivity and pathogenicity of wildlife pathogens. Those pathogens with free-living stages, such as fungi causing catastrophic wildlife declines on a global scale, must confront lengthy exposure to environmental barriers before contact with an uninfected host. Hostile environmental conditions therefore have the ability to decrease the density of infectious particles, reducing the force of infection and ameliorating the impact as well as the probability of establishing an infection. Here we show that, in nature, the risk of infection and infectious burden of amphibians infected by the chytrid fungus Batrachochytrium dendrobatidis (Bd) have a significant, site-specific component, and that these correlate with the microfauna present at a site. Experimental infections show that aquatic microfauna can rapidly lower the abundance and density of infectious stages by consuming Bd zoospores, resulting in a significantly reduced probability of infection in anuran tadpoles. Our findings offer new perspectives for explaining the divergent impacts of Bd infection in amphibian assemblages and contribute to our understanding of ecosystem resilience to colonization by novel pathogens.


Therapeutic potential of gastric electrical stimulation for obesity and its possible mechanisms: a preliminary canine study.
Our aim was to investigate the effects of gastric electrical stimulation on food intake, weight, gastric myoelectrical, and parasympathetic activity. Dogs were implanted with serosal electrodes and a subcutaneous stimulator. The stimulator was turned on and off alternately every month for 4 months. Food intake, weight, gastric myoelectrical activity, and electrocardiograms were recorded. Daily food intake and weight were significantly decreased during the months with stimulation. Stimulation did not show any acute effect on gastric myoelectrical activity; however, it chronically and significantly impaired gastric myoelectrical activity in the fed state, but not in the fasting state. The parasympathetic activity in the fasting state assessed from the spectral analysis of heart rate variability was markedly decreased with stimulation both acutely and chronically. In conclusion, chronic gastric electrical stimulation results in a reduction in food intake, weight loss, a reduction in parasympathetic activity, and chronic inhibition of gastric myoelectrical activity. These data suggest that gastric electrical stimulation is a potential therapy for the treatment of obesity and its inhibitory effect on food intake and weight may involve both muscles and the vagal afferent pathway.


Otariodibacter oris and Bisgaardia genomospecies 1 isolated from infections in pinnipeds.
We document the first associations of two recently described species of Pasteurellaceae bacteria with lesions in wild pinnipeds in rehabilitation. Samples were collected from nine lesions in four California sea lions (Zalophus californianus) and two Pacific harbor seals (Phoca vitulina) during necropsy or admission examinations at a rehabilitation facility in northern California. Seven Pasteurellaceae isolates were identified using phenotypic tests and partial rpoB gene sequencing. Six strains of Otariodibacter oris were isolated from California sea lions. Otariodibacter oris was isolated in pure culture from four abscesses, an affected lymph node, and a bone lesion consistent with osteomyelitis. Otariodibacter oris was also cultured with Arcanobacterium phocae and β-hemolytic streptococci. A pure culture of Bisgaardia genomospecies 1 was obtained from an abscess in a harbor seal. This is the first time, to our knowledge, that O. oris has been associated with infection. Isolation of these bacteria in pure culture from abscesses and osteomyelitis strongly indicates a pathogenic potential of this organism. Likewise, the isolation of Bisgaardia genomospecies 1 in pure culture from an abscess in a harbor seal implies causality.


Longitudinal changes in bone mineral density in male master cyclists and nonathletes.
This study tracked changes in bone mineral density (BMD) over a 7-year period in competitive male master cyclists (n = 19) and nonathletes (n = 18). Participants completed health/exercise history and food frequency (for calcium intake) questionnaires and underwent BMD testing by dual-energy X-ray absorptiometry. At initial and 7-year assessments, there was a consistent pattern of lower BMD in cyclists compared to nonathletes at all bone sites measured. Repeated measures analysis of covariance adjusted for changes in body mass index, lean mass, calcium intake, and exercise habits indicated a significant interaction at the total body site, indicating greater BMD decline in cyclists than nonathletes (p < 0.05). Among all study participants, those who reported participating in weight training or impact exercise since the baseline assessment lost significantly less BMD at the spine and femoral neck compared to participants who reported no weight training/impact exercise since baseline (p < 0.05). A significantly greater percentage of cyclists than nonathletes met the International Society of Clinical Densitometry criteria for osteopenia or osteoporosis at baseline (84.2% vs. 50.0%) and at follow-up (89.5% vs. 61.1%, p < 0.05). Further, 6 of the 19 (31.6%) cyclists who had osteopenia at baseline became osteoporotic, compared to 1 (5.6%) of the nonathletes. The high percentage of male master cyclists with low BMD, combined with a high risk for fracture from falls associated with competitive cycling, warrant attention among this population. Coaches and health professionals interacting with cyclists need to promote alternative exercise such as weight training, plyometrics, or other high impact activity as a complement to cycle training to help minimize bone loss in this population.


Lists2Networks: integrated analysis of gene/protein lists.
Systems biologists are faced with the difficulty of analyzing results from large-scale studies that profile the activity of many genes, RNAs and proteins, applied in different experiments, under different conditions, and reported in different publications. To address this challenge it is desirable to compare the results from different related studies such as mRNA expression microarrays, genome-wide ChIP-X, RNAi screens, proteomics and phosphoproteomics experiments in a coherent global framework. In addition, linking high-content multilayered experimental results with prior biological knowledge can be useful for identifying functional themes and form novel hypotheses. We present Lists2Networks, a web-based system that allows users to upload lists of mammalian genes/proteins onto a server-based program for integrated analysis. The system includes web-based tools to manipulate lists with different set operations, to expand lists using existing mammalian networks of protein-protein interactions, co-expression correlation, or background knowledge co-annotation correlation, as well as to apply gene-list enrichment analyses against many gene-list libraries of prior biological knowledge such as pathways, gene ontology terms, kinase-substrate, microRNA-mRAN, and protein-protein interactions, metabolites, and protein domains. Such analyses can be applied to several lists at once against many prior knowledge libraries of gene-lists associated with specific annotations. The system also contains features that allow users to export networks and share lists with other users of the system. Lists2Networks is a user friendly web-based software system expected to significantly ease the computational analysis process for experimental systems biologists employing high-throughput experiments at multiple layers of regulation. The system is freely available at http://www.lists2networks.org.


Pharmacokinetics of Tranexamic Acid via Intravenous, Intraosseous, and Intramuscular Routes in a Porcine (Sus scrofa) Hemorrhagic Shock Model.
Intravenous (IV) tranexamic acid (TXA) is an adjunct for resuscitation in hemorrhagic shock; however, IV access in these patients may be difficult or impossible. Intraosseous (IO) or intramuscular (IM) administration could be quickly performed with minimal training. We investigated the pharmacokinetics of TXA via IV, IO, and IM routes in a swine model of controlled hemorrhagic shock. Fifteen swine were anesthetized and bled of 35% of their blood volume before randomization to a single 1g/10mL dose of IV, IO, or IM TXA. Serial serum samples were obtained after TXA administration. These were analyzed with high-pressure liquid chromatography-mass spectrometry to determine drug concentration at each time point and define the pharmacokinetics of each route. There were no significant differences in baseline hemodynamics or blood loss between the groups. Peak concentration (Cmax) was significantly higher in IV and IO routes compared with IM (p = .005); however, the half-life of TXA was similar across all routes (p = .275). TXA administration via IO and IM routes during hemorrhagic shock achieves serum concentrations necessary for inhibition of fibrinolysis and may be practical alternatives when IV access is not available.


Injury prevention among friends: the benefits of school connectedness.
Unsafe road behaviors, violence and alcohol use, are primary contributors to adolescent injury. Research suggests that adolescents look out for their friends and engage in protective behavior to reduce others' risk-taking and that school connectedness is associated with reduced injury-risks. This study examined the role of school connectedness in willingness to protect and prevent friends from involvement in alcohol use, fights and unlicensed driving. Surveys were completed at two time points, six months apart, by 545 13-14 year olds from seven Australian high schools. Females were significantly more likely than males to report willingness to protect their friends. School connectedness significantly and positively predicted willingness to protect across all three injury-risk behaviors, after accounting for sex and own involvement in injury-risk behaviors. School connectedness may therefore be an important factor to target in school-based prevention programs, both to reduce adolescents' own injury-risk behavior and to increase injury prevention among friends.


No evidence for recombination between HIV type 1 and HIV type 2 within the envelope region in dually seropositive individuals from Senegal.
To investigate the frequency of recombination between HIV-1 and HIV-2 in vivo during dual infection, we performed a retrospective analysis of blood samples from 46 dual HIV-1/HIV-2-seropositive adults for evidence of recombination. HIV viral DNA from peripheral blood mononuclear cells (PBMC) was subjected to two separate nested polymerase chain reaction (PCR) assays using opposing HIV-1 and HIV-2 primer pairs selected to flank a approximately 650-base pair region including the V3 loop of the envelope gene. In the first assay, primers were chosen to amplify recombinants with HIV-1 on the 5' end and HIV-2 on the 3' end, and in the second assay, primers were chosen to amplify recombinants with the opposite orientation. All PCR experiments were run in parallel with positive controls consisting of partial-length env fragments bearing a single central HIV-1/2 recombination site, and appropriate primer-binding sites on each end. The limit of detection for both assays was <10 copies of recombinant product per 150,000 cell equivalents of input PBMC DNA. In all 46 dually seropositive patients in this study, PCR screening of PBMC failed to detect evidence of HIV-1/HIV-2 recombinants in the C2-V5 env region. Although genetic recombination between HIV-1 and HIV-2 may occur, we conclude that any such events within env are exceedingly rare, and do not result in the outgrowth of recombinant strains.


CYP3A5*3 genotype associated with intrasubject pharmacokinetic variation toward tacrolimus in bioequivalence study.
Tacrolimus is metabolized by CYP3A and has highly variable pharmacokinetics. To study the factors contributing to this high variability in pharmacokinetics and to investigate the possibility of genotype-specific clinical applications, the effect of differing CYP3A5 genotypes on the intrasubject coefficients of variation for tacrolimus was investigated. Genotyping for CYP3A5*3 was performed in healthy volunteers who had previously participated in the pharmacokinetic study of 2 tacrolimus formulations with a 2 x 2 cross-over design. Intrasubject coefficients of variation calculated from analysis of variation in CYP3A5*1/*1+*1/*3 (n = 16) and CYP3A5*3/*3 (n = 13) groups were compared. The intrasubject CVs of AUClast and Cmax in the CYP3A5*3/*3 group were about 41.1% and 52.4% greater than those in the CYP3A5*1*1+*1/*3 group. The estimated total sample size for the bioequivalence study of tacrolimus with a 2 x 2 cross-over design was increased by 93.3% for AUClast (n = 30 versus 58) and 121.4% for Cmax (n = 28 versus 62) in the CYP3A5*3/*3 group compared with the CYP3A5*1/*1+*1/*3 group. The intraindividual variability of tacrolimus PK parameters may be associated with the CYP3A5 genotype. We propose that genotyping for CYP3A5 will provide a more efficient approach for bioequivalence designs and therapeutic drug monitoring.


Risk assessment based prioritization of 200 organic micropollutants in 4 Iberian rivers.
The use of chemicals is continuously growing both in total amount as well as in a number of different substances, among which organic chemicals play a major role. Owing to the growing public awareness on the need of protecting both ecosystems and human health from the risks related to chemical pollution, an increasing attention has been drowned to risk assessment and prioritization of organic pollutants. In this context, the aims of this study were (a) to perform an environmental risk assessment for 200 organic micropollutants including both regulated and emerging contaminants (pesticides, alkylphenols, pharmaceuticals, hormones, personal care products, perflourinated compounds and various industrial organic chemicals) monitored in four rivers located in the Mediterranean side of the Iberian Peninsula, namely, the Ebro, Llobregat, Júcar and Guadalquivir rivers; and (b) to prioritize them for each of the four river basins studied, taking into account their observed concentration levels together with their ecotoxicological potential. For this purpose, a prioritization approach has been developed and a resulting ranking index (RI) associated with each compound. Ranking index is based on the measured concentrations of the chemical in each river and its ecotoxicological potential (EC50 values for algae, Daphnia sp. and fish). Ten compounds were identified as most important for the studied rivers: pesticides chlorpyriphos, chlorfenvinphos, diazinon, dichlofenthion, prochloraz, ethion carbofuran and diuron and the industrial organic chemicals nonylphenol and octylphenol that result from the biodegration of polyethoxylated alkyphenol surfactants. Also, further research into chronic toxicity of emerging contaminants is advocated.


Nutrition support for bone marrow transplant patients.
This is an update of the original Cochrane review published in Issue 2, 2002. Bone marrow transplantation involves administration of toxic chemotherapy and infusion of marrow cells. After treatment, patients can develop poor appetite, mucositis and gastrointestinal failure, leading to malnutrition. To prevent this, parenteral nutrition (PN) support is often first choice but is associated with increased risk of infection. Enteral nutrition (EN) is an alternative, as is addition of substrates. To determine efficacy of EN or PN support for patients receiving bone marrow transplant. Search of The Cochrane Library, MEDLINE, EMBASE and CINAHL in November 2000 and subsequently June 2006. RCTs that compared one form of nutrition support with another, or control, for bone marrow transplant patients. Twenty nine studies were identified. Data were collected on participants' characteristics; adverse effects; neutropaenia; % change in body weight; graft versus host disease; and survival. In two studies (82 participants) glutamine mouthwash reduced number of days patients were neutropenic (6.82 days, 95%CI (1.67 to 11.98) P = 0.009) compared with placebo. Three studies reported (103 participants) that patients receiving PN with glutamine had reduced hospital stay, 6.62 d (95%CI 3.47 to 9.77, P = 0.00004) compared with patients receiving standard PN. However, in the update a further study was added (147 participants) which altered the pooled results: duration in hospital may be increased for those who receive PN with additional glutamine - 0.22 days (95%CI (1.29 to 1.72). Two other studies reported that (73 participants) patients receiving PN plus glutamine had reduced incidence of positive blood cultures (OR 0.23, 95%CI 0.08 to 0.65, P = 0.006) compared to those receiving standard PN. However, a study from the update (113 participants in total) showed the odds of having a positive blood culture have increased but are still less likely if the patient receives PN with glutamine compared to standard PN (OR 0.46, 95%CI 0.20 to 1.04). When patients were given PN versus IV hydration, (25 participants) patients receiving PN had a higher incidence of line infections (OR 21.23, 95%CI 4.15 to 108.73, P = 0.0002) compared to those receiving standard IV fluids. The update identified one study which recognised that (55 participants) those who received IV were likely to spend less time in hospital, 3.30 days (95%CI -0.38 to 6.98, P = 0.08), although this result was not significant. As reported in the original review there remains no evaluable data to properly compare PN with EN. In this update an additional study that compared PN and Glutamine versus standard PN showed that the certain benefits of parenteral nutrition with added glutamine compared to standard PN for reducing hospital stay are no longer definite. When PN with glutamine is compared with standard PN, patients may not leave hospital earlier, but do have reduced incidence of positive blood cultures, than those receiving standard PN. Where possible use of intravenous fluids and oral diet should be considered as a preference to parenteral nutrition, however, in the event of a patient suffering severe gastrointestinal failure even with a trial of enteral feeding, PN with the addition of glutamine could be considered.


Structure and function of Zucchini endoribonuclease in piRNA biogenesis.
PIWI-interacting RNAs (piRNAs) silence transposons to maintain genome integrity in animal germ lines. piRNAs are classified as primary and secondary piRNAs, depending on their biogenesis machinery. Primary piRNAs are processed from long non-coding RNA precursors transcribed from piRNA clusters in the genome through the primary processing pathway. Although the existence of a ribonuclease participating in this pathway has been predicted, its molecular identity remained unknown. Here we show that Zucchini (Zuc), a mitochondrial phospholipase D (PLD) superfamily member, is an endoribonuclease essential for primary piRNA biogenesis. We solved the crystal structure of Drosophila melanogaster Zuc (DmZuc) at 1.75 Å resolution. The structure revealed that DmZuc has a positively charged, narrow catalytic groove at the dimer interface, which could accommodate a single-stranded, but not a double-stranded, RNA. DmZuc and the mouse homologue MmZuc (also known as Pld6 and MitoPLD) showed endoribonuclease activity for single-stranded RNAs in vitro. The RNA cleavage products bear a 5'-monophosphate group, a hallmark of mature piRNAs. Mutational analyses revealed that the conserved active-site residues of DmZuc are critical for the ribonuclease activity in vitro, and for piRNA maturation and transposon silencing in vivo. We propose a model for piRNA biogenesis in animal germ lines, in which the Zuc endoribonuclease has a key role in primary piRNA maturation.


Open-Source 3-D Platform for Low-Cost Scientific Instrument Ecosystem.
The combination of open-source software and hardware provides technically feasible methods to create low-cost, highly customized scientific research equipment. Open-source 3-D printers have proven useful for fabricating scientific tools. Here the capabilities of an open-source 3-D printer are expanded to become a highly flexible scientific platform. An automated low-cost 3-D motion control platform is presented that has the capacity to perform scientific applications, including (1) 3-D printing of scientific hardware; (2) laboratory auto-stirring, measuring, and probing; (3) automated fluid handling; and (4) shaking and mixing. The open-source 3-D platform not only facilities routine research while radically reducing the cost, but also inspires the creation of a diverse array of custom instruments that can be shared and replicated digitally throughout the world to drive down the cost of research and education further.


Neuroimaging evidence implicating cerebellum in support of sensory/cognitive processes associated with thirst.
Recent studies implicate the cerebellum, long considered strictly a motor control structure, in cognitive, sensory, and affective phenomenon. The cerebellum, a phylogenetically ancient structure, has reciprocal ancient connections to the hypothalamus, a structure important in vegetative functions. The present study investigated whether the cerebellum was involved in vegetative functions and the primal emotions engendered by them. Using positron emission tomography, we examined the effects on the cerebellum of the rise of plasma sodium concentration and the emergence of thirst in 10 healthy adults. The correlation of regional cerebral blood flow with subjects' ratings of thirst showed major activation in the vermal central lobule. During the development of thirst, the anterior and posterior quadrangular lobule, lingula, and the vermis were activated. At maximum thirst and then during irrigation of the mouth with water to alleviate dryness, the cerebellum was less activated. However, 3 min after drinking to satiation, the anterior quadrangular lobule and posterior cerebellum were highly activated. The increased cerebellar activity was not related to motor behavior as this did not occur. Instead, responses in ancient cerebellar regions (vermis, fastigal nucleus, archicerebellum) may be more directly related to vegetative and affective aspects of thirst experiences, whereas activity in neocerebellar (posterior) regions may be related to sensory and cognitive aspects. Moreover, the cerebellum is apparently not involved in the computation of thirst per se but rather is activated during changes in thirst/satiation state when the brain is "vigilant" and is monitoring its sensory systems. Some neocerebellar activity may also reflect an intentionality for gratification by drinking inherent in the consciousness of thirst.


Factorial Structure and Validity of Depression (PHQ-9) and Anxiety (GAD-7) Scales after Traumatic Brain Injury.
The dimensionality of depression and anxiety instruments have recently been a source of controversy. In a European-wide sample of patients after Traumatic Brain Injury (TBI), we aim to examine the factorial structure, validity, and association of the Patient Health Questionnaire for depression (PHQ-9) and the Generalized Anxiety Disorder (GAD-7) instruments. This study is based on longitudinal observational data. We conducted analyses of factorial structure and discriminant validity of outcomes six-months after TBI. We also examined the prevalence, co-occurrence, and changes of scores on the PHQ-9 and GAD-7 at 3-, 6-, and 12-month post-TBI assessments. At six-months post-TBI assessment, 2137 (738 (34.5%) women) participants completed the PHQ-9 and GAD-7 questionnaires. For the longitudinal analysis, we had 1922 participants (672 (35.0%) women). The results of exploratory factor analysis suggested a general latent construct underlying both PHQ-9 and GAD-7 measures. Confirmatory factor analyses showed a slight improvement in the fit indices for the bifactorial model. The Omega hierarchical test clearly differentiated two subfactors of PHQ-9 and GAD-7 items over and above the underlying general factor; however, most of the variance (85.0%) was explained by the general factor and the explained variance of the subfactors was small. The PHQ-9 and GAD-7 performed similarly in detecting post-traumatic stress disorder (PTSD). As defined by conventional cut-offs, depression and anxiety have different prevalence rates in the sample. The scales also differed in their relationships with the short form of health survey (SF-36v2) subscales. The longitudinal analysis showed high stability of depression and anxiety symptoms: 49-67% of the post-TBI patients with comorbid depression and anxiety reported the persistence of the symptoms over time. The factorial structure analysis favors a general latent construct underlying both depression and anxiety scales among patients after TBI. We discuss the implications our findings and future research directions.


Peripubertal decline in ovarian LHRH receptor content: characterization and distribution.
In the rat, ovarian LHRH receptor content, as measured by the binding of 125I-D-Ala6, Pro9-LHRH (A-LHRH) to ovarian membranes, decreases markedly during the days preceding the first preovulatory gonadotropin surge. The present study shows that the decrease in LHRH receptor number occurs exclusively in granulosa cells, and that the greatest rate of decline takes place between the juvenile period and the early proestrous phase of puberty. In contrast to granulosa cells, membranes prepared from ovarian tissues after removal of these cells demonstrated no significant change in LHRH binding capacity throughout puberty. Scatchard analysis of competition curves, constructed using membranes from whole ovaries, revealed that receptor affinity remains unchanged (Ka = 9 X 10(9) M-1) as the receptor number decreases. Kinetic binding studies demonstrated that LHRH binding to its receptor reaches equilibrium within 40 min and can be displaced by addition of unlabeled hormone. A kinetic estimate of receptor affinity provided values similar to those obtained by Scatchard analysis. Treatment of ovarian membranes with MgCl2 to uncover occupied binding sites results in more than 70% dissociation of bound labeled ligand. Dissociation of endogenous LHRH using this procedure resulted in some increase in available binding sites only in juvenile rats, but not in first proestrous or first estrous animals in which receptor content was low. The results demonstrate that the decline in ovarian LHRH receptors observed during peripubertal days is confined to granulosa cells, is not due to changes in receptor affinity, and represents a true loss of binding sites.


Retinal microglia: just bystander or target for therapy?
Resident microglial cells can be regarded as the immunological watchdogs of the brain and the retina. They are active sensors of their neuronal microenvironment and rapidly respond to various insults with a morphological and functional transformation into reactive phagocytes. There is strong evidence from animal models and in situ analyses of human tissue that microglial reactivity is a common hallmark of various retinal degenerative and inflammatory diseases. These include rare hereditary retinopathies such as retinitis pigmentosa and X-linked juvenile retinoschisis but also comprise more common multifactorial retinal diseases such as age-related macular degeneration, diabetic retinopathy, glaucoma, and uveitis as well as neurological disorders with ocular manifestation. In this review, we describe how microglial function is kept in balance under normal conditions by cross-talk with other retinal cells and summarize how microglia respond to different forms of retinal injury. In addition, we present the concept that microglia play a key role in local regulation of complement in the retina and specify aspects of microglial aging relevant for chronic inflammatory processes in the retina. We conclude that this resident immune cell of the retina cannot be simply regarded as bystander of disease but may instead be a potential therapeutic target to be modulated in the treatment of degenerative and inflammatory diseases of the retina.


Nonsynaptic communication through ATP release from volume-activated anion channels in axons.
The release of neuronal messengers outside synapses has broad biological implications, particularly with regard to communication between axons and glia. We identify a mechanism for nonsynaptic, nonvesicular release of adenosine triphosphate (ATP) from axons through volume-activated anion channels (VAACs) activated by microscopic axon swelling during action potential firing. We used a combination of single-photon imaging of ATP release, together with imaging for intrinsic optical signals, intracellular calcium ions (Ca(2+)), time-lapse video, and confocal microscopy, to investigate action potential-induced nonsynaptic release of this neurotransmitter. ATP release from cultured embryonic dorsal root ganglion axons persisted when bafilomycin or botulinum toxin was used to block vesicular release, whereas pharmacological inhibition of VAACs or prevention of action potential-induced axon swelling inhibited ATP release and disrupted activity-dependent signaling between axons and astrocytes. This nonvesicular, nonsynaptic communication could mediate various activity-dependent interactions between axons and nervous system cells in normal conditions, development, and disease.


What is the monetary value of a human life?
The resources available to the health service are limited and so the amount the NHS can spend on saving human life is also limited. Rational allocation of resources requires a decision theory model, which in turn demands some monetary valuation of human life. Each of three approaches discussed--basing value on productive capacity, the NHS's implied values, or individuals' values--rests on an underlying set of non-monetary values. Choice of the underlying value will determine the method to be used in placing a monetary value on life. As the Health Service implicitly places certain values on life already, a means of making this valuation more rational and explicity can only improve the quality and quantity of health care.


Substantial conformational change mediated by charge-triad residues of the death effector domain in protein-protein interactions.
Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic death effector domains (DEDs) mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC) data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) protein in the complex with a mitogen-activated protein (MAP) kinase, extracellular regulated kinase 2 (ERK2), which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.


1996 J.B. Wolffe Memorial Lecture. Challenging beliefs: ex Africa semper aliquid novi.
The basis of the scientific method is the development of intellectual models, the predictions of which are then subjected to scientific evaluation. The more robust test of any such model is one that aims to refute or falsify its predictions. Successful refutation forces revision of the model: the revised model persists as the "truth" until its predictions are, in turn, refuted. Thus, any scientific model should persist only as long as it resists refutation. An unusual feature of the exercise sciences is that certain core beliefs are based on an historical physiological model that, it will be argued, has somehow escaped modern, disinterested intellectual scrutiny. This particular model holds that the cardiovascular system has a limited capacity to supply oxygen to the active muscles, especially during maximal exercise. As a result, skeletal muscle oxygen demand outstrips supply causing the development of skeletal muscle hypoxia or even anaerobiosis during vigorous exercise. This hypoxia stimulates the onset of lactate production at the "anaerobic," "lactate," or ventilation thresholds and initiates biochemical processes that terminate maximal exercise. The model further predicts that the important effect of training is to increase oxygen delivery to and oxygen utilization by the active muscles during exercise. Thus, adaptations that reduce skeletal muscle anaerobiosis during exercise explain all the physiological, biochemical, and functional changes that develop with training. The historical basis for this model is the original research of Nobel Laureate A. V. Hill which was interpreted as evidence that oxygen consumption "plateaus" during progressive exercise to exhaustion, indicating the development of skeletal muscle anaerobiosis. This review confirms that Hill's research failed to establish the existence of the "plateau phenomenon" during exercise and argues that this core component of the historical model remains unproven. Furthermore, definitive evidence that skeletal muscle anaerobiosis develops during submaximal exercise at the anaerobic threshold initiating lactate production by muscle and its accumulation in blood is not currently available. The finding that exercise performance can improve and metabolism alter before there are measurable skeletal muscle mitochondrial adaptations could indicate that variables unrelated to oxygen use by muscle might explain some, if not all, training-induced changes. To accommodate these uncertainties, an alternate physiological model is proposed in which skeletal muscle contractile activity is regulated by a series of central, predominantly neural, and peripheral, predominantly chemical, regulators that act to prevent the development of organ damage or even death during exercise in both health and disease and under demanding environmental conditions. During maximal exercise, the peripheral regulation of skeletal muscle function and hence of oxygen use by skeletal muscle, perhaps by variables related to blood flow, would prevent the development of muscle rigor, especially in persons with an impaired capacity to produce ATP by mitochondrial or glycolytic pathways. Regulation of skeletal muscle contractile function by central mechanisms would prevent the development of hypotension and myocardial ischemia during exercise in persons with heart failure, of hyperthermia during exercise in the heat, and of cerebral hypoxia during exercise at extreme altitude. The challenge for future generations of exercise physiologists is to identify how the body anticipates the possibility of organ damage and evokes the appropriate control mechanism(s) at the appropriate instant.


Limited genetic control of specific IgE responses to rye grass pollen allergens in Australian twins.
Both genetic and environmental factors are thought to contribute to specific IgE responses, however, the relative contribution of each in the responses to individual ryegrass pollen allergens is largely unknown even though some responses to allergens have been linked to certain HLA complexes. Using a large group of monozygotic and dizygotic twins, this study was designed to investigate the IgE binding profiles of individual ryegrass pollen (Lolium perenne) components to assess the relative contribution of genetic and environmental factors in determining IgE responses to specific allergens. Ryegrass pollen proteins were separated by electrophoresis and immunoblotted with sera from 191 pairs of twins where at least one sibling had a SPT > 2 mm to perennial ryegrass. Concordance levels for individual ryegrass pollen components were compared between monozygotic and dizygotic twins in a subset group where both twins had SPT > 3 mm to perennial ryegrass. Immunoblotting revealed 23 individual IgE-binding components from ryegrass pollen. Although there was a significantly greater proportion of monozygotic twins with SPT wheals greater than 3 mm when compared with the dizygotic twins, the mean case-wise concordance for the immunoblot components was similar for both groups of twins. The mean case-wise concordance when at least four pairs of sera were involved was 44% for the MZ twins (n=11 components) and 45% for the DZ twins (n=12 components). We found no significant differences in concordance levels for any of the 23 individual components including allergens previously associated with HLA. Evidence for genetic control of allergen-specific IgE responses in a large population sample of twins to individual ryegrass allergens is limited, indicating that the IgE responses to specific ryegrass pollen allergens are determined largely by environmental factors.


Orientation-Preserving Rod Elements for Real-Time Thin-Shell Simulation.
We propose a new computation model for simulating elastic thin shells at interactive rates. Existing graphical simulation methods are mostly based on dihedral angle energy functions, which need to compute the first order and second order partial derivatives with respect to current vertex positions as bending forces and stiffness matrices. The symbolic derivatives are complicated in nonisometric element deformations. To simplify computing the derivatives, instead of directly constructing the dihedral angle energy, we use the orientation change energy of mesh edges. A continuum-mechanics-based orientation-preserving rod element model is developed to provide the bending forces. The advantage of our method is simple bending force and stiffness matrix computation, since in the rod model, we apply a novel incremental construction of the deformation gradient tensor to linearize both tensile and orientation deformations. Consequently, our model is efficient, easy to implement, and supports both quadrilateral and triangle meshes. It also treats shells and plates uniformly.


Optimal but robust N and P removal in Sbrs: a model-based systematic study of operation scenarios.
A systematic approach to determine the optimal operation strategy for nitrogen (N) and phosphorus (P) removal of sequencing batch reactors (SBRs) has been developed and applied successfully to a lab-scale SBR. The methodology developed is based on using a grid of possible scenarios to simulate the effect of the key degrees of freedom in the SBR system. The grid of scenarios is simulated using a calibrated ASM2dN model developed and calibrated in a previous study. Effluent quality in combination with a robustness index for each of the scenarios is used to select the best scenario. With the best scenario, it is possible to improve/increase the current performance of the SBR system by around 54% and 74% for N and P removal respectively.


Bipartite Network Analysis of the Archaeal Virosphere: Evolutionary Connections between Viruses and Capsidless Mobile Elements.
Archaea and particularly hyperthermophilic crenarchaea are hosts to many unusual viruses with diverse virion shapes and distinct gene compositions. As is typical of viruses in general, there are no universal genes in the archaeal virosphere. Therefore, to obtain a comprehensive picture of the evolutionary relationships between viruses, network analysis methods are more productive than traditional phylogenetic approaches. Here we present a comprehensive comparative analysis of genomes and proteomes from all currently known taxonomically classified and unclassified, cultivated and uncultivated archaeal viruses. We constructed a bipartite network of archaeal viruses that includes two classes of nodes, the genomes and gene families that connect them. Dissection of this network using formal community detection methods reveals strong modularity, with 10 distinct modules and 3 putative supermodules. However, compared to similar previously analyzed networks of eukaryotic and bacterial viruses, the archaeal virus network is sparsely connected. With the exception of the tailed viruses related to bacteriophages of the order Caudovirales and the families Turriviridae and Sphaerolipoviridae that are linked to a distinct supermodule of eukaryotic and bacterial viruses, there are few connector genes shared by different archaeal virus modules. In contrast, most of these modules include, in addition to viruses, capsidless mobile elements, emphasizing tight evolutionary connections between the two types of entities in archaea. The relative contributions of distinct evolutionary origins, in particular from nonviral elements, and insufficient sampling to the sparsity of the archaeal virus network remain to be determined by further exploration of the archaeal virosphere. Viruses infecting archaea are among the most mysterious denizens of the virosphere. Many of these viruses display no genetic or even morphological relationship to viruses of bacteria and eukaryotes, raising questions regarding their origins and position in the global virosphere. Analysis of 5,740 protein sequences from 116 genomes allowed dissection of the archaeal virus network and showed that most groups of archaeal viruses are evolutionarily connected to capsidless mobile genetic elements, including various plasmids and transposons. This finding could reflect actual independent origins of the distinct groups of archaeal viruses from different nonviral elements, providing important insights into the emergence and evolution of the archaeal virome.


Quantifying the effect of off-focal radiation on the output of kilovoltage x-ray systems.
In a typical x-ray tube, off-focal radiation is mainly generated by the backscattered electrons that reenter the anode outside the focal spot. In this study, BEAMnrc (an EGSnrc user-code) is modified to simulate off-focal radiation. The modified BEAMnrc code is used to study the characteristics of electrons that backscatter from the anode, and to quantify their effect on the output of typical x-ray systems. Results show that the first generation backscatter coefficient is approximately 50% for tungsten anodes at diagnostic energies, and approximately 38% for molybdenum anodes at mammography energies. Second and higher generations of backscatter have a relatively minor contribution. At the patient plane, our simulation results are in excellent agreement with experimental measurements in the literature for the spectral shape of both the primary and the off-focal components, and also for the integral off-focal-to-primary ratio. The spectrum of the off-focal component at the patient plane is softer than the primary, which causes a slight softening in the overall spectrum. For typical x-ray systems, the off-focal component increases patient exposure (for a given number of incident primary electrons) by up to 11% and reduces the half-value layer and the effective energy of the average spectrum by up to 7% and 3%, respectively. The larger effects are for grounded cathode tubes, smaller interelectrode distance, higher tube voltage, lighter filtration, and less collimation. Simulation time increases by approximately 30% when the off-focal radiation is included, but the overall simulation time remains of the order of a few minutes. This study concludes that the off-focal radiation can have a non-negligible effect on the output parameters of x-ray systems and that it should be included in x-ray tube simulations for more realistic modeling of these systems.


Transcriptional analysis of mutacin I (mutA) gene expression in planktonic and biofilm cells of Streptococcus mutans using fluorescent protein and glucuronidase reporters.
Streptococcus mutans is implicated as the primary pathogen involved in the development of dental caries. The production of specific bacteriocins (called mutacins) by S. mutans is one of the major virulence factors which facilitate the dominance of the bacterium within dental plaque. While much has been revealed about the biochemical structures of mutacins, little is known about the expression and regulation of mutacin genes, largely due to the lack of proper methods to monitor mutacin gene expression, especially under biofilm conditions. In this study, a set of reporter systems with the green fluorescent protein (gfp), the monomeric red fluorescent protein (mrfp1), and the glucuronidase (gusA) are introduced to S. mutans to study the transcriptional activities of the mutacin I gene (mutA). Although the mutA-reporter fusions are in single copy on the chromosome, these reporter systems display strong signals that allow us to effectively monitor mutA gene expression in S. mutans. Using these reporter systems, we show that mutA is expressed in both planktonic and biofilm cells, even though mutacin activities are normally detected only in biofilm cells. Furthermore, we confirm that mutR, the gene upstream of the mutacin operon, is required for mutacin I gene expression. The success of this study validates the feasibility of using these reporter systems to study gene expression and regulation in S. mutans.


Deep GONet: self-explainable deep neural network based on Gene Ontology for phenotype prediction from gene expression data.
With the rapid advancement of genomic sequencing techniques, massive production of gene expression data is becoming possible, which prompts the development of precision medicine. Deep learning is a promising approach for phenotype prediction (clinical diagnosis, prognosis, and drug response) based on gene expression profile. Existing deep learning models are usually considered as black-boxes that provide accurate predictions but are not interpretable. However, accuracy and interpretation are both essential for precision medicine. In addition, most models do not integrate the knowledge of the domain. Hence, making deep learning models interpretable for medical applications using prior biological knowledge is the main focus of this paper. In this paper, we propose a new self-explainable deep learning model, called Deep GONet, integrating the Gene Ontology into the hierarchical architecture of the neural network. This model is based on a fully-connected architecture constrained by the Gene Ontology annotations, such that each neuron represents a biological function. The experiments on cancer diagnosis datasets demonstrate that Deep GONet is both easily interpretable and highly performant to discriminate cancer and non-cancer samples. Our model provides an explanation to its predictions by identifying the most important neurons and associating them with biological functions, making the model understandable for biologists and physicians.


Characteristics and determinants of the sublingual microcirculation in populations of different ethnicity.
No previous population study assessed sublingual capillary density (CD) or perfused boundary region (PBR). Lower PBR indicates greater glycocalyx width. In 252 Han and 220 She Chinese and 254 Flemish people (mean age, 51.1 years; 54.7% women), representing random population samples, we measured total and perfused CD and PBR in the sublingual capillary bed, using oblique profiled epi-illumination, and cardiovascular risk factors. In multivariable analyses, we modeled ethnicity as random effect. Significance level was α ≤ 0.05. Compared with Chinese, Flemish had lower total (577 versus 546 n°/mm(2)) and perfused (338 versus 320 n°/mm(2)) CD, but similar perfused-to-total CD ratio (mean, 0.59). Perfused-to-total CD ratio increased with age (effect size per 1-SD increase, +0.015 per year), body mass index (+0.008 per kg/m(2)), total cholesterol (+0.012 per mmol/L), and Framingham risk score (+0.018 per point) with no ethnic differences in these associations. For age and Framingham risk score, associations with perfused-to-total CD ratio were driven by positive relationships with perfused CD, whereas associations with total CD were nonsignificant. Chinese when compared with Flemish had higher hematocrit (43.0 versus 41.1%), PBR (2010 versus 1876 nm), and pulse rate (72.6 versus 63.3 bpm). PBR standardized for hematocrit, perfused CD, and pulse rate decreased with body mass index (-26.7 nm/kg/m2), mean arterial pressure (-30.6 nm/mm Hg), and diastolic pressure (-28.5 nm/mm Hg) with no ethnic differences in these associations. In conclusion, a higher cardiovascular risk profile is associated with functional recruitment of capillaries with preserved glycocalyx that protects the endothelial lining.


Functional Movement Screen™ in High School Basketball Players: Pre- and Post-Season.
Pre-participation screening and tracking of an athlete's functional status during a competitive season is essential to maintaining optimal performance. The sport of basketball had the third highest number of boys and girls participating during the 2018-2019 season (23), which typically occurs October to March each year. The Functional Movement Screen™ (FMS; 10) has been administered to some youth athletes from various sports, however, both males and females from basketball have not been studied extensively. The purposes of this study were: 1) to assess functional movements before and after the natural progression of a high school competitive basketball season; 2) to determine if there were functional movement differences between male and female youth basketball players. Eighteen male (n = 10) and female (n = 8) high school basketball players completed the FMS pre- and post-season. Scores were analyzed using a mixed-model ANOVA. No significant differences were found for Time or Sex for composite FMS scores (Mean ± SD, Pre-season: 16.2 ± 2.1, Post-season: 17.1 ± 1.4; Males: 16.8 ± 1.8, Females: 16.5 ± 2.0). Specific FMS tests were compared pre- to post-season using Wilcoxon signed-rank tests and were not significantly different after the competitive season or between the sexes. Sex differences relating to overall FMS composite scores or specific test scores were not apparent in this age group or sport. In this small group of high school basketball players, participation in a competitive, high school basketball season did not limit nor enhance functional movement ability.


Associations between interleukin-23 receptor polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis.
The aim of this study was to determine whether interleukin-23 receptor (IL-23R) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-23R rs1343151, rs10489629, rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA using (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 13 studies from eight articles involving 10,016 RA patients and 11,967 controls were considered in the meta-analysis. Meta-analysis identified a significant association between RA and the A allele of the rs1343151 polymorphism in the overall population (OR = 1.110, 95 % CI = 1.056-1.168, p = 4.7 × 10(-6)). Stratification by ethnicity identified a significant association between this polymorphism and RA in Europeans (OR = 1.105, 95 % CI = 1.049-1.163, p = 1.4 × 10(-5)). An association was also found between RA and the A allele carrier of the rs1343151 polymorphism in Europeans (OR = 1.135, 95 % CI = 1.058-1.217, p = 4.0 × 10(-5)). Meta-analysis revealed a significant association between RA and the A allele of the rs10489629 polymorphism in the overall population (OR = 1.079, 95 % CI = 1.029-1.131, p = 0.002) and in Europeans (OR = 1.092, 95 % CI = 1.038-1.149, p = 0.001). Meta-analyses of recessive, dominant, and additive models showed the same pattern as the meta-analysis of the A allele of the rs10489629 polymorphism, that is, a significant association with RA in Europeans. However, no association was found between the IL-23R rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA susceptibility. This meta-analysis shows that the IL-23R rs1343151 and rs10489629 polymorphisms are associated with the development of RA in Europeans. These findings suggest that the IL-23R genes confer susceptibility to RA in the European population, but further study of this association is required in other ethnic groups.


Insulin pricing and other major diabetes-related concerns in the USA: a study of 46 407 tweets between 2017 and 2019.
Little research has been done to systematically evaluate concerns of people living with diabetes through social media, which has been a powerful tool for social change and to better understand perceptions around health-related issues. This study aims to identify key diabetes-related concerns in the USA and primary emotions associated with those concerns using information shared on Twitter. A total of 11.7 million diabetes-related tweets in English were collected between April 2017 and July 2019. Machine learning methods were used to filter tweets with personal content, to geolocate (to the USA) and to identify clusters of tweets with emotional elements. A sentiment analysis was then applied to each cluster. We identified 46 407 tweets with emotional elements in the USA from which 30 clusters were identified; 5 clusters (18% of tweets) were related to insulin pricing with both positive emotions (joy, love) referring to advocacy for affordable insulin and sadness emotions related to the frustration of insulin prices, 5 clusters (12% of tweets) to solidarity and support with a majority of joy and love emotions expressed. The most negative topics (10% of tweets) were related to diabetes distress (24% sadness, 27% anger, 21% fear elements), to diabetic and insulin shock (45% anger, 46% fear) and comorbidities (40% sadness). Using social media data, we have been able to describe key diabetes-related concerns and their associated emotions. More specifically, we were able to highlight the real-world concerns of insulin pricing and its negative impact on mood. Using such data can be a useful addition to current measures that inform public decision making around topics of concern and burden among people with diabetes.