Focused Metabolism of β-Glucans by the Soil Bacteroidetes Species Chitinophaga pinensis.
The genome and natural habitat of Chitinophaga pinensis suggest it has the ability to degrade a wide variety of carbohydrate-based biomass. Complementing our earlier investigations into the hydrolysis of some plant polysaccharides, we now show that C. pinensis can grow directly on spruce wood and on the fungal fruiting body. Growth was stronger on fungal material, although secreted enzyme activity was high in both cases, and all biomass-induced secretomes showed a predominance of β-glucanase activities. We therefore conducted a screen for growth on and hydrolysis of β-glucans isolated from different sources. Most noncrystalline β-glucans supported good growth, with variable efficiencies of polysaccharide deconstruction and oligosaccharide uptake, depending on the polysaccharide backbone linkage. In all cases, β-glucan was the only type of polysaccharide that was effectively hydrolyzed by secreted enzymes. This contrasts with the secretion of enzymes with a broad range of activities observed during growth on complex heteroglycans. Our findings imply a role for C. pinensis in the turnover of multiple types of biomass and suggest that the species may have two metabolic modes: a "scavenging mode," where multiple different types of glycan may be degraded, and a more "focused mode" of β-glucan metabolism. The significant accumulation of some types of β-gluco-oligosaccharides in growth media may be due to the lack of an appropriate transport mechanism, and we propose that this is due to the specificity of expressed polysaccharide utilization loci. We present a hypothetical model for β-glucan metabolism by C. pinensis that suggests the potential for nutrient sharing among the microbial litter community.IMPORTANCE It is well known that the forest litter layer is inhabited by a complex microbial community of bacteria and fungi. However, while the importance of fungi in the turnover of natural biomass is well established, the role of their bacterial counterparts is less extensively studied. We show that Chitinophaga pinensis, a prominent member of an important bacterial genus, is capable of using both plant and fungal biomass as a nutrient source but is particularly effective at deconstructing dead fungal material. The turnover of dead fungus is key in natural elemental cycles in the forest. We show that C. pinensis can perform extensive degradation of this material to support its own growth while also releasing sugars that may serve as nutrients for other microbial species. Our work adds detail to an increasingly complex picture of life among the environmental microbiota.


HIV-1 transmission, by stage of infection.
The epidemiological impact of public health interventions targeted at reducing transmission of human immunodeficiency virus type 1 (HIV-1) during early or late-stage infection depends on the contribution of these disease stages to transmission within a particular epidemic. Transmission hazards and durations of periods of high infectivity during primary, asymptomatic, and late-stage infection were estimated for HIV-1-serodiscordant heterosexual couples in Rakai, Uganda, by use of a robust probabilistic framework. Primary infection and late-stage infection were estimated to be 26 and 7 times, respectively, more infectious than asymptomatic infection. High infectiousness during primary infection was estimated to last for approximately 3 months after seroconversion, whereas high infectiousness during late-stage infection was estimated to be concentrated between 19 months and 10 months before death. Primary and late-stage HIV-1 infection are more infectious than previously estimated, but for shorter periods. In a homogeneous population, the asymptomatic stage of infection will typically contribute more to the net transmission of HIV-1 over the lifetime of an infected individual, because of its longer duration. The dependence of the relative contribution of infectious stages on patterns of sexual behavior and the phase of epidemics is discussed.


Control of muscle tone in the human colon.
Human colonic muscle tone varies diurnally and postprandially in predictable ways. Increased tone reduces the capacity of the colon to store contents after a meal, whereas increased distensibility (lesser tone) during sleep enlarges the storage capabilities and may slow transit. We tested the hypothesis that antidiarrhoeal drugs would also alter tone which, in turn, might reduce diarrhoea by facilitating the storage and salvage of fluids. Using a colonic barostat to create low pressure, isobaric colonic distension in healthy volunteers, we found that intravenous atropine (0.01 mg/kg) relaxed the colon during fasting, reduced the postprandial increase in tone, and enhanced relaxation in the late (1-2 hour) postprandial period. Intravenous morphine (0.1 mg/kg) caused variable effects soon after injection but, in fasting subjects, the descending colon relaxed 70-90 minutes after morphine. These changes in colonic motility were not always obvious by conventional manometric recording. Colonic distensibility is increased by antidiarrhoeal drugs and this effect may contribute to their efficacy in slowing colonic transit and augmenting absorption.


Studies with enteroaggregative Escherichia coli in the gnotobiotic piglet gastroenteritis model.
Two strains of enteroaggregative Escherichia coli of human origin fed to gnotobiotic piglets caused diarrhea or death in the majority of them. Histological examination revealed moderate hyperemia of the distal small intestine and cecum, swelling of small intestinal villi, and layers of aggregated bacteria stacked together in a mucus gel-like matrix overlying intact epithelium. These findings confirm that enteroaggregative E. coli strains produce distinctive intestinal lesions different from those caused by other major categories of diarrheagenic E. coli.


Maternal folic acid supplement use in early pregnancy and child behavioural problems: The Generation R Study.
Folate deficiency during embryogenesis is an established risk factor for neural tube defects in the fetus. An adequate folate nutritional status is also important for normal fetal growth and brain development. The aim of the present research was to study the association between folic acid use of the mother during pregnancy and child behavioural development. Within a population-based cohort, we prospectively assessed folic acid supplement use during the first trimester by questionnaire. Child behavioural and emotional problems were assessed with the Child Behaviour Checklist at the age of 18 months in 4214 toddlers. Results showed that children of mothers who did not use folic acid supplements in the first trimester had a higher risk of total problems (OR 1.44; 95 % CI 1.12, 1.86). Folic acid supplement use protected both from internalising (OR of no supplement use 1.65; 95 % CI 1.24, 2.19) and externalising problems (OR 1.45; 95 % CI 1.17, 1.80), even when adjusted for maternal characteristics. Birth weight and size of the fetal head did not mediate the association between folic acid use and child behaviour. In conclusion, inadequate use of folic acid supplements during early pregnancy may be associated with a higher risk of behavioural problems in the offspring. Folic acid supplementation in early pregnancy, aimed to prevent neural tube defects, may also reduce mental health problems in children.


Explaining primary care physicians' decision to quit patient-centered medical homes: Evidence from Quebec, Canada.
To examine the factors explaining primary care physicians' (PCPs) decision to leave patient-centered medical homes (PCMHs). Five-year longitudinal data on all the 906 PCPs who joined a PCMH in the Canadian province of Quebec, known there as a Family Medicine Group. We use fixed-effects and random-effects logit models, with a variety of regression specifications and various subsamples. In addition to these models, we examine the robustness of our results using survival analysis, one lag in the regressions and focusing on a matched sample of quitters and stayers. We extract information from Quebec's universal health insurer billing data on all the PCPs who joined a PCMH between 2003 and 2005, supplemented by information on their elderly and chronically ill patients. About 17 percent of PCPs leave PCMHs within 5 years of follow-up. Physicians' demographics have little influence. However, those with more complex patients and higher revenues are less likely to leave the medical homes. These findings are robust across a variety of specifications. As expected, higher revenue favors retention. Importantly, our results suggest that PCMH may provide appropriate support to physicians dealing with complex patients.


Pharmacokinetics of nelarabine and 9-beta-D-arabinofuranosyl guanine in pediatric and adult patients during a phase I study of nelarabine for the treatment of refractory hematologic malignancies.
To characterize the pharmacokinetics of nelarabine (506U78), the water-soluble prodrug of 9-beta-D-arabinofuranosyl guanine (ara-G), and ara-G in pediatric and adult patients with refractory hematologic malignancies. Ara-G is phosphorylated within leukemic cells to form ara-G triphosphate (ara-GTP), which acts to terminate DNA chain elongation, resulting in cell death. The pharmacokinetics of nelarabine and/or ara-G were evaluated in 71 patients (25 pediatric and 46 adult patients) on the first day of therapy. Blood was collected at specified times for the determination of plasma nelarabine and ara-G concentrations. There were no statistically significant differences in the pharmacokinetics of nelarabine between any of the groups of patients. The harmonic mean half-life (t1/2) of nelarabine in pediatric and adult patients was 14.1 minutes and 16.5 minutes, respectively. The maximum concentrations (C(max)) of ara-G occurred at or near the end of the nelarabine infusion. The C(max) of ara-G ranged from 11.6 micromol/L to 308.7 micromol/L at nelarabine doses of 5 to 75 mg/kg and was linearly related to the nelarabine dose. No statistically significant differences were noted for the pharmacokinetic parameter estimates of ara-G between adult male and female patients. In children versus adults, the dose-normalized C(max), time of the C(max), and the steady-state volume of distribution of ara-G were similar. However, the clearance of ara-G was higher in pediatric patients (0.312 L.h(-1).kg(-1)) as compared with adult patients (0. 213 L.h(-1).kg(-1)) (P <.001). The t1/2 of ara-G was shorter in pediatric patients as compared with adult patients (2.1 hours v 3.0 hours; P <.01). Nelarabine is an effective prodrug of ara-G, allowing systemic concentrations of ara-G that result in clinical activity.


Understanding the Potential Impact of Different Drug Properties on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission and Disease Burden: A Modelling Analysis.
The public health impact of the coronavirus disease 2019 (COVID-19) pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Using a mathematical model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care. The impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R = 1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalization) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Advances in the treatment of COVID-19 to date have been focused on hospitalized-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.


Plant-bacteria association and symbiosis: are there common genomic traits in alphaproteobacteria?
Alphaproteobacteria show a great versatility in adapting to a broad range of environments and lifestyles, with the association between bacteria and plants as one of the most intriguing, spanning from relatively unspecific nonsymbiotic association (as rhizospheric or endophytic strains) to the highly species-specific interaction of rhizobia. To shed some light on possible common genetic features in such a heterogeneous set of plant associations, the genomes of 92 Alphaproteobacteria strains were analyzed with a fuzzy orthologs-species detection approach. This showed that the different habitats and lifestyles of plant-associated bacteria (soil, plant colonizers, symbiont) are partially reflected by the trend to have larger genomes with respect to nonplant-associated species. A relatively large set of genes specific to symbiotic bacteria (73 orthologous groups) was found, with a remarkable presence of regulators, sugar transporters, metabolic enzymes, nodulation genes and several genes with unknown function that could be good candidates for further characterization. Interestingly, 15 orthologous groupspresent in all plant-associated bacteria (symbiotic and nonsymbiotic), but absent in nonplant-associated bacteria, were also found, whose functions were mainly related to regulation of gene expression and electron transport. Two of these orthologous groups were also detected in fully sequenced plant-associated Betaproteobacteria and Gammaproteobacteria. Overall these results lead us to hypothesize that plant-bacteria associations, though quite variable, are partially supported by a conserved set of unsuspected gene functions.


Immunity to placental malaria. III. Impairment of interleukin(IL)-12, not IL-18, and interferon-inducible protein-10 responses in the placental intervillous blood of human immunodeficiency virus/malaria-coinfected women.
Pregnant women are highly susceptible to malaria, and human immunodeficiency virus (HIV) infection increases this susceptibility. In our previous studies, placental malaria (PM), HIV infection, and HIV/PM coinfection were all associated with decreased interferon (IFN)-gamma production by maternal placental (intervillous) blood mononuclear cells (IVBMC). This study investigated whether in vitro production of the IFN-gamma regulatory cytokines interleukin (IL)-12 and IL-18 and the chemokine IFN-inducible protein (IP)-10 by IVBMC is altered in women who have been exposed to malaria and are infected with HIV. IL-12 production from IVBMC was significantly lower in HIV-positive women, regardless of PM status, in contrast to HIV-negative, PM-negative women. IL-18 and IP-10 production by IVBMC was reduced in HIV-positive, PM-negative women but elevated in HIV-positive, PM-positive women. These results reveal a substantial impairment of IL-12 production by IVBMC in HIV-positive women, implicating this cytokine as a potentially critical regulator of malaria antigen-specific IFN-gamma responses in HIV-infected and HIV/PM-coinfected women.


Chromatographic Detection of 8-Hydroxy-2'-Deoxyguanosine in Leukocytes of Asbestos Exposed Workers for Assessing Past and Recent Carcinogen Exposures.
Asbestos fibers include a group of silicate minerals that occur in the environment and are widely employed in occupational settings. Asbestos exposure has been associated to various chronic diseases; such as pulmonary fibrosis; mesothelioma; and lung cancer; often characterized by a long period of latency. Underlying mechanisms that are behind the carcinogenic effect of asbestos have not been fully clarified. Therefore; we have conducted an epidemiological study to evaluate the relationship between 8-hydroxy-2'-deoxyguanosine (8-oxodG), one of the most reliable biomarkers of oxidative stress and oxidative DNA damage; and asbestos exposure in the peripheral blood of residents in Tuscany and Liguria regions; Italy; stratified by occupational exposure to this carcinogen. Levels of 8-oxodG were expressed such as relative adduct labeling (RAL); the frequency of 8-oxodG per 105 deoxyguanosine was significantly higher among exposed workers with respect to the controls; i.e., 3.0 ± 0.2 Standard Error (SE) in asbestos workers versus a value of 1.3 ± 0.1 (SE) in unexposed controls (p < 0.001). When the relationship with occupational history was investigated; significant higher levels of 8-oxodG were measured in current and former asbestos workers vs. healthy controls; 3.1 ± 0.3 (SE) and 2.9 ± 0.2 (SE), respectively. After stratification for occupational history; a significant 194% excess of adducts was found in workers with 10 or more years of past asbestos exposure (p < 0.001). 8-oxodG can be used for medical surveillance programs of cohorts of workers with past and recent exposures to carcinogens for the identification of subjects requiring a more intense clinical surveillance.


Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats.
Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.


Endoscopic third ventriculostomy (ETV) for idiopathic normal pressure hydrocephalus (iNPH).
Idiopathic normal pressure hydrocephalus (iNPH) is a type of communicating hydrocephalus also known as non-obstructive hydrocephalus. This type of hydrocephalus is caused by impaired cerebrospinal fluid reabsorption without any obstruction in the ventricular system and is associated with normal cerebrospinal fluid pressure. It is characterised clinically by gait disturbance, cognitive dysfunction, and urinary incontinence (known as the Hakim-Adams triad). The exact cause of iNPH is unknown. It may be managed conservatively or treated surgically by inserting a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt. However, a substantial number of patients do not respond well to surgical treatment, complication rates are high and there is often a need for further surgery. Endoscopic third ventriculostomy (ETV) is an alternative surgical intervention. It has been suggested that ETV may lead to better outcomes, including fewer complications. To determine the effectiveness of ETV for treatment of patients with iNPH compared to conservative therapy, or shunting of CSF using VP or VA shunts.To assess the perioperative and postoperative complication rates in patients with iNPH after ETV compared to conservative therapy, VP or VA shunting. We searched for eligible studies using ALOIS: a comprehensive register of dementia studies, The Cochrane Central Register of Controlled Trials (CENTRAL) and several bibliographic databases such as MEDLINE (Ovid SP), EMBASE (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost) and LILACS (BIREME).We also searched the Database of Abstracts of Reviews of Effects (DARE) to identify potentially relevant reviews. The search strategy was adapted for other databases, using the most appropriate controlled vocabulary for each. We did not apply any language or time restrictions. The searches were performed in August 2014. We included randomised controlled trials (RCTs) of ETV treatment of iNPH. Patients had to have at least two symptoms of the Hakim-Adams triad. Exclusion criteria were obstructive causes of hydrocephalus, other significant intracranial pathology and other confirmed causes of dementia. The eligible comparators were conservative treatment or shunting using VP and VA shunts. Two review authors independently screened search results, selected eligible studies, assessed risk of bias and extracted data. We contacted trial authors for additional data. Only one study met the inclusion criteria: an RCT comparing effectiveness of ETV and non-programmable VP shunts in 42 patients with iNPH. The study was conducted in Brazil between 2009 and 2012. The overall study risk of bias was high. The primary outcome in the study was the proportion of patients with improved symptoms one year after surgery, determined as a change of at least two points on the Japanese NPH scale. Due to imprecision in the results, it was not possible to determine whether there was any difference between groups in the proportion of patients who improved 3 or 12 months after surgery (3 months: odds ration (OR) 1.12, 95% confidence interval (CI) 0.26 to 4.76, n = 42; 12 months: OR 2.5, 95% CI 0.62 to 10.11, n = 38). We were unable to estimate the effect of treatment on other efficacy outcomes (cognition, balance, function, gait and mobility) because they were inadequately reported. Of the 26 patients in the VP shunting group, 5 developed subdural hematoma postoperatively, while there were no complications among the 16 patients in the ETV group (OR 0.12, 95% CI 0.01 to 2.3, n = 42), but the estimate was too imprecise to determine whether this was likely to reflect a true difference in complication rates. This was also the case for rates of further surgical intervention (OR 1.4, 95% CI 0.31 to 6.24, n = 42). There were no deaths during the trial. We judged the quality of evidence for all outcomes to be very low because of a high risk of selection, attrition and reporting bias and serious imprecision in the results. The only randomised trial of ETV for iNPH compares it to an intervention which is not a standard practice (VP shunting using a non-programmable valve). The evidence from this study is inconclusive and of very low quality. Clinicians should be aware of the limitations of the evidence. There is a need for more robust research on this topic to be able to determine the effectiveness of ETV in patients with iNPH.


Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating.
We describe the isolation and characterization of Drosophila synaptojanin (synj) mutants. synj encodes a phosphatidylinositol phosphatase involved in clathrin-mediated endocytosis. We show that Synj is specifically localized to presynaptic terminals and is associated with synaptic vesicles. The electrophysiological and ultrastructural defects observed in synj mutants are strikingly similar to those found in endophilin mutants, and Synj and Endo colocalize and interact biochemically. Moreover, synj; endo double mutant synaptic terminals exhibit properties that are very similar to terminals of each single mutant, and overexpression of Endophilin can partially rescue the functional defects in partial loss-of-function synj mutants. Interestingly, Synj is mislocalized and destabilized at synapses devoid of Endophilin, suggesting that Endophilin recruits and stabilizes Synj on newly formed vesicles to promote vesicle uncoating. Our data also provide further evidence that kiss-and-run is able to maintain neurotransmitter release when synapses are not extensively challenged.


Extracting the Infrared Permittivity of SiO2 Substrates Locally by Near-Field Imaging of Phonon Polaritons in a van der Waals Crystal.
Layered materials in which individual atomic layers are bonded by weak van der Waals forces (vdW materials) constitute one of the most prominent platforms for materials research. Particularly, polar vdW crystals, such as hexagonal boron nitride (h-BN), alpha-molybdenum trioxide (α-MoO3) or alpha-vanadium pentoxide (α-V2O5), have received significant attention in nano-optics, since they support phonon polaritons (PhPs)-light coupled to lattice vibrations- with strong electromagnetic confinement and low optical losses. Recently, correlative far- and near-field studies of α-MoO3 have been demonstrated as an effective strategy to accurately extract the permittivity of this material. Here, we use this accurately characterized and low-loss polaritonic material to sense its local dielectric environment, namely silica (SiO2), one of the most widespread substrates in nanotechnology. By studying the propagation of PhPs on α-MoO3 flakes with different thicknesses laying on SiO2 substrates via near-field microscopy (s-SNOM), we extract locally the infrared permittivity of SiO2. Our work reveals PhPs nanoimaging as a versatile method for the quantitative characterization of the local optical properties of dielectric substrates, crucial for understanding and predicting the response of nanomaterials and for the future scalability of integrated nanophotonic devices.


First Report of Papaya Fruit Anthracnose Caused by Colletotrichum brevisporum in Brazil.
Papaya fruits (Carica papaya L.) (cv. Golden) showing post-harvest anthracnose symptoms were observed during surveys of papaya disease in northeastern Brazil from 2008 to 2012. Fruits affected by anthracnose showed sunken, prominent, dark brown to black lesions. Small pieces (4 to 5 mm) of necrotic tissue were surface sterilized for 1 min in 1.5% NaOCl, washed twice with sterile distilled water, and plated onto potato dextrose agar (PDA) amended with 0.5 g liter-1 streptomycin sulfate. Macroscopic colony characters and microscopic morphology characteristics of four isolates were observed after growth on PDA (2) for 7 days at 25°C under a 12-hr light/dark cycle. Colonies varied between colorless and pale brown in reverse, with orange conidial mass. Conidia were hyaline, aseptate, cylindrical with round ends, slightly flattened, smooth-walled, guttulate, and 13.5 (10.5 to 17.1) μm × 3.8 (2.1 to 4.8) μm (l/w ratio = 3.5, n = 50), typical of Colletotrichum spp. DNA sequencing of partial sequences of actin (ACT) gene and the internal transcribed spacer (ITS1-5.8S-ITS2 rRNA) were conducted to accurately identify the species. Sequences of the papaya isolates were 99% similar to those of Colletotrichum brevisporum (GenBank Accession Nos. JN050216, JN050217, JN050238, and JN050239). A phylogenetic analysis using Bayesian inference and including published ACT and ITS data for C. brevisporum and other Colletotrichum species was carried out (1). Based on morphological and molecular data, the papaya isolates were identified as C. brevisporum. Conidia of the papaya isolates were narrower than those described for C. brevisporum (2.9 to 4.8 μm and 5 to 6 μm, respectively) (1), which may be due to differences in incubation temperature or a typical variation in conidial size in Colletotrichum species (3). Sequences of the isolates obtained in this study are deposited in GenBank (ACT Accession Nos. KC702903, KC702904, KC702905, and KC702906; ITS Accession Nos. HM163181, HM015851, HM015854, and HM015859). Cultures are deposited in the Culture Collection of Phytopathogenic Fungi of the Universidade Federal Rural de Pernambuco, Recife, Brazil (CMM 1672, CMM 1702, CMM 1822, and CMM 2005). Pathogenicity testing was conducted with all four strains of C. brevisporum on papaya fruits (cv. Golden). Fruits were wounded at the medium region by pushing the tip of four sterile pins through the surface of the skin to a depth of 3 mm. Mycelial plugs taken from the margin of actively growing colonies (PDA) of each isolate were placed in shallow wounds. PDA discs without fungal growth were used as control. Inoculated fruits were maintained in a humid chamber for 2 days at 25°C in the dark. After 6 days, anthracnose symptoms developed that were typical of diseased fruit in the field. C. brevisporum was successfully reisolated from symptomatic fruits to fulfill Koch's postulates. C. brevisporum was described from Neoregalia sp. and Pandanus pygmaeus in Thailand (1). To our knowledge, this is the first report of C. brevisporum in Brazil and the first report of this species causing papaya fruit anthracnose. References: (1) P. Noireung et al. Cryptogamie Mycol., 33:347, 2012. (2) B. C. Sutton. The Genus Glomerella and its anamorph Colletotrichum. CAB International, Wallingford, UK, 1992. (3) B. S. Weir et al. Stud. Mycol. 73:115, 2012.


Thyroid function after radiation and surgery for head and neck cancer.
Preoperative radiation followed by surgical excision is accepted therapy for head and neck cancer. The effects of these modalities on thyroid function were evaluated in a prospective study. Sixty-one patients were given cobalt 60 radiation. Results showed that 41 patients (67%) were euthyroid, 12 patients (20%) were clinically and chemically hypothyroid, and 8 patients (13%) had transient loss of thyroid reserve. Permanent hypothyroidism occurred frequently in patients with hemithyroidectomy, but rarely in those treated with radiation alone. Onset of hypothyroidism was zero to six months, with transient loss of thyroid reserve occurring up to 18 months. This constitutes the initial report of an ongoing systematic study of thyroid function in such patients. The high incidence of hypothyroidism indicates a need for careful periodic evaluation.


The worse the better? Quantile treatment effects of a conditional cash transfer programme on mental health.
Poor mental health is a pressing global health problem, with high prevalence among poor populations from low-income countries. Existing studies of conditional cash transfer (CCT) effects on mental health have found positive effects. However, there is a gap in the literature on population-wide effects of cash transfers on mental health and if and how these vary by the severity of mental illness. We use the Malawian Longitudinal Study of Family and Health containing 790 adult participants in the Malawi Incentive Programme, a year-long randomized controlled trial. We estimate average and distributional quantile treatment effects and we examine how these effects vary by gender, HIV status and usage of the cash transfer. We find that the cash transfer improves mental health on average by 0.1 of a standard deviation. The effect varies strongly along the mental health distribution, with a positive effect for individuals with worst mental health of about four times the size of the average effect. These improvements in mental health are associated with increases in consumption expenditures and expenditures related to economic productivity. Our results show that CCTs can improve adult mental health for the poor living in low-income countries, particularly those with the worst mental health.


High-resolution imaging of chemical and biological sites on living cells using peak force tapping atomic force microscopy.
Currently, there is a growing need for methods that can quantify and map the molecular interactions of biological samples, both with high-force sensitivity and high spatial resolution. Force-volume imaging is a valuable atomic force microscopy (AFM) modality for probing specific sites on biosurfaces. However, the low speed and poor spatial resolution of this method have severely hampered its widespread use in life science research. We use a novel AFM mode (i.e., peak force tapping with chemically functionalized tips) to probe the localization and interactions of chemical and biological sites on living cells at high speed and high resolution (8 min for 1 μm × 1 μm images at 512 pixels × 512 pixels). First, we demonstrate the ability of the method to quantify and image hydrophobic forces on organic surfaces and on microbial pathogens. Next, we detect single sensor proteins on yeast cells, and we unravel their mechanical properties in relation to cellular function. Owing to its key capabilities (quantitative mapping, resolution of a few nanometers, and true correlation with topography), this novel biochemically sensitive imaging technique is a powerful complement to other advanced AFM modes for quantitative, high-resolution bioimaging.


Assessment of the use of sialogogues in the clinical management of patients with xerostomia.
This study was conducted to assess the clinical efficacy and adverse effects of pilocarpine, bethanechol and cevimeline in patients with xerostomia. In this open-label crossover assessment in 20 patients with xerostomia, a one- to two-week course of each medication with a one-week washout period was prescribed. Side effects, symptoms, whole stimulated and unstimulated saliva were measured. Each sialogogue was found to increase saliva and decrease symptoms. A mixed-effects analysis showed a greater increase in stimulated saliva on bethanechol compared to pilocarpine (0.106, p = 0.0272). Increased sweating was the most common side effect, experienced more frequently with pilocarpine as compared to bethanechol (p = 0.0588) or cevimeline (p = 0.0143). A carryover effect beyond the washout period was seen. Effects on saliva and side effects vary between sialogogues, suggesting a benefit of trials with different sialogogues to determine individual patient preference. The observed carryover effect suggests that intermittent treatment may be an alternative to continuous treatment with sialogogues.


Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus.
In eukaryotes, the activation of mitotic cyclin-dependent kinases (CDKs) induces mitosis, and their inactivation causes cells to leave mitosis. In budding yeast, two redundant mechanisms induce the inactivation of mitotic CDKs. In one mechanism, a specialized ubiquitin-dependent proteolytic system (called the APC-dependent proteolysis machinery) degrades the mitotic (Clb) cyclin subunit. In the other, the kinase-inhibitor Sic1 binds to mitotic CDKs and inhibits their kinase activity. The highly conserved protein phosphatase Cdc14 promotes both Clb degradation and Sic1 accumulation. Cdc14 promotes SIC1 transcription and the stabilization of Sic1 protein by dephosphorylating Sicl and its transcription factor Swi5. Cdc14 activates the degradation of Clb cyclins by dephosphorylating the APC-specificity factor Cdh1. So how is Cdc14 regulated? Here we show that Cdc14 is sequestered in the nucleolus for most of the cell cycle. During nuclear division, Cdc14 is released from the nucleolus, allowing it to reach its targets. A highly conserved signalling cascade, critical for the exit from mitosis, is required for this movement of Cdc14 during anaphase. Furthermore, we have identified a negative regulator of Cdc14, Cfi1, that anchors Cdc14 in the nucleolus.


Ventriculoperitoneal shunt infection rates using a standard surgical technique, including topical and intraventricular vancomycin: the Children's Hospital Oakland experience.
Ventriculoperitoneal (VP) shunt infections are common complications after shunt operations. Despite the use of intravenous antibiotics, the incidence of infections remains high. Though antibiotic-impregnated catheters (AICs) are commonly used, another method of infection prophylaxis is the use of intraventricular (IVT) antibiotics. The authors describe their single-institution experience with a standard shunt protocol utilizing prophylactic IVT and topical vancomycin administration and report the incidence of pediatric shunt infections. Three hundred two patients undergoing VP shunt procedures with IVT and topical vancomycin between 2006 and 2016 were included. Patients were excluded if their age at surgery was greater than 18 years. Shunt operations were performed at a single institution following a standard shunt protocol implementing IVT and topical vancomycin. No AICs were used. Clinical data were retrospectively collected from the electronic health records. Over the 11-year study period, 593 VP shunt operations were performed with IVT and topical vancomycin, and a total of 19 infections occurred (incidence 3.2% per procedure). The majority of infections (n = 10, 52.6%) were caused by Staphylococcus epidermidis. The median time to shunt infection was 3.7 weeks. On multivariate analysis, the presence of a CSF leak (OR 31.5 [95% CI 8.8-112.6]) and age less than 6 months (OR 3.6 [95% CI 1.2-10.7]) were statistically significantly associated with the development of a shunt infection. A post hoc analysis comparing infection rates after procedures that adhered to the shunt protocol and those that did not administer IVT and topical vancomycin, plus historical controls, revealed a difference in infection rates (3.2% vs 6.9%, p = 0.03). The use of a standardized shunt operation technique that includes IVT and topical vancomycin is associated with a total shunt infection incidence of 3.2% per procedure, which compares favorably with the reported rates of shunt infection in the literature. The majority of infections occurred within 2 months of surgery and the most common causative organism was S. epidermidis. Young age (< 6 months) at the time of surgery and the presence of a postoperative CSF leak were statistically significantly associated with postoperative shunt infection on multivariate analysis. The results are hypothesis generating, and the authors propose that IVT and topical administration of vancomycin as part of a standardized shunt operation protocol may be an appropriate option for preventing pediatric shunt infections.


Solution aversion: On the relation between ideology and motivated disbelief.
There is often a curious distinction between what the scientific community and the general population believe to be true of dire scientific issues, and this skepticism tends to vary markedly across groups. For instance, in the case of climate change, Republicans (conservatives) are especially skeptical of the relevant science, particularly when they are compared with Democrats (liberals). What causes such radical group differences? We suggest, as have previous accounts, that this phenomenon is often motivated. However, the source of this motivation is not necessarily an aversion to the problem, per se, but an aversion to the solutions associated with the problem. This difference in underlying process holds important implications for understanding, predicting, and influencing motivated skepticism. In 4 studies, we tested this solution aversion explanation for why people are often so divided over evidence and why this divide often occurs so saliently across political party lines. Studies 1, 2, and 3-using correlational and experimental methodologies-demonstrated that Republicans' increased skepticism toward environmental sciences may be partly attributable to a conflict between specific ideological values and the most popularly discussed environmental solutions. Study 4 found that, in a different domain (crime), those holding a more liberal ideology (support for gun control) also show skepticism motivated by solution aversion.


Contributions of the hippocampal subfields and entorhinal cortex to disambiguation during working memory.
The hippocampus and medial temporal lobes (MTL) support the successful formation of new memories without succumbing to interference from related, older memories. Computational models and animal findings have implicated the dentate gyrus (DG), CA3, CA1, and entorhinal cortex (EC) in the disambiguation and encoding of well-established, episodic events that share common elements. However, it is unknown if these hippocampal subfields and MTL (entorhinal, perirhinal, parahippocampal) cortices also contribute during working memory when overlapping stimuli that share related features are rapidly encoded and subsequently maintained over a brief temporal delay. We hypothesized that activity in CA3/DG hippocampal subfields would be greater for the rapid encoding of stimuli with overlapping features than for the rapid encoding of stimuli with distinct features. In addition, we predicted that CA1 and EC, regions that are associated with creating long-term episodic representations, would show greater sustained activity across both encoding and delay periods for representations of stimuli with overlapping features than for those with distinct features. We used high-resolution fMRI during a delayed matching-to-sample (DMS) task using face pairs that either shared (overlapping condition, OL) or did not share (non-overlapping condition, NOL) common elements. We contrasted the OL condition with the NOL condition separately at sample (encoding) and during a brief delay (maintenance). At sample, we observed activity localized to CA3/DG, the subiculum, and CA1. At delay, we observed activity localized to the subiculum and CA1 and activity within the entorhinal, perirhinal, and parahippocampal cortices. Our findings are consistent with our hypotheses and suggest that CA3/DG, CA1 and the subiculum support the disambiguation and encoding of overlapping representations while CA1, subiculum and entorhinal cortex maintain these overlapping representations during working memory.


A comparison of antimicrobial susceptibility profile of urinary pathogens for the years, 1999 and 2003.
Urinary tract infection is a common condition worldwide; responsible for significant morbidity in both hospitalized and community patients. The laboratory records, for microbial isolates of infected urine and their susceptibility profiles for the years 1999 and 2003 were retrospectively reviewed and compared. In 2003, there was a significant decline in recovery ofCitrobacter spp compared to 1999. Conversely, the proportion of K pneumoniae, E coli and Enterococci increased dramatically in 2003, in both practices. For Proteus vulgaris and Proteus mirabilis, rates of isolation were increased in 2003, in hospital practice and community practice, respectively. Significant changes in antimicrobial susceptibility were also evident. A greater proportion of isolates from both practices were resistant to ampicillin, amoxicillin-clavulanic acid, cefuroxime, ceftazidime and cotrimoxazole in 2003 when compared to 1999. With respect to E coli, there were significant increases in prevalence of resistance to cefuroxime and amoxicillin-clavulanic acid. The overall resistance rate for norfloxacin remained relatively low and was unchanged for E coli. Continued surveillance of uropathogen resistance trends is important and this information should be communicated to clinicians. The feasibility of using the fluoroquinolones as a first line of therapy in urinary tract infection should be considered.


Strigolactone deficiency confers resistance in tomato line SL-ORT1 to the parasitic weeds Phelipanche and Orobanche spp.
The parasitic flowering plants of the genera Orobanche and Phelipanche (broomrape species) are obligatory chlorophyll-lacking root-parasitic weeds that infect dicotyledonous plants and cause heavy economic losses in a wide variety of plant species in warm-temperate and subtropical regions. One of the most effective strategies for broomrape control is crop breeding for broomrape resistance. Previous efforts to find natural broomrape-resistant tomato (Solanum lycopersicon) genotypes were unsuccessful, and no broomrape resistance was found in any wild tomato species. Recently, however, the fast-neutron-mutagenized tomato mutant SL-ORT1 was found to be highly resistant to various Phelipanche and Orobanche spp. Nevertheless, SL-ORT1 plants were parasitized by Phelipanche aegyptiaca if grown in pots together with the susceptible tomato cv. M-82. In the present study, no toxic activity or inhibition of Phelipanche seed germination could be detected in the SL-ORT1 root extracts. SL-ORT1 roots did not induce Phelipanche seed germination in pots but they were parasitized, at the same level as M-82, after application of the synthetic germination stimulant GR24 to the rhizosphere. Whereas liquid chromatography coupled to tandem mass spectrometry analysis of root exudates of M-82 revealed the presence of the strigolactones orobanchol, solanacol, and didehydro-orobanchol isomer, these compounds were not found in the exudates of SL-ORT1. It can be concluded that SL-ORT1 resistance results from its inability to produce and secrete natural germination stimulants to the rhizosphere.


An implementation science protocol of the Women's Health CoOp in healthcare settings in Cape Town, South Africa: A stepped-wedge design.
HIV persists as a public health emergency in South Africa, especially among women of childbearing age. In response to the HIV epidemic, the Joint United Nations Programme on HIV/AIDS has put forth the 90-90-90 global goals to achieve an AIDS-free generation by 2020. This goal aspires to have 90% of people living with HIV diagnosed; 90% of those who test positive on sustained antiretroviral therapy (ART); and 90% of those on ART be virally suppressed. Ensuring access to ART is an important first step in reducing HIV incidence, especially among vulnerable populations such as women who use substances and bear the burden of HIV in South Africa. Additionally, alcohol and other drug (AOD) use and exposure to gender-based violence are associated with increased risk of HIV infection and reduced adherence to ART. However, no research has estimated ART adherence rates for women who use substances in South Africa since the government approved the provision of ART to all people living with HIV. The Women's Health CoOp (WHC) is an evidence-based, woman-focused, behavioral intervention that addresses the intersecting risks of AODs, sex behaviors, and violence and victimization, with the primary goal of increasing skills and knowledge to reduce substance abuse and HIV risks and to improve ART adherence. The WHC has been packaged for further dissemination. This article describes the study protocol used to assess the feasibility and acceptability of implementing the WHC intervention into standard of care in Cape Town health clinics and substance abuse rehabilitation centers to reduce HIV risk behavior and increase ART adherence among women who use substances and are living with HIV. Because few of the interventions that demonstrate efficacy for HIV prevention and ART adherence in randomized trials are sustainable, studies to adapt and test intervention variations are needed to determine the best strategies for implementing them in real-world, high-risk settings. However, implementation in real-world settings presents challenges. Consequently, intervention developers should consider the strengths and limitations of their anticipated implementation setting by engaging with key stakeholders before, during, and after the adaptation and implementation process when developing and attempting to scale-up interventions. NCT 02733003 and date approved 1/21/2016.


Investigating the time course of spoken word recognition: electrophysiological evidence for the influences of phonological similarity.
Behavioral and modeling evidence suggests that words compete for recognition during auditory word identification, and that phonological similarity is a driving factor in this competition. The present study used event-related potentials (ERPs) to examine the temporal dynamics of different types of phonological competition (i.e., cohort and rhyme). ERPs were recorded during a novel picture-word matching task, where a target picture was followed by an auditory word that either matched the target (CONE-cone), or mismatched in one of three ways: rhyme (CONE-bone), cohort (CONE-comb), and unrelated (CONE-fox). Rhymes and cohorts differentially modulated two distinct ERP components, the phonological mismatch negativity and the N400, revealing the influences of prelexical and lexical processing components in speech recognition. Cohort mismatches resulted in late increased negativity in the N400, reflecting disambiguation of the later point of miscue and the combined influences of top-down expectations and misleading bottom-up phonological information on processing. In contrast, we observed a reduction in the N400 for rhyme mismatches, reflecting lexical activation of rhyme competitors. Moreover, the observed rhyme effects suggest that there is an interaction between phoneme-level and lexical-level information in the recognition of spoken words. The results support the theory that both levels of information are engaged in parallel during auditory word recognition in a way that permits both bottom-up and top-down competition effects.


Neurobehavioral functioning and survival following lung transplantation.
Neurobehavioral functioning is widely recognized as being an important consideration in lung transplant candidates, but little is known about whether these factors are related to clinical outcomes. The present study examined the relationship of neurobehavioral functioning, including measures of executive function and memory, depression, and anxiety, to long-term survival among lung transplant recipients. The sample was drawn from 201 patients who underwent transplantation at Duke University and Washington University who participated in a dual-site clinical trial investigating medical and psychosocial outcomes in transplant candidates with end-stage lung disease. All patients completed the Beck Depression Inventory-II (BDI-II) and Spielberger State-Trait Anxiety Inventory at baseline and again after 12 weeks, while a subset of 86 patients from Duke University also completed neurocognitive testing. Patients were followed for survival up to 12 years after completing baseline assessments. One hundred eleven patients died over a mean follow-up of 10.8 years (SD=0.8). Baseline depression, anxiety, and neurocognitive function were examined as predictors of posttransplant survival, controlling for age, 6-min walk distance, FEV, and native disease; education and cardiovascular risk factors were also included in the model for neurocognition. Lower executive function (hazard ratio [HR]=1.09, P=.012) and memory performance (HR=1.11, P=.030) were independently associated with greater mortality following lung transplant. Although pretransplant depression and anxiety were not predictive of mortality, patients who scored>13 on the BDI-II at baseline and after 3 months pretransplant had greater mortality (HR=1.85 [95% CI, 1.04, 3.28], P=.036). Neurobehavioral functioning, including persistently elevated depressive symptoms and lower neurocognitive performance, was associated with reduced survival after lung transplantation. ClinicalTrials.gov; No.: NCT00113139; URL: www.clinicaltrials.gov.


Topography of cerebellar deficits in humans.
The cerebellum is a key-piece for information processing and is involved in numerous motor and nonmotor activities, thanks to the anatomical characteristics of the circuitry, the enormous computational capabilities and the high connectivity to other brain areas. Despite its uniform cytoarchitecture, cerebellar circuitry is segregated into functional zones. This functional parcellation is driven by the connectivity and the anatomo-functional heterogeneity of the numerous extra-cerebellar structures linked to the cerebellum, principally brain cortices, precerebellar nuclei and spinal cord. Major insights into cerebellar functions have been gained with a detailed analysis of the cerebellar outputs, with the evidence that fundamental aspects of cerebrocerebellar operations are the closed-loop circuit and the predictions of future states. Cerebellar diseases result in disturbances of accuracy of movements and lack of coordination. The cerebellar syndrome includes combinations of oculomotor disturbances, dysarthria and other speech deficits, ataxia of limbs, ataxia of stance and gait, as well as often more subtle cognitive/behavioral impairments. Our understanding of the corresponding anatomo-functional maps for the human cerebellum is continuously improving. We summarize the topography of the clinical deficits observed in cerebellar patients and the growing evidence of a regional subdivision into motor, sensory, sensorimotor, cognitive and affective domains. The recently described topographic dichotomy motor versus nonmotor cerebellum based upon anatomical, functional and neuropsychological studies is also discussed.


Systematic global assessment of reef fish communities by the Reef Life Survey program.
The assessment of patterns in macroecology, including those most relevant to global biodiversity conservation, has been hampered by a lack of quantitative data collected in a consistent manner over the global scale. Global analyses of species' abundance data typically rely on records aggregated from multiple studies where different sampling methods and varying levels of taxonomic and spatial resolution have been applied. Here we describe the Reef Life Survey (RLS) reef fish dataset, which contains 134,759 abundance records, of 2,367 fish taxa, from 1,879 sites in coral and rocky reefs distributed worldwide. Data were systematically collected using standardized methods, offering new opportunities to assess broad-scale spatial patterns in community structure. The development of such a large dataset was made possible through contributions of investigators associated with science and conservation agencies worldwide, and the assistance of a team of over 100 recreational SCUBA divers, who undertook training in scientific techniques for underwater surveys and voluntarily contributed skills, expertise and their time to data collection.


Tattoos, piercing, and sexual behaviors in young adults.
Body piercing and tattooing are accepted by a growing number of teenagers and young adults as a way of self-expressing. Some authors suggest association between body piercings/tattoos and early sexual initiation, higher number of sexual partners, or risky sexual behaviors. The aim of the study was to evaluate sexual behaviors among young adults with body modifications (BMs)--tattoos and piercings. One hundred twenty young healthy adults, ages between 20 and 35, were included in the population study. The study group was divided into three subgroups: controls (N = 60), adults with tattoos (N = 28), and adults with piercings (N = 32). The research instrument was a self-prepared questionnaire containing 59 questions assessing socioepidemiological parameters, sexual behaviors, incidents of sexual harassment in the past, and self-attractiveness evaluation, as well as questions concerning tattoos and piercings. Socioepidemiological variables and sexual behaviors were compared between subgroups. To assess and describe the correlation between having BM--tattoos and piercing--and sexual behaviors in the population of young adults by using the logistic regression model. Adults with BMs have had their first intercourse statistically earlier and were more sexually active compared with controls. There were no statically significant differences in sexual orientation, sexual preferences, engaging in risky sexual behaviors, frequency of masturbation, and history of sexual abuse between the groups. In contrast, the frequency of sexual intercourses was statistically higher and oral sex was more likely to be a dominant sexual activity in adults with BM compared with controls. The multivariate logistic model revealed that adults with BM were four times less likely to participate in religious practices and twice more likely to have early sexual initiation. Having BM is associated with early sexual initiation and more liberal attitudes toward sexual behaviors but not with engaging in risky sexual behaviors.


Expanding the phenotype of DNAJC30-associated Leigh syndrome.
Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.


The steady-state assumption in oscillating and growing systems.
The steady-state assumption, which states that the production and consumption of metabolites inside the cell are balanced, is one of the key aspects that makes an efficient analysis of genome-scale metabolic networks possible. It can be motivated from two different perspectives. In the time-scales perspective, we use the fact that metabolism is much faster than other cellular processes such as gene expression. Hence, the steady-state assumption is derived as a quasi-steady-state approximation of the metabolism that adapts to the changing cellular conditions. In this article we focus on the second perspective, stating that on the long run no metabolite can accumulate or deplete. In contrast to the first perspective it is not immediately clear how this perspective can be captured mathematically and what assumptions are required to obtain the steady-state condition. By presenting a mathematical framework based on the second perspective we demonstrate that the assumption of steady-state also applies to oscillating and growing systems without requiring quasi-steady-state at any time point. However, we also show that the average concentrations may not be compatible with the average fluxes. In summary, we establish a mathematical foundation for the steady-state assumption for long time periods that justifies its successful use in many applications. Furthermore, this mathematical foundation also pinpoints unintuitive effects in the integration of metabolite concentrations using nonlinear constraints into steady-state models for long time periods.


Effects of supplemental β-carotene on mucosal IgA induction in the jejunum and ileum of mice after weaning.
An adequate immune system is required to prevent diarrhoea in neonates, and IgA provides protection against microbial antigens on mucosal surfaces. Although β-carotene supplementation has been expected to enhance the retinoic acid (RA)-mediated immune response in neonates, the exact mechanism of the enhancement of mucosal IgA production in the small intestine by β-carotene is still unclear. In the present study, we investigated the effect of supplemental β-carotene on the concentrations of IgA, the numbers of IgA antibody-secreting cells (ASC) and the mRNA expressions of IgA C-region, CCL25, retinoid X receptor (RXR) α, retinoic acid receptor (RAR) α and RARγ in the jejunum and ileum of weanling mice. Weanling mice were fed rodent feed or 50 mg/kg β-carotene-supplemented rodent feed for 7, 14 or 21 d. The concentrations of IgA and the numbers of IgA ASC in the jejunum and ileum of mice increased markedly with age, and supplemental β-carotene increased the concentrations of IgA, the numbers of IgA ASC and the mRNA expressions of IgA C-region, CCL25 and RARγ in the jejunum after 14 and 21 d of treatment. Supplemental β-carotene increased the numbers of IgA ASC in the ileum after 14 and 21 d of treatment, but the concentrations of IgA in the ileum were not affected by β-carotene supplementation. The mRNA expressions of RXRα and RARα in the jejunum and those of RXRα and RARγ in the ileum after 21 d of treatment were enhanced by β-carotene supplementation. These results indicate that β-carotene supplementation in weanling mice is effective to enhance mucosal IgA induction in the jejunum or ileum and that the effects are mainly due to the RA-mediated immune response.


Diagnostic value of a pancreatic mass on computed tomography in patients undergoing pancreatoduodenectomy for presumed pancreatic cancer.
Previous studies have shown that 5-14% of patients undergoing pancreatoduodenectomy for suspected malignancy ultimately are diagnosed with benign disease. A "pancreatic mass" on computed tomography (CT) is considered to be the strongest predictor of malignancy, but studies describing its diagnostic value are lacking. The aim of this study was to determine the diagnostic value of a pancreatic mass on CT in patients with presumed pancreatic cancer, as well as the interobserver agreement among radiologists and the additional value of reassessment by expert-radiologists. Reassessment of preoperative CT scans was performed within a previously described multicenter retrospective cohort study in 344 patients undergoing pancreatoduodenectomy for suspected malignancy (2003-2010). Preoperative CT scans were reassessed by 2 experienced abdominal radiologists separately and subsequently in a consensus meeting, after defining a pancreatic mass as "a measurable space occupying soft tissue density, except for an enlarged papilla or focal steatosis". CT scans of 86 patients with benign and 258 patients with (pre)malignant disease were reassessed. In 66% of patients a pancreatic mass was reported in the original CT report, versus 48% and 50% on reassessment by the 2 expert radiologists separately and 44% in consensus (P < .001 vs original report). Interobserver agreement between the original CT report and expert consensus was fair (kappa = 0.32, 95% confidence interval 0.23-0.42). Among both expert-radiologists agreement was moderate (kappa = 0.47, 95% confidence interval 0.38-0.56), with disagreement on the presence of a pancreatic mass in 29% of cases. The specificity for malignancy of pancreatic masses identified in expert consensus was twice as high compared with the original CT report (87% vs 42%, respectively). Positive predictive value increased to 98% after expert consensus, but negative predictive value was low (12%). Clinicians need to be aware of potential considerable disagreement among radiologists about the presence of a pancreatic mass. The specificity for malignancy doubled by expert radiologist reassessment when a uniform definition of "pancreatic mass" was used.


The combined presence of H pylori infection and gastro-oesophageal reflux disease leads to an up-regulation of CDX2 gene expression in antrum and cardia.
CDX2 is an epithelial transcription factor that regulates intestinal differentiation and is involved in the development of intestinal metaplasia (IM). To analyse the expression of CDX2 in the gastric mucosa in various locations and its relationship to Helicobacter pylori infection and gastro-oesophageal reflux disease (GORD). 69 patients with upper gastrointestinal symptoms were stratified into four groups according to their H pylori and GORD status. Patients without infection and without GORD were the reference group (H pylori(-)/GORD(-)). Biopsies from the antrum, corpus and cardia were assessed by histopathology according to the updated Sydney System. CDX2 transcription levels were determined by quantitative RT-PCR and immunohistochemistry. CDX2 gene expression was significantly up-regulated in antral and cardia mucosa of patients with both H pylori infection and GORD (26- and 100-fold, respectively; p<0.05), but remained unchanged in corpus mucosa. If only H pylori infection or GORD was present, CDX2 expression levels were 6- to 11-fold increased in the antrum, but without reaching statistical significance. CDX2 expression correlated positively with the degree of IM (p<0.01) and the degree of H pylori induced inflammation (p<0.05). Gene expression data were confirmed immunohistochemically by the detection of CDX2 in areas of IM and in focally distributed CDX2-expressing cells in non-metaplastic gastric mucosa. The combined presence of H pylori infection and GORD leads to an up-regulation of CDX2 gene expression in cardia and antral mucosa, but not in the corpus.


Development and implementation of a women's health promotion program: the Moms for Moms approach.
The Moms for Moms (M4M) program provides mothers the arena necessary to explore new ideas and definitions about mothering as well as skills and strategies concerning parenting, family management, and healthy habits. A participatory approach has been used to understand the development and implementation of the program from the perspective of the participants and community agency staff in an urban city. This approach provides detailed descriptions and interpretations of the shared beliefs, behaviors, and values of the participants as well as how these attributes are shaped by involvement in M4M. The findings from a needs assessment and program feasibility study conducted from August 2006 to June 2008 are used to inform a recently launched Healthy Lifestyles Initiative at a community-based agency for women, to determine if M4M fits within the culture of the organization and to determine the relevance of participatory methods to engage mothers and community agencies in creating health promotion programming.


Recommendations of the International Medical Informatics Association (IMIA) on Education in Biomedical and Health Informatics. First Revision.
Objective: The International Medical Informatics Association (IMIA) agreed on revising the existing international recommendations in health informatics/medical informatics education. These should help to establish courses, course tracks or even complete programs in this field, to further develop existing educational activities in the various nations and to support international initiatives concerning education in biomedical and health informatics (BMHI), particularly international activities in educating BMHI specialists and the sharing of courseware. Method: An IMIA task force, nominated in 2006, worked on updating the recommendations' first version. These updates have been broadly discussed and refined by members of IMIA's National Member Societies, IMIA's Academic Institutional Members and by members of IMIA's Working Group on Health and Medical Informatics Education. Results and Conclusions: The IMIA recommendations center on educational needs for health care professionals to acquire knowledge and skills in information processing and information and communication technology. The educational needs are described as a three-dimensional framework. The dimensions are: 1) professionals in health care (e.g. physicians, nurses, BMHI professionals), 2) type of specialization in BMHI (IT users, BMHI specialists), and 3) stage of career progression (bachelor, master, doctorate). Learning outcomes are defined in terms of knowledge and practical skills for health care professionals in their role a) as IT user and b) as BMHI specialist. Recommendations are given for courses/course tracks in BMHI as part of educational programs in medicine, nursing, health care management, dentistry, pharmacy, public health, health record administration, and informatics/computer science as well as for dedicated programs in BMHI (with bachelor, master or doctor degree). To support education in BMHI, IMIA offers to award a certificate for high-quality BMHI education. It supports information exchange on programs and courses in BMHI through its Working Group on Health and Medical Informatics Education.


Control of Listeria species food safety at a poultry food production facility.
Surveillance and control of food-borne human pathogens, such as Listeria monocytogenes, is a critical aspect of modern food safety programs at food production facilities. This study evaluated contamination patterns of Listeria species at a poultry food production facility, and evaluated the efficacy of procedures to control the contamination and transfer of the bacteria throughout the plant. The presence of Listeria species was studied along the production chain, including raw ingredients, food-contact, non-food-contact surfaces, and finished product. All isolates were sub-typed by pulsed-field gel electrophoresis (PFGE) to identify possible entry points for Listeria species into the production chain, as well as identifying possible transfer routes through the facility. The efficacy of selected in-house sanitizers against a sub-set of the isolates was evaluated. Of the 77 different PFGE-types identified, 10 were found among two or more of the five categories/areas (ingredients, food preparation, cooking and packing, bulk packing, and product), indicating potential transfer routes at the facility. One of the six sanitizers used was identified as unsuitable for control of Listeria species. Combining PFGE data, together with information on isolate location and timeframe, facilitated identification of a persistent Listeria species contamination that had colonized the facility, along with others that were transient.


The effectiveness of a monetary reimbursement model for weight reduction via a smartphone application: a preliminary retrospective study.
Weight loss for obese populations has been a challenging subject. There are numerous mobile applications to address weight loss, but the low retention rate is a barrier for the intervention. This is a retrospective study, aiming to investigate the effectiveness of financial incentives to achieve weight loss via a monetary reimbursement model on a smartphone application. Participants voluntarily purchased a 16-week mobile weight loss application program, and those who logged food intake three times a day received monetary reimbursement up to the full amount they initially paid. We analyzed health-related information and logged in-app activities from participants (N = 2,803) including age, sex, weight, food intake, and physical activity on their mobile healthcare application called Noom from January 2017 to April 2019. Analysis of covariance (ANCOVA) was used to compare differences between groups who succeeded and failed at food logging, controlling for baseline BMI. The ANCOVA found that participants who completed the food logging successfully for 16 weeks (N = 1,565) lost significantly more weight than those who failed food logging (N = 1,238, F = 56.0, p < 0.001). In addition, participants who were able to log their food intake successfully exercised more (F = 41.5, p < 0.001), read more in-app articles (F = 120.7, p < 0.001), and consumed more quantity of healthy foods (F = 12.8, p < 0.001). Monetary reimbursement is an effective tool for weight reduction by encouraging participants to monitor their health-related behaviors regularly.


Community mental health care in Europe--an overview.
Europe shares some historical roots of modern psychiatry. Even before the 19th century, there had been institutions for the mentally ill, such as the Bethlem in London which was founded more than 750 years ago, and organised forms of care in the community for people with mental illness, such as the tradition of family care in Geel in Belgium. Modern psychiatry, however, was initiated through the spirit of enlightenment and began around 1800. This beginning was marked by the symbolic cutting of the chains of mentally ill patients in Paris, the first publication of the term 'psychiatry' ("Psychiatric") in Germany in 1803, and the establishment of the retreat in York, England. The rise of modern psychiatry as a speciality of medicine was closely linked to the development of new institutions in both health care and academia. In the 19th century, various universities established chairs and academic departments of psychiatry, and large asylums for the mentally ill were built across Europe. The asylums were meant to replace the family as carriers for the material needs of patients--since many families could not fulfill that function in an industrialising society anymore--remove the mentally ill from the public scenes of urban life and provide a therapeutic environment.


Single-pill amlodipine/atorvastatin helps patients of diverse ethnicity attain recommended goals for blood pressure and lipids (the Gemini-AALA study).
The Gemini-AALA (Australia, Asia, Latin America, Africa/Middle East) study evaluated the efficacy and safety of single-pill amlodipine/atorvastatin (Caduet) for the treatment of patients of diverse ethnicity with concomitant hypertension and dyslipidaemia. This was a 14-week, open-label study including patients from 27 countries across the Middle East, Asia-Pacific, Africa and Latin America. Eight dosage strengths of single-pill amlodipine/atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80 and 10/80 mg) were titrated to improve blood pressure and lipid control. Blood pressure and lipid goals were determined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines, respectively (blood pressure, <140/90 or <130/80 mm Hg; low-density lipoprotein cholesterol (LDL-C), <4.1 to <2.6 mmol l(-1) (<160 to <100 mgdl(-1))). Overall, 1649 patients received study medication. Most patients (91.4%) had >or=1 cardiovascular risk factor (as defined by NCEP ATP III guidelines) in addition to hypertension/dyslipidaemia, and 61.7% had coronary heart disease/risk equivalent. At baseline, mean blood pressure was 146.6/88.3 mm Hg and LDL-C was 3.4 mmol l(-1) (130.2 mgdl(-1)). At week 14, 55.2% of patients reached both blood pressure and lipid goals, 61.3% reached blood pressure goal and 87.1% reached lipid goal (34.0% were at lipid goal at baseline). Mean blood pressure reduction was 20.2/11.4 mm Hg. For patients who were lipid-lowering drug naive at baseline, mean reduction in LDL-C was 41.0%. Treatment-related adverse events led to the discontinuation of 3.6% of patients. Single-pill amlodipine/atorvastatin therapy was well tolerated and effective for the reduction of blood pressure and lipids to recommended goals in patients from diverse ethnic backgrounds.


Pharmacological MRI in animal models: a useful tool for 5-HT research?
Pharmacological magnetic resonance imaging (phMRI) offers the potential to provide novel insights into the functioning of neurotransmitter systems and drug action in the central nervous system. To date, much of the neuropharmacological research that has applied phMRI techniques has focused on the dopaminergic system with relatively few studies into serotonergic function. In this article, we discuss the current capabilities of, and future potential for phMRI to address fundamental questions in serotonergic research using animal models. Firstly we review existing literature on the application of phMRI to the serotonergic system by exploring 3 broad research themes: (i) the functional anatomy of the serotonergic system; (ii) drug-receptor targeting and distribution; and (iii) disease models and drug development. Subsequently, we discuss the interpretation of phMRI data in terms of neuropharmacological action with a focus on issues specific to neuroimaging studies of the serotonergic system. Unlike other neuroimaging approaches such as positron emission tomography, phMRI methods do not currently offer sensitivity to markers of specific pharmacological action. However, they can provide in vivo markers of the neuropharmacological modulation of neuronal activity across the whole brain with unparalleled spatial and temporal resolution. Furthermore, due to the non-invasive nature of MRI, these markers are readily translatable to human studies. Whilst there are a number of constraints and limitations to phMRI methods that necessitate careful data interpretation, we argue that phMRI could become a valuable research tool in neuropharmacological studies of the serotonergic system.


Is type-D a stable construct? An examination of type-D personality in patients before and after cardiac surgery.
Type-D personality-negative affectivity and social inhibition-are related to poor prognosis in cardiovascular diseases. At present, little is known about type-D personality and its stability before and after cardiac surgery. One hundred twenty-six patients recommended for coronary bypass and/or valve surgery were examined at pre-surgery and 6 months post-surgery to investigate the stability of type-D (14-item Type-D Scale) and its relationship to anxiety, depression (Hospital Anxiety and Depression Scale) and quality of life (Short Form 12). Preoperatively, 26% were assessed to have type-D, while only 11% fulfilled type-D criteria both pre- and post-surgery. Patients were assessed and identified as belonging to one of the four type-D groups: Stable type-D (11%), non-type-D (61%), type-D pre (15%), and type-D post (13%). In comparison to the stable non-type D group, the stable type-D reported more symptoms of anxiety, depression, lower physical quality of life post-surgery, and lower mental quality of life both pre- and post-surgery. When compared to the population at large, stable type-D had more symptoms of depression pre-surgery, and more anxiety as well as lower physical and mental quality of life pre- and post-surgery. Type-D diagnosis changed in nearly 60% of the cases post-surgery. Only those patients with stable type-D exhibited a relationship to emotional distress, such as anxiety and depression and reduced quality of life. Additional research on the critical cut-off scores and stability of type-D as it relates to critical life events would likely enhance our ability to more effectively diagnose and treat patients who are at high risk for insufficient coping.


High throughput solid phase microextraction: A new alternative for analysis of cellular lipidome?
A new SPME method for untargeted lipidomic study of cell line cultures was proposed for the first time. In this study the feasibility to monitor changes in lipid profile after external stimuli was demonstrated and compared to the conventional Bligh & Dyer method. The human hepatocellular carcinoma (HCC) cell line was used as a model. The obtained results provided a list of up-regulated and down-regulated lipids through a comparison between control (non-stimulated) cells versus the group of cells treated with polyunsaturated fatty acid (20:5). Use of the SPME technique yielded a list of 77 lipid species whose concentrations were recognized to be significantly different between control and treated cells, from which 63 lipids were up-regulated in treated cells. In general, the list was comparable to the peer list obtained by the Bligh & Dyer method. However, more diversity of lipid classes and subclasses such as LPC, sphingomyelins, ceramides, and prenol lipids were observed with the application of the SPME method. Method precision for the SPME approach was within the acceptable analytical range (5-18% RSD) for all detected lipids, which was advantageous over solvent extraction applied. The evaluation of ionization efficiency indicated no matrix effect for the SPME technique, while Bligh & Dyer presented significant ionization suppression for low abundant species such as LysoPC, PG, ceramides, and sphingomyelins, and ionization enhancement for high abundant phospholipids such as PE.


Integration of social cues and individual experiences during instrumental avoidance learning.
Learning to avoid harmful consequences can be a costly trial-and-error process. In such situations, social information can be leveraged to improve individual learning outcomes. Here, we investigated how participants used their own experiences and others' social cues to avoid harm. Participants made repeated choices between harmful and safe options, each with different probabilities of generating shocks, while also seeing the image of a social partner. Some partners made predictive gaze cues towards the harmful choice option while others cued an option at random, and did so using neutral or fearful facial expressions. We tested how learned social information about partner reliability transferred across contexts by letting participants encounter the same partner in multiple trial blocks while facing novel choice options. Participants' decisions were best explained by a reinforcement learning model that independently learned the probabilities of options being safe and of partners being reliable and combined these combined these estimates to generate choices. Advice from partners making a fearful facial expression influenced participants' decisions more than advice from partners with neutral expressions. Our results showed that participants made better decisions when facing predictive partners and that they cached and transferred partner reliability estimates into new blocks. Using simulations we show that participants' transfer of social information into novel contexts is better adapted to variable social environments where social partners may change their cuing strategy or become untrustworthy. Finally, we found no relation between autism questionnaire scores and performance in our task, but do find autism trait related differences in learning rate parameters.


Plasmodium falciparum sexual parasites develop in human erythroblasts and affect erythropoiesis.
Plasmodium falciparum gametocytes, the sexual stage responsible for malaria parasite transmission from humans to mosquitoes, are key targets for malaria elimination. Immature gametocytes develop in the human bone marrow parenchyma, where they accumulate around erythroblastic islands. Notably though, the interactions between gametocytes and this hematopoietic niche have not been investigated. Here, we identify late erythroblasts as a new host cell for P falciparum sexual stages and show that gametocytes can fully develop inside these nucleated cells in vitro and in vivo, leading to infectious mature gametocytes within reticulocytes. Strikingly, we found that infection of erythroblasts by gametocytes and parasite-derived extracellular vesicles delay erythroid differentiation, thereby allowing gametocyte maturation to coincide with the release of their host cell from the bone marrow. Taken together, our findings highlight new mechanisms that are pivotal for the maintenance of immature gametocytes in the bone marrow and provide further insights on how Plasmodium parasites interfere with erythropoiesis and contribute to anemia in malaria patients.


Protection of stromal cell-derived factor 2 by heat shock protein 72 prevents oxaliplatin-induced cell death in oxaliplatin-resistant human gastric cancer cells.
Heat shock protein 72 (Hsp72) is a molecular chaperone that assists in the folding of nascent polypeptides and in the refolding of denatured proteins. In many cancers, Hsp72 is constitutively expressed at elevated levels, which can result in enhanced stress tolerance. Similarly, following treatment with anticancer drugs, Hsp72 binds to denatured proteins that may be essential for survival. We therefore hypothesized that Hsp72 client proteins may play a crucial role in drug resistance. Here, we aimed to identify proteins that are critical for oxaliplatin (OXA) resistance by analyzing human gastric cancer cell lines, as well as OXA-resistant cells via a mass spectrometry-based proteomic approach combined with affinity purification using anti-Hsp72 antibodies. Stromal cell-derived factor 2 (SDF-2) was identified as an Hsp72 client protein unique to OCUM-2M/OXA cells. SDF-2 was overexpressed in OXA-resistant cells and SDF-2 silencing promoted the apoptotic effects of OXA. Furthermore, Hsp72 prevented SDF-2 degradation in a chaperone activity-dependent manner. Together, our data demonstrate that Hsp72 protected SDF-2 to avoid OXA-induced cell death. We propose that inhibition of SDF-2 may comprise a novel therapeutic strategy to counteract OXA-resistant cancers.


Substrate-Borne Marking in the Parasitoid Wasp Urolepis rufipes (Hymenoptera: Pteromalidae).
Many animals use pheromone marking as a way to identify their territory or other resources. Among insects, substrate-borne marking is frequently reported for females, which in many species make marks containing oviposition-deterring pheromone, which other females avoid. However, there are fewer reports of substrate-borne marking for males. Here, marking in males of the parasitoid wasp Urolepis rufipes (Ashmead) is described. The conditions under which males mark and whether males and females respond to the males' marks were examined using behavioral observations. Males marked by dragging the tips of their abdomens across a substrate. They marked much more after mating and after consuming honey. They also marked more when with a female, irrespective of copulation, although not when with a male. Females spent more time on or near marked substrates, and males also responded to their own marks. Although males aggressively and successfully defended areas that they had marked against other males, males did not respond to another male's marks in the conspecific's absence. In contrast to males, females did not mark, either on the surface of hosts or on other surfaces, and males showed no detectable response to surfaces which females had recently occupied.


Acute effects of lysergic acid diethylamide (LSD) on resting brain function.
Lysergic acid diethylamide (LSD) is a potent hallucinogenic substance that was extensively investigated by psychiatrists during the 1950s and 1960s. Researchers were interested in the unique effects induced by this substance, some of which resemble symptoms seen in schizophrenia. Moreover, during that period LSD was studied and used for the treatment of several mental disorders such as depression, anxiety, addiction and personality disorders. Despite this long history of research, how LSD induces its specific effects on a neuronal level has been relatively unclear. In recent years there has been a revival of research in hallucinogenic drugs and their possible clinical applications. These contemporary studies in the UK and Switzerland include neuroimaging studies using functional magnetic resonance imaging (fMRI). In this review, we collect and interpret these recent neuroimaging findings. Overall, previous results across studies indicate that LSD administration is associated with extensive alterations in functional brain connectivity, measuring the correlated activities between different brain regions. The studies mostly reported increases in connectivity between regions and, more specifically, consistently found increased connectivity within the thalamocortical system. These latter observations are in agreement with models proposing that hallucinogenic drugs exert their effects by inhibiting cerebral filtering of external and internal data. However, studies also face several limitations, including potential biases of neuroimaging measurements.


Transoral thyroidectomy: why is it needed?
Transoral thyroidectomy (TOT) represents reasonably the desirable minimally invasive approach to the gland due to the scarless non-visible incisions, the limited distance between the gland and the access that minimize tissue dissection and respect of the surgical anatomical planes. Patients are routinely selected according to an extensive inclusion criteria: (I) ultrasonographically (US) estimated thyroid diameter not larger than 10 cm; (II) US gland volume ≤45 mL; (III) nodule size ≤50 mm; (IV) a benign tumor, such as a thyroid cyst, single-nodular goiter, or multinodular goiter; (V) follicular neoplasm; (VI) papillary microcarcinoma without lymph node metastasis. The operation is realized through median, central approach which allows bilateral exploration of the thyroid gland and central compartment. TOT is succeed both endoscopically adopting ordinary endoscopic equipments or robotically. In detail three ports are placed at the inferior oral vestibule: one 10-mm port for 30° endoscope and two 5-mm ports for dissecting, coagulating and neuromonitoring instruments. Low CO2 insufflation pressure is set at 6 mmHg. An anterior cervical subplatysmal space is created from the oral vestibule down to the sternal notch, laterally to the sterncleidomuscles similar to that of conventional thyroidectomy. TOT is now reproducible in selective high volume endocrine centers.


Personalization of electro-mechanical models of the pressure-overloaded left ventricle: fitting of Windkessel-type afterload models.
Computer models of left ventricular (LV) electro-mechanics (EM) show promise as a tool for assessing the impact of increased afterload upon LV performance. However, the identification of unique afterload model parameters and the personalization of EM LV models remains challenging due to significant clinical input uncertainties. Here, we personalized a virtual cohort of N = 17 EM LV models under pressure overload conditions. A global-local optimizer was developed to uniquely identify parameters of a three-element Windkessel (Wk3) afterload model. The sensitivity of Wk3 parameters to input uncertainty and of the EM LV model to Wk3 parameter uncertainty was analysed. The optimizer uniquely identified Wk3 parameters, and outputs of the personalized EM LV models showed close agreement with clinical data in all cases. Sensitivity analysis revealed a strong dependence of Wk3 parameters on input uncertainty. However, this had limited impact on outputs of EM LV models. A unique identification of Wk3 parameters from clinical data appears feasible, but it is sensitive to input uncertainty, thus depending on accurate invasive measurements. By contrast, the EM LV model outputs were less sensitive, with errors of less than 8.14% for input data errors of 10%, which is within the bounds of clinical data uncertainty. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.


Prediction of short-term antidepressant response using probabilistic graphical models with replication across multiple drugs and treatment settings.
Heterogeneity in the clinical presentation of major depressive disorder and response to antidepressants limits clinicians' ability to accurately predict a specific patient's eventual response to therapy. Validated depressive symptom profiles may be an important tool for identifying poor outcomes early in the course of treatment. To derive these symptom profiles, we first examined data from 947 depressed subjects treated with selective serotonin reuptake inhibitors (SSRIs) to delineate the heterogeneity of antidepressant response using probabilistic graphical models (PGMs). We then used unsupervised machine learning to identify specific depressive symptoms and thresholds of improvement that were predictive of antidepressant response by 4 weeks for a patient to achieve remission, response, or nonresponse by 8 weeks. Four depressive symptoms (depressed mood, guilt feelings and delusion, work and activities and psychic anxiety) and specific thresholds of change in each at 4 weeks predicted eventual outcome at 8 weeks to SSRI therapy with an average accuracy of 77% (p = 5.5E-08). The same four symptoms and prognostic thresholds derived from patients treated with SSRIs correctly predicted outcomes in 72% (p = 1.25E-05) of 1996 patients treated with other antidepressants in both inpatient and outpatient settings in independent publicly-available datasets. These predictive accuracies were higher than the accuracy of 53% for predicting SSRI response achieved using approaches that (i) incorporated only baseline clinical and sociodemographic factors, or (ii) used 4-week nonresponse status to predict likely outcomes at 8 weeks. The present findings suggest that PGMs providing interpretable predictions have the potential to enhance clinical treatment of depression and reduce the time burden associated with trials of ineffective antidepressants. Prospective trials examining this approach are forthcoming.


Gender-related invasion differences associated with mRNA expression levels of melatonin membrane receptors in colorectal cancer.
Melatonin inhibits growth and invasive capacity of colon cancer cells in vitro through its membrane (MT1 and MT2) and/or nuclear receptors (RORα). Previous studies showed that this indoleamine is present in both the normal and colon cancer at similar levels. Therefore, we analyzed MT1, MT2, and RORα expression in tumor samples versus normal mucosa (NM) from patients suffering from colorectal cancer (CRC). Given the existence of sex differences in the incidence and pathology of CRC and the involvement of steroid receptors in the oncostatic actions of melatonin in some types of cancer, we also analyzed the expression of androgen (AR) and estrogen receptor (ER) α and ERβ. Finally, we conducted some experiments in colon cancer cell lines to corroborate the experiments carried out in human tumors. We found a decreased expression of MT1, MT2, AR, ERα, and ERβ in tumor samples versus NM, but no changes in RORα expression in the whole cohort of patients. Classifying tumors by stage and gender, MT1, MT2, AR, ERα, and ERβ expression decreased in both early stage and advanced tumors, but only in male patients. On the other hand, MT1 and MT2 expression correlated positively with AR, ERα, and ERβ expression in male patients and with ERα or ERβ in female patients. In vitro, the invasive capacity was higher in cells with the least expression of MT1, MT2, and AR, and nonselective MT1/MT2 agonists inhibited cell growth and invasion. These results could indicate a possible interaction of these pathways.


Outcomes of Subacromial Balloon Spacer Implantation for Massive and Irreparable Rotator Cuff Tears: A Systematic Review.
Selection of optimal treatment for massive to irreparable rotator cuff tears (RCTs) entails a challenging decision-making process in which surgeons must consider several factors, including duration of symptoms, tear pattern, tear size, and muscle quality, as well as patient characteristics such as age, comorbidities, shoulder dominance, and activity level. Unfortunately, no clear consensus has been reached regarding optimal management. To systematically review the published literature assessing outcomes after subacromial balloon spacer implantation for treatment of massive and irreparable RCTs. Systematic review; Level of evidence, 4. A comprehensive literature search was performed in September 2018 through use of MEDLINE and the Cochrane Library electronic databases. Studies were assessed for multiple outcomes of interest including Constant score, Oxford Shoulder Score (OSS), University of California Los Angeles (UCLA) Shoulder Score, complications, and patient satisfaction. After applying the selection criteria, 12 clinical studies were included for data extraction and analysis. In total, 291 shoulders (in 284 patients) treated with subacromial balloon spacer implantation were pooled for evaluation, with a mean follow-up of 22.9 ± 14.9 months (range, 6-60 months). Constant scores were used as an outcome metric for 267 shoulders (91.7%; 11 studies), with improvements in mean Constant score ranging from 18.5 to 49.6 points. Patient satisfaction was assessed in 105 patients (37.0%; 5 studies), with rates of patients indicating they were satisfied or very satisfied with their treatment outcome ranging from 45.8% to 100%. A total of 6 patients (2.1%) experienced complications related to balloon spacer implantation, including transient neurapraxia of the lateral antebrachial cutaneous nerve, superficial wound infection, deep wound infection, and balloon migration. Of these, 3 patients (2 balloon migration, 1 deep wound infection) required subsequent surgeries for balloon removal. Placement of the subacromial balloon spacer is a minimally invasive, technically simple procedure with favorable patient-reported outcomes at limited short-term follow-up. However, inherent methodological limitations and patient heterogeneity between studies may impair our ability to fully characterize the longer term efficacy, particularly relative to other potential surgical options. Further prospective randomized or comparative studies are warranted to ascertain clinical outcomes of subacromial balloon spacer in the management of massive and irreparable RCTs.


Complete genome sequence of Bacteroides helcogenes type strain (P 36-108).
Bacteroides helcogenes Benno et al. 1983 is of interest because of its isolated phylogenetic location and, although it has been found in pig feces and is known to be pathogenic for pigs, occurrence of this bacterium is rare and it does not cause significant damage in intensive animal husbandry. The genome of B. helcogenes P 36-108(T) is already the fifth completed and published type strain genome from the genus Bacteroides in the family Bacteroidaceae. The 3,998,906 bp long genome with its 3,353 protein-coding and 83 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project.


Near-infrared dyes as contrast-enhancing agents for spectroscopic optical coherence tomography.
Optical coherence tomography (OCT) images of biological tissues often have low contrast. Spectroscopic optical coherence tomography (SOCT) methods have been developed to enhance contrast but remain limited because most tissues are not spectrally active in the frequency bands of laser sources commonly used in OCT. Near-infrared (NIR) dyes with absorption spectra features within the OCT source spectrum can be used for enhancing contrast in this situation. We introduce and demonstrate the use of NIR dyes as contrast agents for SOCT. Contrast-enhanced images are compared with fluorescence microscopy, demonstrating a link between SOCT and fluorescence imaging.