Gender-related differences in care-seeking behaviour for newborns: a systematic review of the evidence in South Asia.
Data indicate substantial excess mortality among female neonates in South Asia compared with males. We reviewed evidence on sex and gender differences in care-seeking behaviour for neonates as a driver for this. We conducted a systematic review of literature published between January 1st, 1996 and August 31st, 2016 in Pubmed, Embase, Eldis and Imsear databases, supplemented by grey literature searches. We included observational and experimental studies, and reviews. Two research team members independently screened titles, abstracts and then full texts for inclusion, with disagreements resolved by consensus. Study quality was assessed using National Institute for Health and Care Excellence (NICE) checklists and summary judgements given using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Data were extracted into Microsoft Excel. Of 614 studies initially identified, 17 studies were included. Low quality evidence across several South Asian countries suggests that care-seeking rates for female neonates are lower than males, especially in households with older female children. Parents are more likely to pay more, and seek care from providers perceived as higher quality, for males than females. Evidence on drivers of these care-seeking behaviours is limited. Care-seeking rates are suboptimal, ranging from 20% to 76% across male and female neonates. Higher mortality observed among female neonates in South Asia may be partly explained by differences in care-seeking behaviour, though good quality evidence on drivers for this is lacking. Further research is needed, but policy interventions to improve awareness of causes of neonatal mortality, and work with households with predominantly female children may yield population health benefits. The social, economic and cultural norms that give greater value and preference to boys over girls must also be challenged through the creation of legislation and policy that support greater gender equality, as well as context-specific strategies in partnership with local influencers to change these practices.PROSPERO registration number CRD42016052256.


Photothermally driven decoupling of gas evolution at the solid-liquid interface for boosted photocatalytic hydrogen production.
The slow mass transfer, especially the gas evolution process at the solid-liquid interface in photocatalytic water splitting, restricts the overall efficiency of the hydrogen evolution reaction. Here, we report a novel gas-solid photocatalytic reaction system by decoupling hydrogen generation from a traditional solid-liquid interface. The success relies on annealing commercial melamine sponge (AMS) for effective photothermal conversion that leads to rapid water evaporation. The vapor flows towards the photocatalyst covering the surface of the AMS and is split by the catalyst therein. This liquid-gas/gas-solid coupling system avoids the formation of photocatalytic bubbles at the solid-liquid interface, leading to significantly improved mass transfer and conversion. Utilizing CdS nanorods anchored by highly dispersed nickel atoms/clusters as a model photocatalyst, the highest hydrogen evolution rate from water splitting reaches 686.39 μmol h-1, which is 5.31 times that of the traditional solid-liquid-gas triphase system. The solar-to-hydrogen (STH) efficiency can be up to 2.06%. This study provides a new idea for the design and construction of efficient practical photocatalytic systems.


FARVAT: a family-based rare variant association test.
Individuals in each family are genetically more homogeneous than unrelated individuals, and family-based designs are often recommended for the analysis of rare variants. However, despite the importance of family-based samples analysis, few statistical methods for rare variant association analysis are available. In this report, we propose a FAmily-based Rare Variant Association Test (FARVAT). FARVAT is based on the quasi-likelihood of whole families, and is statistically and computationally efficient for the extended families. FARVAT assumed that families were ascertained with the disease status of family members, and incorporation of the estimated genetic relationship matrix to the proposed method provided robustness under the presence of the population substructure. Depending on the choice of working matrix, our method could be a burden test or a variance component test, and could be extended to the SKAT-O-type statistic. FARVAT was implemented in C++, and application of the proposed method to schizophrenia data and simulated data for GAW17 illustrated its practical importance. The software calculates various statistics for the analysis of related samples, and it is freely downloadable from http://healthstats.snu.ac.kr/software/farvat. email@example.com or firstname.lastname@example.com supplementary data are available at Bioinformatics online.


A 2-to-4 decoder switch in SiGe/Si multimode inteference.
Based on multimode interference principle and free-carrier plasma dispersion effect, a SiGe/Si 2-to-4 decoder switch is proposed and simulated. The decoder switch consists of two input single-mode ridge waveguides, a multimode interference section, and four output single-mode ridge waveguides. In the multimode interference section, two index-modulation regions are introduced. Design principle of the decoder switch is described and the device characteristics are demonstrated theoretically by beam propagation method. Simulated results show that the insertion loss of the decoder switch is less than 0.36 dB and the crosstalk is less than -19.7 dB. The device can divert input optical signals to any one of the four output waveguides when a forward bias voltage is applied to the two index-modulation regions.


Dissociation between small and large numerosities in newborn infants.
In the first year of life, infants possess two cognitive systems encoding numerical information: one for processing the numerosity of sets of 4 or more items, and the second for tracking up to 3 objects in parallel. While a previous study showed the former system to be already present a few hours after birth, it is unknown whether the latter system is functional at this age. Here, we adapt the auditory-visual matching paradigm that previously revealed sensitivity to large numerosities to test sensitivity to numerosities spanning the range from 2 to 12. Across studies, newborns discriminated pairs of large numerosities in a 3:1 ratio, even when the smaller numerosity was 3 (3 vs. 9). In contrast, newborn infants failed to discriminate pairs including the numerosity 2, even at the same ratio (2 vs. 6). These findings mirror the dissociation that has been reported with older infants, albeit with a discontinuity situated between numerosities 2 and 3. Two alternative explanations are compatible with our results: either newborn infants have a separate system for processing small sets, and the capacity of this system is limited to 2 objects; or newborn infants possess only one system to represent numerosities, and this system either is not functional or is extremely imprecise when it is applied to small numerosities.


Three paths to better tyrosine kinase inhibition behind the blood-brain barrier in treating chronic myelogenous leukemia and glioblastoma with imatinib.
Chronic myelogenous leukemia (CML) can be controlled for years with the tyrosine kinase inhibitor imatinib but because imatinib poorly penetrates the blood-brain barrier (BBB), on occasion, the CML clone will thrive and evolve to an accelerated phase in the resulting imatinib sanctuary within the central nervous system. In this, CML resembles glioblastoma in that imatinib, which otherwise may be effective, cannot get to the tumor. Although a common street drug of abuse, methamphetamine is Food and Drug Administration-approved and marketed as a pharmaceutical drug to treat attention-deficit disorders. It has shown the ability to open the BBB in rodents. We have some clinical hints that it may do so in humans as well. This short note presents three new points potentially leading to better tyrosine kinase inhibition behind the BBB: 1) Pharmaceutical methamphetamine may have a useful role in treating both CML and glioblastoma by allowing higher imatinib concentrations behind the BBB. 2) The old antidepressant and monoamine oxidase inhibitor selegiline, used to treat Parkinson disease, is catabolized to methamphetamine. Selegiline, as a nonscheduled drug,may therefore be an easier way to open the BBB, allowing more effective chemotherapy with tyrosine kinases. 3) Dasatinib is a tyrosine kinase inhibitor with a spectrum of inhibition only partially overlapping that of imatinib and a mechanism of tyrosine kinase inhibition that is different from that of imatinib. The two should be additive. In addition, dasatinib crosses the BBB poorly, and it can therefore be expected to benefit from methamphetamine-assisted entry.


Translation and validation of the Finnish version of index of dental anxiety and fear (IDAF-4C+) among dental students.
Dental fear accounts for 41% of the non-habitual dental attendance such as visiting only when in pain among adult Finns. Dentists should be able to recognize patients in risk for irregular attendance due to dental fear and measure their fear with valid and reliable instrument that capture the multidimensionality of dental fear. The study's aim was to translate the Index of Dental Anxiety and Fear (IDAF-4C+) into Finnish and test its reliability and validity. The study population consisted of dental students in a Finnish university (n = 202). The IDAF-4C+ was back-and forward translated by experts as well as a native English translator, blinded to the original version. Reliability was assessed using Cronbach's alpha. Validity of the IDAF-4C+ was assessed against the Modified Dental Anxiety Scale (MDAS) using Spearman correlation coefficients and through the use of Exploratory factor analysis (EFA) and between genders using Mann-Whitney U tests. The reliability of the IDAF-4C+ was good, the Cronbach's alpha being 0.88. The IDAF-4C+ and MDAS and their subscales were correlated, with coefficients varying between 0.34 and 0.85. Correlations were stronger with the emotional and physiological components of the IDAF-4C+. EFA revealed one factor explaining 51.7% of the common variance (eigenvalue = 4.6). Women tended to have slightly higher mean scores than men (1.49 vs. 1.36, p = 0.247). The translation and localization of the Finnish version of the IDAF-4C+ can be considered as providing some evidence of the validity and reliability of the scale. It adds to previously used measures as it considers also the behavioral, cognitive and physiological dimension involved in dental fear.


Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.
Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.


Estrogen rapidly attenuates a GABAB response in hypothalamic neurons.
GABA is a predominant neurotransmitter in the hypothalamus and an important regulator of hypothalamic function. To elucidate the cellular basis for GABAergic action in this region, we used intracellular recordings from identified hypothalamic neurons. Ninety-three percent of the mediobasal hypothalamic neurons responded to GABAB receptor stimulation, and the presence of bicuculline-sensitive synaptic potentials indicated a tonic, GABAA receptor-mediated input. Stimulation of GABAB receptors hyperpolarized these cells by activating an inwardly rectifying potassium conductance. We characterized GABAB responses by generating concentration-response curves to the GABAB agonist baclofen. There was heterogeneity in the responses to baclofen, with one third of the cells having low baclofen potency (EC50 = 5.0 microM). Two thirds of the neurons had a 4-fold higher potency (EC50 = 1.2 microM), larger somas and a more lateral distribution. Previous work has shown that hypothalamic GABAB and mu-opioid receptors open the same K+ channels and that the response to mu-opioid agonists is rapidly attenuated by 17 beta-estradiol (E2). In order to test the hypothesis that the coupling of GABAB receptors to K+ channels is also altered, baclofen concentration-response curves were generated before and after an E2 challenge (100 nM, 20 min). Consistent with our hypothesis, the potency of baclofen was decreased nearly 4-fold in a subset of the cells that had a high potency response to baclofen. Furthermore, decreased baclofen potency only occurred in those cells in which E2 also altered the mu-opioid responses. Therefore, our findings suggest that a discrete subpopulation of hypothalamic neurons is sensitive to estrogen actions to alter inhibitory transmission. We propose that the alteration of GABAB and mu-opioid input is consistent with estrogen's rapid inhibition of the reproductive axis.


Phylogenetic reconciliation reveals the natural history of glycopeptide antibiotic biosynthesis and resistance.
Glycopeptide antibiotics are produced by Actinobacteria through biosynthetic gene clusters that include genes supporting their regulation, synthesis, export and resistance. The chemical and biosynthetic diversities of glycopeptides are the product of an intricate evolutionary history. Extracting this history from genome sequences is difficult as conservation of the individual components of these gene clusters is variable and each component can have a different trajectory. We show that glycopeptide biosynthesis and resistance in Actinobacteria maps to approximately 150-400 million years ago. Phylogenetic reconciliation reveals that the precursors of glycopeptide biosynthesis are far older than other components, implying that these clusters arose from a pre-existing pool of genes. We find that resistance appeared contemporaneously with biosynthetic genes, raising the possibility that the mechanism of action of glycopeptides was a driver of diversification in these gene clusters. Our results put antibiotic biosynthesis and resistance into an evolutionary context and can guide the future discovery of compounds possessing new mechanisms of action, which are especially needed as the usefulness of the antibiotics available at present is imperilled by human activity.


Effects of Adrenomedullin and Glucagon-like Peptide on Distal Flap Necrosis and Vascularity: The Role of Receptor Systems and Nitric Oxide.
Flap necrosis in the distal area due to the deficiency of blood circulation is a major complication in flap treatment. In many previous studies, some natural substances such as chlorogenic acid, adrenomedullin (ADM), and glucagon-like peptide-1 (GLP-1) have been used to improve flap viability via their vasodilator, angiogenic, and antioxidant effects. The aim of this study is to clarify the mechanism through the use of selective antagonists for calcitonin gene-related peptide (CGRP) receptors and GLP-1 receptors such as CGRP-(8-37), exendin-(9-39), respectively, in the flap healing effects of ADM and GLP-1. The role of nitric oxide (NO) was investigated in the mechanism as well. Seventy adult female Wistar rats (200 g-250 g) were used in the study. The cutaneous skin flap (8 cm x 3 cm) on the abdominal wall was raised based on the superficial inferior epigastric artery (SIEA). Single-dose substance injections were administered into the SIEA. Necrosis in the flap area was evaluated on postoperative day 7. The proportion of the necrosis area (necrosis area % = [necrosis area/flap area] x 100) and vascularity (vascular number/cm2) in the distal area were calculated. The administrations of ADM or GLP-1 increased the vascularity and decreased the necrosis area in the distal flap region. The ADM receptor antagonist, CGRP-(8-37), did not prevent the positive effects of ADM on flap healing and vascularity. A GLP-1 receptor antagonist, exendin-(9-39), prevented the effect of GLP-1 on flap healing and vascularity. Nitric oxide mediated the beneficial effects of both peptides on flap healing. The CGRP receptors have no direct role, but NO acts as a mediator in the beneficial effect of ADM on flap healing. The GLP-1 specific receptors and NO act as important interagents for the effects of GLP-1 on flap healing.


The demise of a wonder: Evolutionary history and conservation assessments of the Wonder Gecko Teratoscincus keyserlingii (Gekkota, Sphaerodactylidae) in Arabia.
Effective biodiversity conservation planning starts with genetic characterization within and among focal populations, in order to understand the likely impact of threats for ensuring the long-term viability of a species. The Wonder Gecko, Teratoscincus keyserlingii, is one of nine members of the genus. This species is distributed in Iran, Afghanistan, and Pakistan, with a small isolated population in the United Arab Emirates (UAE), where it is classified nationally as Critically Endangered. Within its Arabian range, anthropogenic activity is directly linked to the species' decline, with highly localised and severely fragmented populations. Here we describe the evolutionary history of Teratoscincus, by reconstructing its phylogenetic relationships and estimating its divergence times and ancestral biogeography. For conservation implications of T. keyserlingii we evaluate the genetic structure of the Arabian population using genomic data. This study supports the monophyly of most species and reveals considerable intraspecific variability in T. microlepis and T. keyserlingii, which necessitate broad systematic revisions. The UAE population of T. keyserlingii likely arrived from southern Iran during the Pleistocene and no internal structure was recovered within, implying a single population status. Regional conservation of T. keyserlingii requires improved land management and natural habitat restoration in the species' present distribution, and expansion of current protected areas, or establishment of new areas with suitable habitat for the species, mostly in northern Abu Dhabi Emirate.


Report of gossypiboma from the standpoint in medicine and law.
We report on a case of gossypiboma. A 78-year-old man was admitted to our hospital with acute abdomen. He had undergone an operation for colon cancer 4 mo previously. Abdominal ultrasonography revealed an echogenic lesion with a hypoechoic rim and strong posterior acoustic shadowing in the lower abdomen. Diagnosis of gossypiboma can be made by ultrasonography to avoid loss-of-chance of survival. We reviewed the English literature briefly of gossypiboma from the medical and juridical view. According to the theory of loss-of-chance, the damage of plaintiff is the loss of the chance of survival or recovery, rather than the final harm. The victim would allow recovery for the loss of the chance from the defendant. But the plaintiff would show by a preponderance that he was deprived of a better chance of a cure. Under the proposed rule, the compensable value of the victim would be the plaintiff's compensation for the loss of the victim's chance of survival.


Prolonged immunomodulation in inflammatory arthritis using the selective Kv1.3 channel blocker HsTX1[R14A] and its PEGylated analog.
Effector memory T lymphocytes (TEM cells) that lack expression of CCR7 are major drivers of inflammation in a number of autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. The Kv1.3 potassium channel is a key regulator of CCR7- TEM cell activation. Blocking Kv1.3 inhibits TEM cell activation and attenuates inflammation in autoimmunity, and as such, Kv1.3 has emerged as a promising target for the treatment of TEM cell-mediated autoimmune diseases. The scorpion venom-derived peptide HsTX1 and its analog HsTX1[R14A] are potent Kv1.3 blockers and HsTX1[R14A] is selective for Kv1.3 over closely-related Kv1 channels. PEGylation of HsTX1[R14A] to create a Kv1.3 blocker with a long circulating half-life reduced its affinity but not its selectivity for Kv1.3, dramatically reduced its adsorption to inert surfaces, and enhanced its circulating half-life in rats. PEG-HsTX1[R14A] is equipotent to HsTX1[R14A] in preferential inhibition of human and rat CCR7- TEM cell proliferation, leaving CCR7+ naïve and central memory T cells able to proliferate. It reduced inflammation in an active delayed-type hypersensitivity model and in the pristane-induced arthritis (PIA) model of rheumatoid arthritis (RA). Importantly, a single subcutaneous dose of PEG-HsTX1[R14A] reduced inflammation in PIA for a longer period of time than the non-PEGylated HsTX1[R14A]. Together, these data indicate that HsTX1[R14A] and PEG-HsTX1[R14A] are effective in a model of RA and are therefore potential therapeutics for TEM cell-mediated autoimmune diseases. PEG-HsTX1[R14A] has the additional advantages of reduced non-specific adsorption to inert surfaces and enhanced circulating half-life.


Patient-centered management of actinic keratosis. Results of a multi-center clinical consensus analyzing non-melanoma skin cancer patient profiles and field-treatment strategies.
Introduction: Actinic keratosis (AK) is a chronic skin condition that can be a precursor to cutaneous squamous cell carcinoma. AK can recur and patients are likely to undergo multiple treatments. It is important that AK lesions are managed appropriately, and that patients are involved in treatment decisions.Materials and methods: The Supporting Professional Expertise in AK (SPEAK) program aims to facilitate this patient-centered care by identifying patient needs and aiding healthcare practitioners (HCPs) in selecting optimal treatment and communication strategies for different types of patients. Twenty-two dermato-oncologists with established expertise in the treatment of AK collaborated to describe commonly encountered psychosocial patient profiles, and to develop respective communication and treatment strategies.Results and conclusion: Six patient profiles were defined based on different psychosocial characteristics and were used to develop appropriate management approaches. We provide a systematic way of identifying these patient profiles in clinical practice and we outline communication strategies tailored to the primary needs of each type of patient. In addition, we provide recommendations for potential field-treatments that may be best suited for each profile. The recommendations provided here may help improve the communication and relationship between patients and HCPs, resulting in higher treatment adherence and improved patient outcomes.


Gene delivery into malignant cells in vivo by a conjugated adenovirus/DNA complex.
Current viral delivery systems suffer from disadvantages that may limit the rate at which therapeutic gene expressing constructs can be tested both in vitro and in vivo. In this study, our focus was to develop a simple gene delivery system for the rapid and reproducible testing of therapeutic genes in cancer cells both in vitro and in vivo. We report here that a delivery system based on using a conjugated adenovirus in complex from with a DNA plasmid can be used for not only delivering genes in vitro but also for efficient and reproducible delivery in vivo. Replication defective adenoviral particles were chemically modified by covalent attachment of poly-L-lysine (PLL) to the viral capsid, allowing for direct interaction with DNA. The adenovirus/PLL conjugate (Adv/PLL) was used to deliver the plasmid pCMV/beta-gal to several different cancer cell lines (i.e., lung, cervical) in vitro and resulted in transduction efficiencies as high as 52% as determined by histochemical staining. On direct intralesional injection of the Adv/PLL/DNA complex into subcutaneous tumors, transduction efficiencies greater than 35% could also be achieved. As a result, this system provides a simple method for delivering and testing therapeutic genes in cells both in vitro and in vivo, prior to the further development of gene therapy vectors for both malignant and benign disease.


The Burden of Genetic and Epigenetic Traits in Prematurity.
Despite decades of investigations and accumulated scientific knowledge, preterm birth (PTB) remains a significant burden worldwide. Several mechanisms have been proposed to explain this condition, and a number of risk factors from infectious to behavioral and genetic/epigenetic factors influence this outcome. The heritability of PTB is estimated to be 17% to 36%, which demonstrates that genetic predisposition plays a key role in PTB. Structural DNA modifications without changes in the DNA sequence and post-transcriptional regulation also have an impact on gene expression and thus influence pregnancy outcomes. There is a complex interplay between environmental factors and the individual's genetics and epigenetics that may culminate in PTB, but the complete regulatory pathways and networks involved in this context are still unclear. Here, we outline what is known so far about the genetic and epigenetic factors involved in preterm delivery, including polymorphisms, DNA methylation, and microRNAs, and suggest fields for research.


Midodrine: a role in the management of neurocardiogenic syncope.
To determine the benefit of midodrine, an alpha agonist, on symptom frequency and haemodynamic responses during head up tilt in patients with neurocardiogenic syncope. Cardiovascular investigation unit (a secondary and tertiary referral centre for the investigation and management of syncope). 16 outpatients (mean (SD) age 56 (18) years; five men) with frequent hypotensive symptoms (more than two syncopal episodes and fewer than 20 symptom free days per month), and reproducible syncope with glyceryl trinitrate (GTN) during head up tilt. Randomised double blind placebo controlled study. Patients were randomised to receive either placebo or midodrine for one month. Symptom events were recorded during each study month. At the end of each study month patients completed a quality of life scoring scale (Short Form 36) and a global assessment of therapeutic response. They received GTN with head up tilt for measurement of heart rate (electrocardiography), phasic blood pressure (digital photoplethysmography), and thoracic fluid index (transthoracic impedance plethysmography) during symptom provocation. Patients administered midodrine had an average of 7.3 more symptom free days than those who received placebo (95% confidence interval (CI) 4.6 to 9; p < 0.0001). Eleven patients reported a positive therapeutic response with midodrine (p = 0.002). All domains of quality of life showed improvement with midodrine, in particular physical function (8.1; 95% CI 3.7 to 12.2), energy and vitality (14.6; 95% CI 7.3 to 22.1), and change in health status (22.2; 95% CI 11 to 33.4). Fourteen patients who were given placebo had tilt induced syncope compared with six given midodrine (p = 0.01). Baseline supine systolic blood pressure was higher and heart rate lower in patients who received midodrine than in those who were given placebo (p < 0.05). A lower thoracic fluid index in patients administered midodrine indicates increased venous return when supine and during head up tilt. There were no serious adverse effects. Midodrine had a conspicuous beneficial effect on symptom frequency, symptoms during head up tilt, and quality of life. Midodrine is recommended for the treatment of neurocardiogenic syncope in patients with frequent symptoms.


Factors associated with healthcare workers willingness to participate in disasters: a cross-sectional study in Sana'a, Yemen.
Willingness to participate in disasters is usually overlooked and not addressed in disaster preparedness training courses to ensure health service coverage. This will lead to issues during the disaster's response. This study, therefore, aims to assess healthcare workers willingness to participate in biological and natural disasters, and to identify its associated factors. This is a cross-sectional study using a self-administered questionnaire. The questionnaire was distributed to 1093 healthcare workers. The data were analysed using multiple logistic regression with significance level p<0.05. Ethical clearance and consent of the participants were duly obtained. In three public hospitals that provide tertiary-level healthcare in Sana'a City, Yemen. There were 692 nurses and doctors (response rate 63.3%) completed the questionnaires. Almost half of the participants 55.1% were nurses and 44.9% were doctors. The study found that self-efficacy was associated with willingness to participate in disaster response for any type of disasters (OR 1.319, 95% CI 1.197 to 1.453), natural disasters (OR 1.143, 95% CI 1.069 to 1.221) and influenza pandemic (OR 1.114, 95% CI 1.050 to 1.182). The results further show that willingness is associated with healthcare workers being young, male and having higher educational qualifications. Self-efficacy has been found to be an important factor associated with willingness. Improving self-efficacy through training in disaster preparedness may increase willingness of healthcare workers to participate in a disaster.


A nuclease-polymerase chain reaction enables amplification of probes used for capture-based DNA target enrichment.
DNA target enrichment via hybridization capture is a commonly adopted approach which remains expensive due in-part to using biotinylated-probe panels. Here we provide a novel isothermal amplification reaction to amplify rapidly existing probe panels without knowledge of the sequences involved, thereby decreasing a major portion of the overall sample preparation cost. The reaction employs two thermostable enzymes, BST-polymerase and duplex-specific nuclease DSN. DSN initiates random 'nicks' on double-stranded-DNA which enable BST to polymerize DNA by displacing the nicked-strand. Displaced strands re-hybridize and the process leads to an exponential chain-reaction generating biotinylated DNA fragments within minutes. When starting from single-stranded-DNA, DNA is first converted to double-stranded-DNA via terminal-deoxynucleotidyl-transferase (TdT) prior to initiation of BST-DSN reaction. Biotinylated probes generated by TdT-BST-DSN (TBD) reactions using panels of 33, 190 or 7186 DNA targets are used for hybrid-capture-based target enrichment from amplified circulating-DNA, followed by targeted re-sequencing. Polymerase-nuclease isothermal-chain-reactions generate random amplified probes with no apparent sequence dependence. One round of target-capture using TBD probes generates a modest on-target sequencing ratio, while two successive rounds of capture generate >80% on-target reads with good sequencing uniformity. TBD-reactions generate enough capture-probes to increase by approximately two to three orders-of-magnitude the target-enrichment experiments possible from an initial set of probes.


Research effort on birds' reservoir host potential for Lyme borreliosis: A systematic review and perspectives.
Zoonotic tick-borne diseases threat human and animal health. Understanding the role of hosts in the production of infected ticks in an epidemiological system is essential to be able to design effective measures to reduce the exposure of humans and animals to infectious tick bites. The reservoir host potential, that is, number of infected ticks produced by a host species, depends on three components: tick production, realized reservoir competence and host density. The parameters and factors that determine the reservoir host potential need to be characterized to achieve a robust understanding of the dynamics of pathogen-tick-host systems, and thus to mitigate the acarological risk of emerging infections. Few studies have investigated the role of birds in the local spread of Lyme borreliosis Borrelia. Knowledge of the research effort on the reservoir host potential of birds in Lyme borreliosis Borrelia circulation is necessary to prioritize future research on this topic. We provide a systematic review of the research effort on components of the reservoir host potential of wild birds for Lyme borreliosis Borrelia circulation, and factors that modulate these components in the European epidemiological system. Our review of 242 selected publications showed that tick production has been 1.4 and 21 times more studied than realized reservoir competence and bird density respectively. Only one study achieved to characterize the global host reservoir potential of birds in a given epidemiological system. Investigated factors were mostly related to bird species identity, individual characteristics of birds and tick characteristics, whereas the influence of bird life-history traits have been largely under-investigated. Because simultaneous characterization of all parameters is notoriously complex, interdisciplinary research is needed to combine and accumulate independent field and laboratory investigations targeting each parameter on specific epidemiological system or host species. This can help gain an integrated appraisal of the functioning of the studied system at a local scale.


Periodontitis and the risk for non-fatal stroke in Korean adults.
The association between periodontal inflammation and non-fatal stroke is still controversial and limited to evidence in Western countries. The aim of this study was to investigate whether periodontitis is independently associated with non-fatal stroke in Korean adults. A case-control study was conducted on 265 non-fatal chronic stroke cases at the National Rehabilitation Center, Seoul, Korea, and 214 non-stroke population controls. Medical specialists diagnosed stroke by using brain imaging from magnetic resonance imaging and/or computerized tomography. A dentist recorded the clinical attachment level (CAL), the distance between the cemento-enamel junction and the probed base of the periodontal pocket, using a University of North Carolina-15 manual probe. An interview assessed 17 sociodemographic, behavioral, systemic/oral health-related possible confounders. Multiple logistic regression analysis was used to evaluate the association between periodontitis and stroke while controlling for age, gender, income, education, smoking, drinking, history of systemic disease, body mass index, familial cardiovascular risk factors, and oral health behaviors. Subgroup analyses were also performed. Stroke was strongly associated with periodontitis (presence of CAL > or =6 mm): the odds ratio was 4.0 (95% confidence interval: 2.3 to 7.0) after controlling for all possible confounders. The association with periodontitis (tertiary percentage of CAL > or =5 mm) had a dose-response effect. The association between periodontitis and stroke was higher among adults younger than age 60 (6.0 versus 2.6) and normotensives (4.8 versus 3.2). Our data suggested that periodontitis is independently associated with non-fatal stroke, and its impact seems to be greater among younger or normotensive Korean adults.


Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation.
Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.


Disclosing the Mechanism of Spontaneous Aggregation and Template-Induced Misfolding of the Key Hexapeptide (PHF6) of Tau Protein Based on Molecular Dynamics Simulation.
The microtubule-associated protein tau is critical for the development and maintenance of the nervous system. Tau dysfunction is associated with a variety of neurodegenerative diseases called tauopathies, which are characterized by neurofibrillary tangles formed by abnormally aggregated tau protein. Studying the aggregation mechanism of tau protein is of great significance for elucidating the etiology of tauopathies. The hexapeptide 306VQIVYK311 (PHF6) of R3 has been shown to play a vital role in promoting tau aggregation. In this study, long-term all-atom molecular dynamics simulations in explicit solvent were performed to investigate the mechanisms of spontaneous aggregation and template-induced misfolding of PHF6, and the dimerization at the early stage of nucleation was further specifically analyzed by the Markov state model (MSM). Our results show that PHF6 can spontaneously aggregate to form multimers enriched with β-sheet structure and the β-sheets in multimers prefer to exist in a parallel way. It is observed that PHF6 monomer can be induced to form a β-sheet structure on either side of the template but in a different way. In detail, the β-sheet structure is easier to form on the left side but does not extend well, but on the right side, the monomer can form the extended β-sheet structure. Furthermore, MSM analysis shows that the formation of dimer mainly occurs in three steps. First, the separated monomers collide with each other at random orientations, and then a dimer with short β-sheet structure at the N-terminal forms; finally, β-sheets elongate to form an extended parallel β-sheet dimer. During these processes, multiple intermediate states are identified and multiple paths can form a parallel β-sheet dimer from the disordered coil structure. Moreover, the residues I308, V309, and Y310 play an essential role in the dimerization. In a word, our results uncover the aggregation and misfolding mechanism of PHF6 from the atomic level, which can provide useful theoretical guidance for rational design of effective therapeutic drugs against tauopathies.


Future risk for disability pension among people with sickness absence due to otoaudiological diagnoses: a population-based cohort study with a 12-year follow-up.
Hearing difficulties is a growing public health problem and more knowledge of consequences of those difficulties in working life is warranted. To study the future risk of being granted a disability pension (DP) among people with sickness absence with an otoaudiological diagnoses (OAD) compared to other sickness absentees. A population-based prospective cohort study of all 40,786 people in a Swedish county who in 1985 were aged 16-64 and had a new sick-leave spell >7 days. Those were followed for 12 years with regard to DP. Hazard ratios (HR) + 95% confidence intervals (CI) of being granted DP was calculated among those with sick leave due to OAD compared to people with sickness absence with other diagnoses. In 1985, 515 people had a new sick-leave spell with an OAD. Twelve years later, 36% of those had been granted DP, compared to 24% of all other sickness absentees. Their HR for DP was 1.42 (95% CI 1.23-1.64) adjusting for gender and age. Compared to men, women with an OAD had a HR of DP of 1.24 (95% CI 0.90-1.71), when adjusted for age. The HR for DP regarding those aged>45 years and sickness absent with OAD was 2.63 (95% CI 1.95-3.55) compared to the sickness absentees with OAD below 45 years of age, adjusted for gender. The risk for future DP was more than 40% higher among those initially on sickness absence due to OAD than among other sickness absentees.


Quantifying trace elements in individual aquatic protist cells with a synchrotron X-ray fluorescence microprobe.
The study of trace metal cycling by aquatic protists is limited by current analytical techniques. Standard "bulk" element analysis techniques that rely on physical separations to concentrate cells for analysis cannot separate cells from co-occurring detrital material or other cells of differing taxonomy or trophic function. Here we demonstrate the ability of a synchrotron-based X-ray fluorescence (SXRF) microprobe to quantify the elements Si, Mn, Fe, Ni, and Zn in individual aquatic protist cells. This technique distinguishes between different types of cells in an assemblage and between cells and other particulate matter. Under typical operating conditions, the minimum detection limits are 7.0 x 10(-16) mol microm(-2) for Si and between 5.0 x 10(-20) and 3.9 x 10(-19) mol microm(-2) for Mn, Fe, Ni, and Zn; this sensitivity is sufficient to detect these elements in cells from even the most pristine waters as demonstrated in phytoplankton cells collected from remote areas of the Southern Ocean. Replicate analyses of single cells produced variations of <5% for Si, Mn, Fe, and Zn and <10% for Ni. Comparative analyses of cultured phytoplankton cells generally show no significant differences in cellular metal concentrations measured with SXRF and standard bulk techniques (spectrophotometry and graphite furnace atomic absorption spectrometry). SXRF also produces two-dimensional maps of element distributions in cells, thereby providing information not available with other analytical approaches. This technique enables the accurate and precise measurement of trace metals in individual aquatic protists collected from natural environments.


Patterns of growth in adaptive social abilities among children with autism spectrum disorders.
Adaptive social skills were assessed longitudinally at approximately ages 2, 3, 5, 9, and 13 years in a sample of 192 children with a clinical diagnosis of autism (n = 93), PDD-NOS (n = 51), or nonspectrum developmental disabilities (n = 46) at age 2. Growth curve analyses with SAS proc mixed were used to analyze social trajectories over time. Both individual characteristics and environmental resources emerged as key predictors of adaptive social behavior outcome. The gap between children with autism and the other two diagnostic groups widened with time as the social skills of the latter groups improved at a higher rate. However, within diagnostic groups, improvement ranged from minimal to very dramatic. Children with autism most at risk for problems with social adaptive abilities later in life can be identified with considerable accuracy at a very young age so they can be targeted for appropriate early intervention services.


Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.
Leber's hereditary optic neuropathy (LHON) is a mitochondrial complex I disorder and causes inexorable painless vision loss. Recent studies from India reported that a significant proportion of LHON patients lack primary mitochondrial DNA mutations, suggesting that alternative genetic factors contribute to disease development. Therefore, this study investigated the genetic profile of LHON-affected individuals in order to understand the role of mito-nuclear genetic factors in LHON. A total of thirty probands displaying symptoms consistent with LHON have undergone whole mitochondrial and whole exome sequencing. Interestingly, whole mtDNA sequencing revealed primary mtDNA mutations in 30 % of the probands (n=9), secondary mtDNA mutations in 40 % of the probands (n=12) and no mitochondrial changes in 30 % of individuals (n=9). Further, WES analysis determined pathogenic mutations in 11 different nuclear genes, especially in cases with secondary mtDNA mutations (n=6) or no mtDNA mutations (n=6). These findings provide valuable insight into LHON genetic predisposition, particularly in cases lacking primary mtDNA mutations. See also Figure 1(Fig. 1).


Principles responsible for trace element concentrations in chronic kidney disease.
Derangements of trace elements often occur in patients with renal failure and play a crucial role in chronic kidney disease. The natural history of trace element deposition with worsening chronic kidney disease has been poorly described. Some essential trace elements may get wasted (e.g., selenium, zinc, and manganese) while other trace elements accumulate (e.g., cobalt, lead, molybdenum, and vanadium). Data are most readily available relating to hemodialysis patients. Continuous renal replacement therapies (for the treatment of acute kidney injury) and chronic kidney disease patients without need for renal replacement therapy remain largely unstudied. We have synthesized all available data on mode of absorption and elimination, volume of distribution, plasma protein binding, and proteinuria to summarize the existing literature, identify future areas of research and to allow some prediction of the fate of individual trace elements in clinical scenarios where no direct observational data are available. More prospective studies evaluating the impact of abnormal trace elements and the possible therapeutic value of intervention are required to improve how robust the current international guideline recommendations (KDOQI) are with respect to trace element monitoring.


Rough endoplasmic reticulum in the adult mammalian cardiac muscle cell.
The morphology, distribution and extent of rough endoplasmic reticulum (RER) was investigated in normal and ischaemic left ventricular 'working' myocytes of the adult rabbit. Continuity of RER with membranes of the Golgi apparatus, nuclear envelope and sarcoplasmic reticulum (SR) is documented, though 48% of RER profiles appear as discrete entities in the interfibrillar and perinuclear sarcoplasm. Of the RER intercalated in the SR, 31% of the segments occur adjacent to the Z-tubule, 15% in longitudinal elements of free SR and 5% adjacent to junctional SR. Quantitative analysis of profile lengths shows the RER to be more extensive than hitherto suspected, with 73% of profiles having lengths in excess of 200 nm and some (albeit uncommonly) in excess of 8 micron.


Design, synthesis and in silico screening of benzoxazole-thiazolidinone hybrids as potential inhibitors of SARS-CoV-2 proteases.
Hybrid molecules in the recent years have gained significant importance in drug research as promising therapeutic agents. We report a novel combination of two such bioactive scaffolds (benzoxazole and 4-thiazolidinone B-T hybrids) as inhibitors of SARS-CoV-2. The study uses an in silico approach to identify the potential of B-T hybrids as possible inhibitors of the SARS-CoV-2 proteases. Molecular docking was employed to identify the interactions of B-T hybrids with the two proteases - 3CLp (the 3-chymotrypsin-like protease) and PLp (the papain-like protease). Docking results of the screened 81 hybrids indicated that BT10 and BT14 interacted with the catalytic dyad residue of 3CLp (Cys145) with the best binding energy. MD simulations revealed that BT10 formed stable interactions via 4 hydrogen bonds with the catalytic site residues of 3CLp. In the case of PLp, BT27 and MBT9 interacted with the catalytic triad residue of PLp (His272) with high binding energy. MD simulations demonstrated that the reference drug Tipranavir relocated to the thumb region of the protease whereas BT27 remained in the active site of PLp stabilized by 2 hydrogen bonds, while MBT9 relocated to the BL2 loop of the palm region. The MM-PBSA and interaction entropy (IE) analysis indicated that BT14 exhibited the best ΔG (of -6.83 kcal mol-1) with 3CLp, while BT27 exhibited the best ΔG (of -7.76 kcal mol-1) with PLp. A four-step synthetic procedure was employed to synthesize the B-T hybrids starting from ammonium thiocyanate. The short-listed compounds in the case of 3CLp were synthesized and characterized using IR, NMR, and HRMS spectroscopic techniques.


Antioxidant properties, phytochemical composition, and antiproliferative activity of Maryland-grown soybeans with colored seed coats.
This study characterized and compared 18 colored seed coat soybeans for the isoflavone, total phenolic, and cyanidin-3-glucoside (Cy-3-glc) contents of their flour extracts and the fatty acid composition and carotenoid and alpha-tocopherol contents of their oils. Antioxidant assays also assessed activity of the flour extracts against peroxyl, hydroxyl, and ABTS(+) radicals. Black seed coat soybeans had the highest TPC, ORAC, HOSC, and ABTS(+) radical scavenging values, in addition to the highest isoflavone content, and were the only color to contain Cy-3-glc. Five soybeans (two black and one each brown, yellow, and green) were selected to test their effects on HT-29 human colorectal cancer cell growth. The effects of the hydrolyzed and unhydrolyzed extracts were compared to an aglycone isoflavone standard mixture of the same total molar concentration as the highest soybean concentration of 15 mg of seed flour equiv/mL of treatment media. All high doses of hydrolyzed soybean treatments except the green genotype significantly reduced cell number compared to control at 3 h of treatment time, whereas the high dose of isoflavone standard treatment took 72 h to show a significant reduction (P < 0.05).


Bounding the Accuracy of Diagnostic Tests, With Application to COVID-19 Antibody Tests.
Tests used to diagnose illness commonly have imperfect accuracy, with some false-positive and negative results. For risk assessment and clinical decisions, predictive values are of interest. Positive predictive value (PPV) is the chance that a member of a relevant population who tests positive has been ill. Negative predictive value (NPV) is the chance that someone who tests negative has not been ill. The medical literature regularly reports sensitivity and specificity. Sensitivity is the chance that an ill person receives a positive test result. Specificity is the chance that a nonill person receives a negative result. Knowledge of sensitivity and specificity enables one to predict the test result given a person's illness status. These predictions are not directly relevant to patient care but, given knowledge of sensitivity and specificity, PPV and NPV can be derived if one knows the prevalence of the disease, the population rate of illness. There is considerable uncertainty about the prevalence of some diseases, a notable case being COVID-19. This paper addresses the problem of identification of PPV and NPV given knowledge of sensitivity and specificity and given bounds on prevalence. I explain the problem and show how to bound PPV and NPV as well as the risk ratio and difference, which are functions thereof. I apply the findings to COVID-19 antibody tests. I question the realism of supposing that sensitivity and specificity are known.


Negative mood induction normalizes decision making in male cocaine dependent individuals.
Decision making is thought to play a key role in psychostimulant relapse, but very few studies have addressed the issue of how to counteract decision-making deficits in addicted individuals. According to the somatic marker framework, pervasive decision-making problems in addicted individuals may relate to abnormalities in the processing of emotional signals that work to anticipate the prospective outcomes of potential decisions. The present study was conducted to test whether the induction of different emotional states (positive, negative, or drug-related) could either normalize or further impair decision-making performance in male cocaine polysubstance-using individuals (CPSI), as indexed by the Iowa gambling task (IGT). Forty-two CPSI and 65 healthy control individuals (all males) were randomly allocated in four affective conditions using a parallel-group design. Participants in the different conditions performed the IGT during exposure to neutral, positive, negative, or drug-related sets of affective images. The results showed that the CPSI exposed to the negative affective context showed a preference for the risk-averse safe choices of the IGT and had a net performance indistinguishable from that of controls. On the other hand, CPSI exposed to positive, drug-related, and neutral contexts showed the typical pattern of disadvantageous performance in the IGT and performed significantly poorer than controls. The impact of the negative mood induction could not be explained in terms of baseline differences in decision-making skills, personality traits related to sensitivity to reward/punishment, or trait positive/negative affect. We conclude that negative mood induction can normalize decision-making performance in male CPSI, which may have important implications for the treatment of cocaine use-related disorders.


Four tyrosine residues of the rice immune receptor XA21 are not required for interaction with the co-receptor OsSERK2 or resistance to Xanthomonas oryzae pv. oryzae.
Tyrosine phosphorylation has emerged as an important regulator of plasma membrane-localized immune receptors activity. Here, we investigate the role of tyrosine phosphorylation in the regulation of rice XANTHOMONAS RESISTANCE 21 (XA21)-mediated immunity. We demonstrate that the juxtamembrane and kinase domain of Escherichia coli-expressed XA21 (XA21JK) autophosphorylates on tyrosine residues. Directed mutagenesis of four out of the nine tyrosine residues in XA21JK reduced autophosphorylation. These sites include Tyr698 in the juxtamembrane domain, and Tyr786, Tyr907, and Tyr909 in the kinase domain. Rice plants expressing XA21-GFP fusion proteins or proteins with these tyrosine residues individually mutated to phenylalanine (XA21YF-GFP), which prevents phosphorylation at these sites, maintain resistance to Xanthomonas oryzae pv. oryzae. In contrast, plants expressing phosphomimetic XA21 variants with tyrosine mutated to aspartate (XA21YD-GFP) were susceptible. In vitro purified XA21JKY698F, XA21JKY907F, and XA21JKY909F variants are catalytically active, whereas activity was not detected in XA21JKY768F and the four XA21JKYD variants. We previously demonstrated that interaction of XA21 with the co-receptor OsSERK2 is critical for biological function. Four of the XA21JKYF variants maintain interaction with OsSERK2 as well as the XA21 binding (XB) proteins XB3 and XB15 in yeast, suggesting that these four tyrosine residues are not required for their interaction. Taken together, these results suggest that XA21 is capable of tyrosine autophosphorylation, but the identified tyrosine residues are not required for activation of XA21-mediated immunity or interaction with predicted XA21 signaling proteins.


An update on thalassemia intermedia.
Thalassemia intermedia is a genetically diverse group of diseases that is the result of an imbalance in the production of the alpha and beta chains with ensuing chronic hemolysis, ineffective erythropoiesis, and iron overload. Resulting complications include bone changes, hypercoagulability, and end-organ damage due to iron overload. This decade has witnessed major breakthroughs in the management of thalassemia. In this article, we examine these novelties in therapy including iron chelation therapy, stem cell transplant, and gene therapy. Iron chelation therapy has been revolutionized with the advent of deferasirox, a once-daily oral iron chelator, that has been shown to be safe and efficacious. Gene therapy was also at the core of this revolution with the discovery of novel gene elements and viral vectors allowing for better control and improved outcomes.


Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.
We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.


AUTOMATON: A Program That Combines a Probabilistic Cellular Automata and a Genetic Algorithm for Global Minimum Search of Clusters and Molecules.
A novel program for the search of global minimum structures of atomic clusters and molecules in the gas phase, AUTOMATON, is introduced in this work. This program involves the following: first, the generation of an initial population, using a simplified probabilistic cellular automaton method, which allows easy control of the adequate distribution of atoms in space; second, the fittest individuals are selected to evolve, through genetic operations (mating and mutations), until the best candidate for a global minimum surfaces. In addition, we propose a simple way to build the descendant structures by establishing a ranking of genes to be inherited. Thus, by means of a chemical formula checker procedure, genes are transferred to the offspring, ensuring that they always have the appropriate type and number of atoms. It is worth noting that a fraction of the fittest group is subject to mutation operations. This program also includes algorithms to identify duplicate structures: one based on geometric similarity and another on the similar distribution of atomic charges. The effectiveness of the program was evaluated in a group of 45 molecules, considering organic and organometallic compounds (benzene, cyclopentadienyl anion, and ferrocene), Zintl ion clusters [Sn9- m- nGe mBi n](4- n)- ( n = 1-4 and m = 0-(9- n)), star-shaped clusters (Li7E5+, E = BH, C, Si, Ge) and a variety of boron-based clusters. The global minimum and the lowest-energy isomers reported in the literature were found for all the cases considered in this article. These results successfully prove AUTOMATON's effectiveness on the identification of energetically preferred structures of a wide variety of chemical species.


Understanding the public's profile of mental health literacy in China: a nationwide study.
In the wake of China's massive economic development, attention has only recently turned to the enormous treatment gap that exists for mental health problems. Our study is the first comprehensive, national examination of the levels and correlates of the public's ability to recognize mental illness in the community and suggest sources of help, setting a baseline to assess contemporary Chinese efforts. Data were collected in China as part of the Stigma in Global Context - Mental Health Study (SGC-MHS) through face-to-face interviews using vignettes meeting clinical criteria for schizophrenia and major depression. Our analysis targets the Han Chinese participants (n = 1812). Differences in the recognition of mental health problems were assessed using a chi-square test and further stratified by vignette illness type and urban vs. rural residence. Adjusted regression models estimated the effects of each predictor towards the endorsement three types of help-seeking: medical doctor, psychiatrist, and mental health professional. As expected, recognition of mental health problems is low; it is better for depression and most accurate in urban areas. Perceived severity increases endorsement of the need for care and for treatment by all provider types. Recognition of a mental health problem specifically decreases endorsement of medical doctors while increasing recommendations for psychiatrists and mental health professionals. Neurobiological attributions decrease recommendations for mental health professionals as opposed to general or specialty physicians. Continued efforts are needed in China to promote mental illness recognition within rural areas, and of schizophrenia specifically. Promoting recognition of mental illness, while balancing the special challenges among individuals who understand the neurobiological roots of mental illness, may constitute a key strategy to reduce the sizeable mental health treatment gap in China.


Mechanism of myofibril growth and proliferation in fish muscle.
The mechanisms of myofibril growth proliferation were investigated in the red and white muscles of fish. In both types of muscle the ratio of lattice filament spacings between the Z disk and M line was found to be greater than that required for perfect transformation of a square into a hexagonal lattice. This mismatch was considered to result in the thin filaments being pulled obliquely instead of at right angles to the Z disk. The angle of pull of the thin filaments was measured in longitudinal sections. The splitting process was found to decrease the degree of pull. Splitting was also observed in transverse sections of the peripheral myofibrils. In both red and white fibres these myofibrils were found to commence splitting when they reached a size of approximately 1-2 mum diameter. Evidence from ultrastructural and autoradiographical studies suggested that growth of the myofibrils within the fibres is centrifugal. The outermost myofibrils appear to be the ones which are being built up and which split. The data indicated that in fish muscle a considerable number of filaments may be added to the daughter regions whilst splitting of the myofibril is still continuing.


COIL emission of a modified negative branch confocal unstable resonator.
A modified negative branch confocal unstable resonator (MNBUR) was coupled to the chemical oxygen-iodine laser (COIL) device of the German Aerospace Center. It consists of two spherical mirrors and a rectangular scraper for power extraction. Experimentally measured distributions of the near- and far-field intensities and the near-field phase were found in close agreement to numerical calculations. The extracted power came up to approximately 90% of the power as expected for a stable resonator coupled to the same volume of the active medium. The output power revealed a considerable insensitivity towards tilts of the resonator mirrors and the ideal arrangement of the scraper was found to be straightforward by monitoring the near-field distributions of intensity and phase. The beam quality achieved with the MNBUR of an extremely low magnification of only 1.04 was rather poor but nevertheless in accordance with theory. The demonstrated consistency between theory and experiment makes the MNBUR an attractive candidate for lasers that allow for higher magnification. In particular, it promises high brilliance in application to 100 kW class COIL devices, superior to the conventional negative branch confocal unstable resonator.


Irritable Bowel Syndrome: A Clinical Review.
Symptoms of irritable bowel syndrome (IBS) are common in population studies including chronic abdominal pain associated with altered bowel habits. Patients often have associated gastrointestinal and somatic symptoms suggesting a possible common contributing mechanism, but the heterogeneous symptom patterns of individual patients make generalizations difficult. The pathophysiology of IBS is incompletely understood but includes disturbances of the brain-gut axis. Central mechanisms are: the psychosocial history and environment, dysfunctional brain processing of peripheral signals attributed to the intestine including the enteric nervous system, the microbiome and the innate and adaptive immune system. As a result there is visceral hypersensitivity and disturbed intestinal secretory and motor activity. Some mechanisms of visceral pain hypersensitivity may overlap with other pain syndromes including fibromyalgia (FMS). Central Sensitization (CS) would offer a way to conceptualize an integration of life experience and psychologic response into a biopsychosocial framework of pathophysiology, diagnosis and treatment of IBS. Corticotropin-releasing factor, a principle regulator in the stress and pain response may contribute to a neuroendocrine mechanism for the brain-gut interaction. The positive diagnostic approach to IBS symptoms to avoid excess testing and enhance the patient-provider therapeutic relationship requires the recognition of the "cluster" of IBS symptoms while identifying "alarm" symptoms requiring specific attention. The severity of the symptoms and other individual psychosocial factors characterize patients who seek medical care. The presence of significant psychosocial comorbidities adds to the complexity of management which often requires a multidisciplinary approach. Several treatment options exist but no single method is effective for all the symptoms of IBS. The therapeutic benefit of the well-executed physician-patient relationship is considered essential to success in managing IBS symptoms over the long term.


Evaluation of a pharmacist-managed anticoagulation clinic.
Medical records were retrospectively analyzed to evaluate the success of a pharmacist-managed Anticoagulation Surveillance Clinic (ASC). The 78 patients in group I were followed by the ASC. The 17 patients in Group II were followed by other Veterans Administration Medical Center clinics. Demographic characteristics, warfarin indication and potentially complicating conditions were comparable between the groups. Group I patients had shorter intervals between visits to the clinic than Group II patients. Although not statistically different compared to Group II, Group I patients had better prothrombin time control. Group I patients also had fewer complications per treatment year (6.9% vs 9.0%) and received fewer potentially interacting drugs. The ASC was at least as successful as the other clinics in managing patients on warfarin, and results compared very favorably to those reported in the literature for other anticoagulation clinics.


Matrix metalloproteinases in immunity.
Matrix metalloproteinases (MMPs) are a family of zinc-containing endo-proteinases that share structural domains but differ in substrate specificity, cellular sources, and inducibility. Macrophage production and secretion of large quantities of many MMPs, after contact with matrix proteins, is enhanced by surface determinants on activated T cells and suppressed by cytokines from Th1 and Th2 cells. T cells secrete predominantly the gelatinases MMP-2 and -9, after beta 1, integrin- or vascular cell adhesion molecule (VCAM)-1-dependent stimulation by cytokines and inflammatory mediators. MMPs of both T cells and macrophages facilitate secretion of TNF-alpha, by cleavage of the membrane-bound form. T cell MMPs prepare connective tissue matrices for T cell chemotaxis across basement membranes and through tissues. The greater amounts of diverse MMPs from macrophages are capable of degrading connective tissues, which may release stored growth factors. In limited studies of animal models of autoimmunity, specific MMP inhibitors have significantly decreased edema and inflammatory tissue damage, suggesting possible therapeutic benefits.


Challenges in understanding psychiatric disorders and developing therapeutics: a role for zebrafish.
The treatment of psychiatric disorders presents three major challenges to the research and clinical community: defining a genotype associated with a disorder, characterizing the molecular pathology of each disorder and developing new therapies. This Review addresses how cellular and animal systems can help to meet these challenges, with an emphasis on the role of the zebrafish. Genetic changes account for a large proportion of psychiatric disorders and, as gene variants that predispose to psychiatric disease are beginning to be identified in patients, these are tractable for study in cellular and animal systems. Defining cellular and molecular criteria associated with each disorder will help to uncover causal physiological changes in patients and will lead to more objective diagnostic criteria. These criteria should also define co-morbid pathologies within the nervous system or in other organ systems. The definition of genotypes and of any associated pathophysiology is integral to the development of new therapies. Cell culture-based approaches can address these challenges by identifying cellular pathology and by high-throughput screening of gene variants and potential therapeutics. Whole-animal systems can define the broadest function of disorder-associated gene variants and the organismal impact of candidate medications. Given its evolutionary conservation with humans and its experimental tractability, the zebrafish offers several advantages to psychiatric disorder research. These include assays ranging from molecular to behavioural, and capability for chemical screening. There is optimism that the multiple approaches discussed here will link together effectively to provide new diagnostics and treatments for psychiatric patients.


Denominator doesn't matter: standardizing healthcare-associated infection rates by bed days or device days.
To examine the impact on infection rates and hospital rank for catheter-associated urinary tract infection (CAUTI), central line-associated bloodstream infection (CLABSI), and ventilator-associated pneumonia (VAP) using device days and bed days as the denominator Retrospective survey from October 2010 to July 2013 SETTING: Veterans Health Administration medical centers providing acute medical and surgical care Patients admitted to 120 Veterans Health Administration medical centers reporting healthcare-associated infections We examined the importance of using device days and bed days as the denominator between infection rates and hospital rank for CAUTI, CLABSI, and VAP for each medical center. The relationship between device days and bed days as the denominator was assessed using a Pearson correlation, and changes in infection rates and device utilization were evaluated by an analysis of variance. A total of 7.9 million bed days were included. From 2011 to 2013, CAUTI decreased whether measured by device days (2.32 to 1.64, P=.001) or bed days (4.21 to 3.02, P=.006). CLABSI decreased when measured by bed days (1.67 to 1.19, P=.04). VAP rates and device utilization ratios for CAUTI, CLABSI, and VAP were not statistically different across time. Infection rates calculated with device days were strongly correlated with infection rates calculated with bed days (r=0.79-0.94, P<.001). Hospital relative performance measured by ordered rank was also strongly correlated for both denominators (r=0.82-0.96, P<.001). These findings suggest that device days and bed days are equally effective adjustment metrics for comparing healthcare-associated infection rates between hospitals in the setting of stable device utilization.


Generation of Recombinant Snakehead Rhabdovirus (SHRV) Expressing Artificial MicroRNA Targeting Spring Viremia of Carp Virus (SVCV) P Gene and In Vivo Therapeutic Use Against SVCV Infection.
Spring viremia of carp virus (SVCV) is a highly lethal virus in common carp (Cyprinus carpio) and other cyprinid fish species. The aim of the present study was to develop an in vivo therapeutic measure against SVCV using artificial microRNA (AmiRNA) targeting the SVCV P gene transcript. Three candidates of AmiRNAs (AmiR-P1, -P2, and -P3) were selected, and their ability to downregulate SVCV P gene transcript was analyzed by both synthesized AmiRNA mimics and AmiRNA-expressing vector system, in which AmiR-P3 showed the strongest inhibitory activity among the three candidates. To overcome in vivo limitation of miRNA mimics or plasmid-based miRNA expression systems, we rescued recombinant snakehead rhabdoviruses (SHRVs) expressing SVCV P gene-targeting AmiRNA (rSHRV-AmiR-P3) or control AmiRNA (rSHRV-AmiR-C) using reverse genetic technology. The successful expression of AmiR-P3 and AmiR-C in cells infected with the rescued viruses was verified by quantitative PCR. To evaluate the availability of rSHRV-AmiR-P3 for in vivo control of SVCV, zebrafish (Danio rerio) were (i) infected with either rSHRV-AmiR-C or rSHRV-AmiR-P3 followed by SVCV infection or (ii) infected with SVCV followed by either rSHRV-AmiR-C or rSHRV-AmiR-P3 infection. Fish infected with rSHRVs before and after SVCV infection showed significantly higher survival rates than fish infected with SVCV alone. There was no significant difference in survival rates between groups of fish infected with rSHRV-AmiR-C and rSHRV-AmiR-P3 before SVCV infection; however, fish infected with SVCV followed by infection with rSHRV-AmiR-P3 showed significantly higher survival rates than fish infected with rSHRV-AmiR-C. These results suggest that rSHRV-AmiR-P3 has therapeutic potential against SVCV in fish when administered after SVCV infection, and rSHRVs expressing artificial microRNAs targeting SVCV transcripts could be used as a tool to control SVCV infection in fish for a therapeutic purpose.


Detection of tissue harmonic motion induced by ultrasonic radiation force using pulse-echo ultrasound and Kalman filter.
A method using pulse echo ultrasound and the Kalman filter is developed for detecting submicron harmonic motion induced by ultrasonic radiation force. The method estimates the amplitude and phase of the motion at desired locations within a tissue region with high sensitivity. The harmonic motion generated by the ultrasound radiation force is expressed as extremely small oscillatory Doppler frequency shifts in the fast time (A-line) of ultrasound echoes, which are difficult to estimate. In slow time (repetitive ultrasound echoes) of the echoes, the motion also is presented as oscillatory phase shifts, from which the amplitude and phase of the harmonic motion can be estimated with the least mean squared error by Kalman filter. This technique can be used to estimate the traveling speed of a harmonic shear wave by tracking its phase changes during propagation. The shear wave propagation speed can be used to solve for the elasticity and viscosity of tissue as reported in our earlier study. Validation and in vitro experiments indicate that the method provides excellent estimations for very small (submicron) harmonic vibrations and has potential for noninvasive and quantitative stiffness measurements of tissues such as artery.


[Effect of diet overloaded by fats on the enzyme systems of metabolism in rats].
The feeding of rats with high-fat diet (a part of fats was 50% of energy value of ration against 20% in control) during 4 weeks increased the level of cytochrome P-450 in the liver and enhanced aniline- and p-nitrophenol hydroxylase activity of CYP2E1 as well as erythromycin N-demethylase activity of CYP3A; the activity of aldehyde dehydrogenase class 3, UDP-glucuronosyl transferase, glutathione-S-transferase and N-acetyl transferase. At the same time, the moderate decrease of indomethacin-O-demethylase of CYP2C both phenolsulfotransferase activity were fixed. The changes of enzymatic activity correlated with activating of processes of gluconeogenesis, glycogenolysis and, especially, ketogenesis. A high-fat diet enhanced reactions of biotransformation of amidopyrine, acetanilide, toluene, sulfadimezine, were catalyzed with CYP2E1, CYP3A and enzymes of conjugation, simultaneously it increased the hepatotoxicity of paracetamol.


Atherosis revisited: current concepts on the pathophysiology of implantation site disorders.
There are two distinct histological manifestations of impaired placental implantation in humans--incomplete trophoblastic vascular invasion and atherosis. Both have been described to occur in pregnancies affected by a variety of disorders such as preeclampsia, fetal growth restriction, systemic lupus erythematosus, and diabetes. Our purpose was to integrate recent developments in the understanding of implantation site disorders into a pathophysiological scenario that interrelates these placentation disorders and associated pregnancy complications. Sources were identified from a MEDLINE search of English-language articles published from 1966 to 1997. Additional sources were identified from references cited in relevant reports. We selected articles relating to the following topics: atherosis, implantation site disorders, trophoblastic invasion, preeclampsia, fetal growth restriction, implantation site development, atherosclerosis, and endothelial activation-damage. A contemporary version of normal placentation, including vascular adaptation, was reviewed with comments on normal trophoblastic differentiation and vascular invasion. Specific abnormalities of the implantation site, including atherosis and incomplete trophoblastic invasion, were discussed in the context of placental site hypoperfusion and the association with pregnancy complications. It was concluded that atherosis and incomplete trophoblastic invasion may be both a consequence and a cause of placental site hypoperfusion resulting in the development of preeclampsia and a variety of other pregnancy disorders.


Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia.
As more pediatric patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) survive, comparison of the late effects of various therapies becomes increasingly important. This study of survivors of AML is the largest to date comparing the late effects of patients treated with chemotherapy (CT) with or without irradiation (RT) or CT followed by bone marrow transplantation (BMT). In a retrospective review of 228 patients with AML or MDS from 1970 to 1995, 62 survived and had follow-up data available more than 1 year following completion of therapy. Ten patients with Down syndrome were excluded. Twenty-six received CT and 26 underwent BMT. Weight and height Z scores, endocrine, ophthalmologic, renal, and cardiac function following CT +/- RT or BMT +/- total body irradiation (TBI) were compared at a mean follow-up of 7.4 and 5.6 years, respectively. Both groups experienced a decrement in height and increase in weight. The mean height Z score in the CT group fell from -0.29 to -0.72 (P = 0.02) and mean weight Z score rose from -0.06 at diagnosis (T0) to 0.51 at last follow-up (T2) (P = 0.02), a finding no longer significant when patients who received RT were excluded. The mean height Z score in the BMT group fell from -0.17 at TO to -0.65 at T2 (P = 0.02), while the mean weight rose from 0.29 at T0 to 0.84 at T2, (P = 0.07). Six of 9 BMT adolescent girls experienced ovarian failure versus 0 of 11 girls treated with CT (P = 0.002). Seven adolescent CT males and seven BMT males showed normal pubertal progression. Two BMT patients require thyroid hormone supplementation, and one receives growth hormone. Six BMT patients and one CT patient developed cataracts, all of whom received irradiation (P = 0.10). Serum creatinine level, hypertension, or left ventricular shortening fraction were not different in the two groups. One BMT patient has chronic graft versus host disease. Growth, renal, and cardiac functions were similar in the two groups. The need for estrogen supplementation was more frequent following BMT. Recommendations concerning therapy for AML should depend on the probability of cure.


Predicting Disease Recurrence, Early Progression, and Overall Survival Following Surgical Resection for High-risk Localized and Locally Advanced Renal Cell Carcinoma.
Risk stratification for localized renal cell carcinoma (RCC) relies heavily on retrospective models, limiting their generalizability to contemporary cohorts. To introduce a contemporary RCC prognostic model, developed using prospective, highly annotated data from a phase III adjuvant trial. The model utilizes outcome data from the ECOG-ACRIN 2805 (ASSURE) RCC trial. The primary outcome for the model is disease-free survival (DFS), with overall survival (OS) and early disease progression (EDP) as secondary outcomes. Model performance was assessed using discrimination and calibration tests. A total of 1735 patients were included in the analysis, with 887 DFS events occurring over a median follow-up of 9.6 yr. Five common tumor variables (histology, size, grade, tumor necrosis, and nodal involvement) were included in each model. Tumor histology was the single most powerful predictor for each model outcome. The C-statistics at 1 yr were 78.4% and 81.9% for DFS and OS, respectively. Degradation of the DFS, DFS validation set, and OS model's discriminatory ability was seen over time, with a global c-index of 68.0% (95% confidence interval or CI [65.5, 70.4]), 68.6% [65.1%, 72.2%], and 69.4% (95% CI [66.9%, 71.9%], respectively. The EDP model had a c-index of 75.1% (95% CI [71.3, 79.0]). We introduce a contemporary RCC recurrence model built and internally validated using prospective and highly annotated data from a clinical trial. Performance characteristics of the current model exceed available prognostic models with the added benefit of being histology inclusive and TNM agnostic. Important decisions, including treatment protocols, clinical trial eligibility, and life planning, rest on our ability to predict cancer outcomes accurately. Here, we introduce a contemporary renal cell carcinoma prognostic model leveraging high-quality data from a clinical trial. The current model predicts three outcome measures commonly utilized in clinical practice and exceeds the predictive ability of available prognostic models.


[Gastric necrosis caused by acute gastric dilatation. Total gastrectomy. Recovery].
Acute gastric dilatation, a rare affection, has multiple origins. An episode of bulimia following a fast in relation to an anorexia nervosa is one of the classical causes of its onset. Diagnosis is by radiology and should be made urgently before instituting medical treatment combining aspiration and effective intensive care measures. Recovery is the general rule. The formation of an infarct and gastric perforation are complications of delayed diagnosis and are of extreme gravity, leading to a fatal outcome in more than 80% of cases. In the case reported, recovery was obtained by emergency total gastrectomy for global gastric infarction. Perioperative fibroscopy is the essential key to the choice between temporary esophageal exclusion or immediate re-establishment of digestive continuity.


Instrumentation of Stratospheric Balloon Straps with Optical Fibre for Temperature and Strain Monitoring.
This article is devoted to the instrumentation, with optical fibres, of the straps holding the envelope of stratospheric balloons. This instrumentation is motivated in the first instance by the need to validate the numerical models used in the design of balloons. It must also be used to measure the temperature along the envelope in order to deduce the pressure field. It is shown at first that the optical fibres can be inserted inside a strap during its fabrication. Different kinds of insertion are considered, none of them perturb the industrial process. The instrumented straps were then submitted to thermal and mechanical tests and the distributed Brillouin frequency shifts were measured. We thus determined the type of insertion to be used according to the parameter (temperature or strain) to be measured and assessed the performance of the measurement chain.


Regulation of NuA4 histone acetyltransferase activity in transcription and DNA repair by phosphorylation of histone H4.
The NuA4 complex is a histone H4/H2A acetyltransferase involved in transcription and DNA repair. While histone acetylation is important in many processes, it has become increasingly clear that additional histone modifications also play a crucial interrelated role. To understand how NuA4 action is regulated, we tested various H4 tail peptides harboring known modifications in HAT assays. While dimethylation at arginine 3 (R3M) had little effect on NuA4 activity, phosphorylation of serine 1 (S1P) strongly decreased the ability of the complex to acetylate H4 peptides. However, R3M in combination with S1P alleviates the repression of NuA4 activity. Chromatin from cells treated with DNA damage-inducing agents shows an increase in phosphorylation of serine 1 and a concomitant decrease in H4 acetylation. We found that casein kinase 2 phosphorylates histone H4 and associates with the Rpd3 deacetylase complex, demonstrating a physical connection between phosphorylation of serine 1 and unacetylated H4 tails. Chromatin immunoprecipitation experiments also link local phosphorylation of H4 with its deacetylation, during both transcription and DNA repair. Time course chromatin immunoprecipitation data support a model in which histone H4 phosphorylation occurs after NuA4 action during double-strand break repair at the step of chromatin restoration and deacetylation. These findings demonstrate that H4 phospho-serine 1 regulates chromatin acetylation by the NuA4 complex and that this process is important for normal gene expression and DNA repair.


Effect of routinely assessing and addressing depression and diabetes distress using patient-reported outcome measures in improving outcomes among adults with type 2 diabetes: a systematic review protocol.
Type 2 diabetes is a global health priority. People with diabetes are more likely to experience mental health problems relative to people without diabetes. Diabetes guidelines recommend assessment of depression and diabetes distress during diabetes care. This systematic review will examine the effect of routinely assessing and addressing depression and diabetes distress using patient-reported outcome measures in improving outcomes among adults with type 2 diabetes. MEDLINE, Embase, CINAHL Complete, PsycInfo, The Cochrane Library and Cochrane Central Register of Controlled Trials will be searched using a prespecified strategy using a prespecified Population, Intervention, Comparator, Outcomes, Setting and study design strategy. The date range of the search of all databases will be from inception to 3 August 2020. Randomised controlled trials, interrupted time-series studies, prospective and retrospective cohort studies, case-control studies and analytical cross-sectional studies published in peer-reviewed journals in the English language will be included. Two review authors will independently screen abstracts and full texts with disagreements resolved by a third reviewer, if required, using Covidence software. Two reviewers will undertake risk of bias assessment using checklists appropriate to study design. Data will be extracted using prespecified template. A narrative synthesis will be conducted, with a meta-analysis, if appropriate. Ethics approval is not required for this review of published studies. Presentation of results will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidance. Findings will be disseminated via peer-reviewed publication and conference presentations. CRD42020200246.


Differences in telomerase activity between colon and rectal cancer.
Colorectal cancer is one of the most common cancers and the third leading cause of cancer death in both sexes. The disease progresses as a multistep process and is associated with genetic alterations. One of the characteristic features of cancer is telomerase activation. We sought to evaluate the differences in telomerase activity between colon cancer and adjacent normal tissue and to correlate the differences in telomerase activity between different locations with clinicopathological factors and survival. Matched colon tumour samples and adjacent normal mucosa samples 10 cm away from the tumour were collected during colectomy. We assessed telomerase activity using real time polymerase chain reaction. Several pathological characteristics of tumours, including p53, Ki-67, p21, bcl2 and MLH1 expression were also studied. We collected samples from 49 patients. There was a significantly higher telomerase activity in colon cancer tissue than normal tissue. Adenocarcinomas of the right colon express significantly higher telomerase than left-side cancers. Colon cancers and their adjacent normal tissue had significantly more telomerase and were more positive to MLH1 than rectal cancers. The expression of p53 negatively correlated to telomerase activity and was linked to better patient survival. Colon and rectal cancers seem to have different telomerase and MLH1 profiles, and this could be another factor for their different biologic and clinical behaviour and progression. These results support the idea that the large bowel cannot be considered a uniform organ, at least in the biology of cancer.


Rituximab in psoriatic arthritis: an exploratory evaluation.
Current therapies for psoriatic arthritis (PsA) comprise synthetic drugs and tumour necrosis factor inhibitors. In contrast, other biologicals including rituximab (RTX) are available for treating rheumatoid arthritis (RA). RTX is effective in autoantibody positive RA patients, although some efficacy has been reported in seronegative individuals. RTX has not yet been assessed in PsA. Therefore, an open label study of RTX in PsA was performed. Nine patients with PsA and 14 with RA received RTX at 1000 mg twice within 14 days and were evaluated over 6 months. A PsA response criteria response was attained in 56% of patients. DAS28 improved from 6.2 to 4.9 (medians) in PsA and 6.4 to 5.2 in RA, and Health Assessment Questionnaire from 1.5 to 1.0 and from 2.1 to 1.4, respectively (all p≤0.05). Disease Activity index for PSoriatic Arthritis changed from 52.0 to 32.5 (p<0.05); C reactive protein and Psoriasis Area and Severity Index did not change significantly. RTX was tolerated well. In this exploratory open study, RTX exhibited significant efficacy in PsA patients with long-standing disease. Thus, RTX may have efficacy in PsA warranting a randomised controlled clinical trial.


Intersection of race-ethnicity and gender in depression care: screening, access, and minimally adequate treatment.
This study examined the interaction of race-ethnicity and gender in depression screening, receipt of any mental health care, and receipt of adequate care. Data from electronic health records (2010-2012) of adult primary care patients from a New England urban health care system were used (N=65,079). Multivariate logit regression models were estimated to assess associations between race-ethnicity, gender, and other covariates and depression screening, any depression care among those with a positive screen, and adequate depression care. To measure disparities in utilization, we controlled for need variables but not for non-need variables, including insurance, marital status, and socioeconomic status. Among males and females, blacks and Asians were less likely and Latinos were more likely to be screened for depression compared with whites. Among those with moderate or severe depression, black males and females, Latino males, and Asian males and females were less likely than whites to receive any mental health care. The disparity in screening between blacks and whites was greater among females compared with males. The disparity between Latinos and whites in receipt of any mental health care and of adequate care was greater among males than females. This approach underscored the importance of identifying disparities at each step of depression care by both race-ethnicity and gender. Targeting certain groups in specific stages of care, for example, screening of black females or providing any mental health care and adequate care for Latino males, would be more effective than a blanket approach to disparities reduction.


Ultrabright NIR fluorescent mesoporous silica nanoparticles.
Near-infrared (NIR) water-dispersible fluorescent tags are of big importance for biomedical imaging. Bright, stable, biocompatible NIR fluorescent nanoparticles have great translation potential to improve diagnosis of early stages of different diseases. Here we report on the synthesis of exceptionally bright ("ultrabright") fluorescent meso(nano)porous silica nanoparticles of 28 ± 3 nm in diameter. The NIR fluorescent dye LS277 is encapsulated inside these silica nanoparticles. The wavelengths of the maximum excitation/fluorescence of the particles are 804/815 nm. The absorptivity coefficient of the particles is 2.1 × 108 M-1 cm-1 at 805 nm and the quantum yield of the dye increased by a factor of 5 after encapsulating to 1.5%. The fluorescent brightness of these particles is more than 2000× higher than the fluorescence of one molecule of LS277 in water. When exited in NIR spectral region (>700 nm), these particles are up to 4× brighter than QD800 commercial quantum dots emitting at 800 nm. We demonstrate that the synthesized NIR mesoporous silica nanoparticles easily internalize 4T1luc breast tumor cells, and remain bright for more than 9 weeks whereas the dye is completely bleached by that time.


Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease.
Mutations in complement factor H (HF1) gene have been reported in non-Shiga toxin-associated and diarrhoea-negative haemolytic uraemic syndrome (D-HUS). We analysed the complete HF1 in 101 patients with HUS, in 32 with thrombotic thrombocytopenic purpura (TTP) and in 106 controls to evaluate the frequency of HF1 mutations, the clinical outcome in mutation and non-mutation carriers and the role of HF1 polymorphisms in the predisposition to HUS. We found 17 HF1 mutations (16 heterozygous, one homozygous) in 33 HUS patients. Thirteen mutations were located in exons XXII and XXIII. No TTP patient carried HF1 mutations. The disease manifested earlier and the mortality rate was higher in mutation carriers than in non-carriers. Kidney transplants invariably failed for disease recurrences in patients with HF1 mutations, while in non-mutated patients half of the grafts were functioning after 1 year. Three HF1 polymorphic variants were strongly associated with D-HUS: -257T (promoter region), 2089G (exonXIV, silent) and 2881T (963Asp, SCR16). The association was stronger in patients without HF1 mutations. Two or three disease-associated variants led to a higher risk of HUS than a single one. Analysis of available relatives of mutated patients revealed a penetrance of 50%. In 5/9 families the proband inherited the mutation from one parent and two disease-associated variants from the other, while unaffected carriers inherited the protective variants. In conclusion HF1 mutations are frequent in patients with D-HUS (24%). Common polymorphisms of HF1 may contribute to D-HUS manifestation in subjects with and without HF1 mutations.


Real-time probing of granular dynamics with magnetic resonance.
Granular dynamics govern earthquakes, avalanches, and landslides and are of fundamental importance in a variety of industries ranging from energy to pharmaceuticals to agriculture. Nonetheless, our understanding of the underlying physics is poor because we lack spatially and temporally resolved experimental measurements of internal grain motion. We introduce a magnetic resonance imaging methodology that provides internal granular velocity measurements that are four orders of magnitude faster compared to previous work. The technique is based on a concerted interplay of scan acceleration and materials engineering. Real-time probing of granular dynamics is explored in single- and two-phase systems, providing fresh insight into bubble dynamics and the propagation of shock waves upon impact of an intruder. We anticipate that the methodology outlined here will enable advances in understanding the propagation of seismic activity, the jamming transition, or the rheology and dynamics of dense suspensions.