The Economic Burden of Malaria: Revisiting the Evidence.
A portion of the economics literature has long debated about the relative importance of historical, institutional, geographical, and health determinants of economic growth. In 2001, Gallup and Sachs quantified the association between malaria and the level and growth of per capita income over the period 1965-1995 in a cross-country regression framework. We took a contemporary look at Gallup and Sachs' seminal work in the context of significant progress in malaria control achieved globally since 2000. Focusing on the period 2000-2017, we used the latest data available on malaria case incidence and other determinants of economic growth, as well as macro-econometric methods that are now the professional norm. In our preferred specification using a fixed-effects model, a 10% decrease in malaria incidence was associated with an increase in income per capita of nearly 0.3% on average and a 0.11 percentage point faster per capita growth per annum. Greater average income gains were expected among higher burden countries and those with lower income. Growth of industries with the same level of labor intensity was found to be significantly slower in countries with higher malaria incidence. To analyze the causal impact of malaria on economic outcomes, we used malaria treatment failure and pyrethroid-only insecticide resistance as exogeneous instruments in two-stage least squares estimations. Despite several methodological challenges, as expected in these types of analyses, our findings confirm the intrinsic link between malaria and economic growth and underscore the importance of malaria control in the agenda for sustainable development.


Effect of food and sediment pre-treatment in experiments with a deposit-feeding amphipod, Monoporeia affinis.
We experimentally investigated the effects of different pre-treatments of the sediment, and the effect of daily addition of fresh phytoplankton, on the growth and survival of 1-year-old (1+) individuals of the deposit feeder Monoporeia affinis (Amphipoda). We used three different types of sieved sediment: pre-frozen muddy clay, non-pre-frozen muddy clay, and fine sand. The muddy clay contained phytoplankton originating from the surface sediment sampled in the field during the late spring bloom. No phytoplankton was initially present in sand. The experiment lasted for 18 days. M. affinis responded to the daily phytoplankton addition by increasing growth. Phytoplankton addition had no significant effects on the survival of M. affinis. Upon phytoplankton addition, the sandy and non-frozen muddy clay gave similar growth and survival responses. In contrast, the pre-frozen sediment resulted in significantly lower growth and survival. The growth was negative in all treatments without phytoplankton. Thus, the high initial chlorophyll content in the muddy clay was not of sufficient quality or concentration to allow a positive growth response in M. affinis. The growth of M. affinis was significantly correlated with the reduction of the chlorophyll. Our results indicated that M. affinis is capable of assimilating settled phytoplankton with no, or only a few days' time delay.


(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity.
The stimulus properties of 3,4-methylenedioxymethamphetamine (MDMA)-like compounds were studied in rats trained to discriminate saline from (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine [(+)-MBDB] hydrochloride (7.18 mumol/kg; 1.75 mg/kg), the alpha-ethyl homolog of MDMA. In previous experiments with (+)-MBDB as a test drug, complete substitution was observed for MDMA but not for (+)-lysergic acid diethylamide or (+)-amphetamine. In the study reported here, the (+)-MBDB cue generalized to MDMA and the parent drug, 3,4-methylenedioxyamphetamine. All three drugs exhibited a similar stereoselectivity, the (+)-isomer having potency greater than the (-)-isomer. By contrast, the hallucinogens, (+)-lysergic acid diethylamide, 2,5-dimethoxy-4-methylamphetamine and mescaline and the psychostimulants (+)-amphetamine and (+)-methamphetamine did not substitute for (+)-MBDB. Cocaine produced partial substitution. The results support the hypothesis that the primary behavioral activity of MDMA-like compounds is unlike that of hallucinogens and stimulants and may represent the effects of a novel drug class, given the name entactogens. Although the mechanism of action for the discriminative stimulus properties of MDMA-like compounds is not known, there is evidence that presynaptic serotonergic, but not dopaminergic, mechanisms are critical. Finally, 5,6-methylenedioxy-2-aminoindan a non-neurotoxic 3,4-methylenedioxyamphetamine rigid analog that was previously found to substitute for MDMA but not for (+)-lysergic acid diethylamide was found in the study described here to substitute completely for (+)-MBDB. The N-methyl derivative 5,6-methylenedioxy-2-methylminoindan produced similar results. The demonstration of entactogen-like discriminative stimulus properties, for drugs devoid of neuronal degenerative toxicity potential, serves as evidence of the independent mechanisms for these effects in rats.


Ethical conflicts in long-term care of the aged: nutritional problems and the patient-care worker relationship.
The patient-care worker relationship was analysed by observation and unstructured group discussion in four long-stay somatogeriatric wards at Saint Lars Hospital. Investigation centred on patients entering the terminal phase who could no longer be spoon-fed. The relationship was complicated and reciprocal, and failure by the care worker to interpret her role and the dying patient's behaviour correctly led to emotional conflict and double-binding, with resultant anxiety for both herself and the patient. Infusions and tube-feeding prescribed in such cases were given not for the patient's benefit but to relieve anxiety in care workers and relatives. Permitting the patient a natural, painless death from water deficiency may be preferable to prolonging pain and discomfort by intervening with infusion and tube-feeding.


Amniotic fluid metabolomic analysis in spontaneous preterm birth.
To identify metabolic changes associated with early spontaneous preterm birth (PTB; <34 weeks) and term births, using high-throughput metabolomics of amniotic fluid (AF) in African American population. In this study, AF samples retrieved from spontaneous PTB (<34 weeks [n = 25]) and normal term birth (n = 25) by transvaginal amniocentesis at the time of labor prior to delivery were subjected to metabolomics analysis. Equal volumes of samples were subjected to a standard solvent extraction method and analyzed using gas chromatography/mass spectrometry (MS) and liquid chromatography/MS/MS. Biochemicals were identified through matching of ion features to a library of biochemical standards. After log transformation and imputation of minimum observed values for each compound, t test, correlation tests, and false discovery rate corrections were used to identify differentially regulated metabolites. Data were controlled for clinical/demographic variables and medication during pregnancy. Of 348 metabolites measured in AF samples, 121 metabolites had a gestational age effect and 116 differed significantly between PTB and term births. A majority of significantly altered metabolites could be classified into 3 categories, namely, (1) liver function, (2) fatty acid and coenzyme A (CoA) metabolism, and (3) histidine metabolism. The signature of altered liver function was apparent in many cytochrome P450-related pathways including bile acids, steroids, xanthines, heme, and phase II detoxification of xenobiotics with the largest fold change seen with pantothenol, a CoA synthesis inhibitor that was 8-fold more abundant in PTB. Global metabolic profiling of AF revealed alteration in hepatic metabolites involving xenobiotic detoxification and CoA metabolism in PTB. Maternal and/or fetal hepatic function differences may be developmentally related and its contribution PTB as a cause or effect of PTB is still unclear.


The prevalence of mental illness in refugees and asylum seekers: A systematic review and meta-analysis.
Globally, the number of refugees and asylum seekers has reached record highs. Past research in refugee mental health has reported wide variation in mental illness prevalence data, partially attributable to methodological limitations. This systematic review aims to summarise the current body of evidence for the prevalence of mental illness in global refugee populations and overcome methodological limitations of individual studies. A comprehensive search of electronic databases was undertaken from 1 January 2003 to 4 February 2020 (MEDLINE, MEDLINE In-Process, EBM Reviews, Embase, PsycINFO, CINAHL, PILOTS, Web of Science). Quantitative studies were included if diagnosis of mental illness involved a clinical interview and use of a validated assessment measure and reported at least 50 participants. Study quality was assessed using a descriptive approach based on a template according to study design (modified Newcastle-Ottawa Scale). Random-effects models, based on inverse variance weights, were conducted. Subgroup analyses were performed for sex, sample size, displacement duration, visa status, country of origin, current residence, type of interview (interpreter-assisted or native language), and diagnostic measure. The systematic review was registered with PROSPERO (CRD) 42016046349. The search yielded a result of 21,842 records. Twenty-six studies, which included one randomised controlled trial and 25 observational studies, provided results for 5,143 adult refugees and asylum seekers. Studies were undertaken across 15 countries: Australia (652 refugees), Austria (150), China (65), Germany (1,104), Italy (297), Lebanon (646), Nepal (574), Norway (64), South Korea (200), Sweden (86), Switzerland (164), Turkey (238), Uganda (77), United Kingdom (420), and the United States of America (406). The prevalence of posttraumatic stress disorder (PTSD) was 31.46% (95% CI 24.43-38.5), the prevalence of depression was 31.5% (95% CI 22.64-40.38), the prevalence of anxiety disorders was 11% (95% CI 6.75-15.43), and the prevalence of psychosis was 1.51% (95% CI 0.63-2.40). A limitation of the study is that substantial heterogeneity was present in the prevalence estimates of PTSD, depression, and anxiety, and limited covariates were reported in the included studies. This comprehensive review generates current prevalence estimates for not only PTSD but also depression, anxiety, and psychosis. Refugees and asylum seekers have high and persistent rates of PTSD and depression, and the results of this review highlight the need for ongoing, long-term mental health care beyond the initial period of resettlement.


ATR-mediated phosphorylation of DNA polymerase η is needed for efficient recovery from UV damage.
DNA polymerase η (polη) belongs to the Y-family of DNA polymerases and facilitates translesion synthesis past UV damage. We show that, after UV irradiation, polη becomes phosphorylated at Ser601 by the ataxia-telangiectasia mutated and Rad3-related (ATR) kinase. DNA damage-induced phosphorylation of polη depends on its physical interaction with Rad18 but is independent of PCNA monoubiquitination. It requires the ubiquitin-binding domain of polη but not its PCNA-interacting motif. ATR-dependent phosphorylation of polη is necessary to restore normal survival and postreplication repair after ultraviolet irradiation in xeroderma pigmentosum variant fibroblasts, and is involved in the checkpoint response to UV damage. Taken together, our results provide evidence for a link between DNA damage-induced checkpoint activation and translesion synthesis in mammalian cells.


The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: A randomized, double-blinded, placebo-controlled trial.
Precise cannabis treatment dosing remains a major challenge, leading to physicians' reluctance to prescribe medical cannabis. To test the pharmacokinetics, analgesic effect, cognitive performance and safety effects of an innovative medical device that enables the delivery of inhaled therapeutic doses of Δ9 -Tetrahydrocannabinol (THC) in patients with chronic pain. In a randomized, three-arms, double-blinded, placebo-controlled, cross-over trial, 27 patients received a single inhalation of Δ9 -THC: 0.5mg, 1mg, or a placebo. Δ9 -THC plasma levels were measured at baseline and up to 150-min post-inhalation. Pain intensity and safety parameters were recorded on a 10-cm visual analogue scale (VAS) at pre-defined time points. The cognitive performance was evaluated using the selective sub-tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Following inhalation of 0.5 mg or 1mg, Δ9 -THC plasma Cmax ± SD were 14.3 ± 7.7 and 33.8 ± 25.7 ng/ml. Tmax ± SD were 3.7 ± 1.4 and 4.4 ± 2.1 min, and AUC0 → infinity ±SD were 300 ± 144 and 769 ± 331 ng*min/ml, respectively. Both doses, but not the placebo, demonstrated a significant reduction in pain intensity compared with baseline and remained stable for 150-min. The 1-mg dose showed a significant pain decrease compared to the placebo. Adverse events were mostly mild and resolved spontaneously. There was no evidence of consistent impairments in cognitive performance. This feasibility trial demonstrated that a metered-dose cannabis inhaler delivered precise and low THC doses, produced a dose-dependent and safe analgesic effect in patients with neuropathic pain/ complex-regional pain syndrome (CRPS). Thus, it enables individualization of medical cannabis regimens that can be evaluated pharmacokinetically and pharmacodynamically by accepted pharmaceutical models. Evidence suggests that cannabis-based medicines are an effective treatment for chronic pain in adults. The pharmacokinetics of THC varies as a function of its route of administration. Pulmonary assimilation of inhaled THC causes rapid onset of analgesia. However, currently used routes of cannabinoids delivery provide unknown doses, making it impossible to implement a pharmaceutical standard treatment plan. A novel selective-dose cannabis inhaler delivers significantly low and precise doses of THC, thus allowing the administration of inhaled cannabis-based medicines according to high pharmaceutical standards. These low doses of THC can produce safe and effective analgesia in patients with chronic pain.


Augmentation of deglutitive thyrohyoid muscle shortening by the Shaker Exercise.
Earlier studies of the effect of 6 weeks of the Shaker Exercise have shown significant increase in UES opening and anterior excursion of larynx and hyoid during swallowing in patients with upper esophageal sphincter (UES) dysfunction, resulting in elimination of aspiration and resumption of oral intake. This effect is attributed to strengthening of the suprahyoid muscles, as evidenced by comparison of electromyographic changes in muscle fatigue before and after completion of the exercise regime. The effect of this exercise on thyrohyoid muscle shortening is unknown. Therefore the aim of this study was to determine the effect of the exercise on thyrohyoid muscle shortening. We studied 11 dysphagic patients with UES dysfunction. Six were randomized to traditional swallowing therapy and five to the Shaker Exercise. Videofluoroscopy was used to measure deglutitive thyrohyoid shortening before and after completion of assigned therapy regimen. Maximum thyrohyoid muscle shortening occurred at close temporal proximity to the time of maximal thyroid cartilage excursion. The percent change in thyrohyoid distance from initiation of deglutition to maximal anterior/superior hyoid excursion showed no statistically significant difference between the two groups prior to either therapy (p = 0.54). In contrast, after completion of therapy, the percent change in thyrohyoid distance in the Shaker Exercise group was significantly greater compared to the traditional therapy (p = 0.034). The Shaker Exercise augments the thyrohyoid muscle shortening in addition to strengthening the suprahyoid muscles. The combination of increased thyrohyoid shortening and suprahyoid strengthening contributes to the Shaker Exercise outcome of deglutitive UES opening augmentation.


Interplay Between Chronic Kidney Disease, Hypertension, and Stroke: Insights From a Multivariable Mendelian Randomization Analysis.
Chronic kidney disease (CKD) increases the risk of stroke, but the extent through which this association is mediated by hypertension is unknown. We leveraged large-scale genetic data to explore causal relationships between CKD, hypertension, and cerebrovascular disease phenotypes. We used data from genome-wide association studies of European ancestry to identify genetic proxies for kidney function (CKD diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]), systolic blood pressure (SBP), and cerebrovascular disease (ischemic stroke and its subtypes and intracerebral hemorrhage). We then conducted univariable, multivariable, and mediation Mendelian randomization (MR) analyses to investigate the effect of kidney function on stroke risk and the proportion of this effect mediated through hypertension. Univariable MR revealed associations between genetically determined lower eGFR and risk of all stroke (odds ratio [OR] per 1-log decrement in eGFR, 1.77; 95% CI 1.31-2.40; p < 0.001), ischemic stroke (OR 1.81; 95% CI 1.31-2.51; p < 0.001), and most strongly with large artery stroke (LAS) (OR 3.00; 95% CI 1.33-6.75; p = 0.008). These associations remained significant in the multivariable MR analysis, controlling for SBP (OR 1.98; 95% CI 1.39-2.82; p < 0.001 for all stroke; OR 2.16; 95% CI 1.48-3.17; p < 0.001 for ischemic stroke; OR 4.35; 95% CI 1.84-10.27; p = 0.001 for LAS), with only a small proportion of the total effects mediated by SBP (6.5% [0.7%-16.8%], 6.6% [0.8%-18.3%], and 7.2% [0.5%-24.8%], respectively). Total, direct and indirect effect estimates were similar across a number of sensitivity analyses (weighted median, MR-Egger regression). Our results demonstrate an independent causal effect of impaired kidney function, as assessed by decreased eGFR, on stroke risk, particularly LAS, even when controlled for SBP. Targeted prevention of kidney disease could lower atherosclerotic stroke risk independent of hypertension.


Sleep habits and susceptibility to the common cold.
Sleep quality is thought to be an important predictor of immunity and, in turn, susceptibility to the common cold. This article examines whether sleep duration and efficiency in the weeks preceding viral exposure are associated with cold susceptibility. A total of 153 healthy men and women (age range, 21-55 years) volunteered to participate in the study. For 14 consecutive days, they reported their sleep duration and sleep efficiency (percentage of time in bed actually asleep) for the previous night and whether they felt rested. Average scores for each sleep variable were calculated over the 14-day baseline. Subsequently, participants were quarantined, administered nasal drops containing a rhinovirus, and monitored for the development of a clinical cold (infection in the presence of objective signs of illness) on the day before and for 5 days after exposure. There was a graded association with average sleep duration: participants with less than 7 hours of sleep were 2.94 times (95% confidence interval [CI], 1.18-7.30) more likely to develop a cold than those with 8 hours or more of sleep. The association with sleep efficiency was also graded: participants with less than 92% efficiency were 5.50 times (95% CI, 2.08-14.48) more likely to develop a cold than those with 98% or more efficiency. These relationships could not be explained by differences in prechallenge virus-specific antibody titers, demographics, season of the year, body mass, socioeconomic status, psychological variables, or health practices. The percentage of days feeling rested was not associated with colds. Poorer sleep efficiency and shorter sleep duration in the weeks preceding exposure to a rhinovirus were associated with lower resistance to illness.


Emerging infectious disease or evidence of endemicity? A multi-season study of beak and feather disease virus in wild red-crowned parakeets (Cyanoramphus novaezelandiae).
Beak and feather disease virus (BFDV) is a single-stranded DNA virus that is the etiological agent of beak and feather disease in both wild and captive parrots. Given that BFDV is globally recognized as a conservation threat for wild parrots, between 2011-2013, red-crowned parakeets (Cyanoramphus novaezelandiae, n = 229), which are endemic to New Zealand, were captured in mist nets on Tiritiri Matangi Island and Hauturu-o-Toi/Little Barrier Island (LBI), New Zealand, for disease surveillance. Blood and feathers from all birds were tested by PCR for BFDV, and full genomes were recovered and sequenced. A subset of blood samples (n = 96) were tested for antibodies to BFDV by the haemagglutination inhibition (HI) test. A further 238 feather samples were obtained from red-crowned parakeets from three sites in the Wellington region of the North Island, and these were screened for BFDV. The DNA-based prevalence of BFDV infection determined on Tiritiri Matangi Island was 1.09% (CI 95 %, 0.1-3.9%); on Hauturu-o-Toi/LBI, 4.4% (95% CI, 0.5%-15.1%); on Kapiti Island, 3.4% (CI 95%, 1.1-7.8%); at the ZEALANDIA-Karori sanctuary, 1.6% (95% CI, 0-8.4%); and on Matiu-Somes Island, 0% (CI 95%, 0-12.3%). Seroprevalence for BFDV, indicating prior or current exposure, in the Tiritiri Matangi Island population, it was 2% (CI 95%, 0-10.1%), and in the Hauturu-o-Toi/LBI population was 14% (CI 95%, 5.3-27.9%). BFDV-positive birds showed no signs of clinical disease, with the exception of an individual bird obtained opportunistically from Shakespear Regional Park during the study period, which had classical signs of feather loss. Phylogenetic analysis of the 11 full genome sequences recovered from BFDV-positive red-crowned parakeets revealed evidence of ongoing viral flow between red-crowned parakeets and eastern rosellas (Platycercus eximius) in the Hauraki Gulf/Auckland region, with separate but closely related strains from the Wellington region of the North Island. This is the first study to report HI results for a New Zealand endemic parrot species, and the first epidemiological analysis of serial cross-sectional surveys in a BFDV-infected population of red-crowned parakeets in New Zealand. We postulate that although BFDV remains a threat to small, isolated or naïve populations of parrots globally, the low viral prevalence in this and other studies suggests that native parakeets in New Zealand may act as dead-end or spillover hosts.


The orexin/hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms.
Hypocretin-1 and 2 (or orexin A and B) are neuropeptides exclusively produced by a group of neurons in the lateral and dorsomedial hypothalamus that project throughout the brain. In accordance with this, the two different hypocretin receptors are also found throughout the brain. The hypocretin system is mainly involved in sleep-wake regulation, but also in reward mechanisms, food intake and metabolism, autonomic regulation including thermoregulation, and pain. The disorder most strongly linked to the hypocretin system is the primary sleep disorder narcolepsy type 1 caused by a lack of hypocretin signaling, which is most likely due to an autoimmune process targeting the hypocretin-producing neurons. However, the hypocretin system may also be affected, but to a lesser extent and less specifically, in various other neurological disorders. Examples are neurodegenerative diseases such as Alzheimer's, Huntington's and Parkinson's disease, immune-mediated disorders such as multiple sclerosis, neuromyelitis optica, and anti-Ma2 encephalitis, and genetic disorders such as type 1 diabetus mellitus and Prader-Willi Syndrome. A partial hypocretin deficiency may contribute to the sleep features of these disorders.


Proton-proton homonuclear dipolar decoupling in solid-state NMR using rotor-synchronized z-rotation pulse sequences.
We present a theoretical analysis of rotor-synchronized homonuclear dipolar decoupling schemes that cause a z-rotation of the spins. These pulse sequences applicable at high spinning rates (nu(r) > or = 30 kHz) yield high-resolution proton NMR spectra that are free of artifacts, such as zero lines and image peaks. We show that the scaled isotropic chemical-shift positions of proton lines can be calculated from the zero-order average Hamiltonian and that the scaling factor does not depend on offset. The effects of different adjustable parameters (rf field, spinning rate, pulse shape, offset) on the decoupling performance are analyzed by numerical simulations of proton spectra and by (1)H solid-state NMR experiments on NaH(2)PO(4) and glycine.


Human rabies deaths in Africa: breaking the cycle of indifference.
The current outbreak of Ebola virus disease has mobilized the international community against this deadly disease. However, rabies, another deadly disease, is greatly affecting the African continent, with an estimated 25 000 deaths every year. And yet, the disease can be prevented by a vaccine, if necessary with immunoglobulin, even when administered after exposure to the rabies virus. Rabies victims die because of neglect and ignorance, because they are not aware of these life-saving biologicals, or because they cannot access them or do not have the money to pay for them. Breaking the cycle of indifference of rabies deaths in humans in Africa should be a priority of governments, international organizations and all stakeholders involved.


Genetic and metabolic predictors of chemosensitivity in oligodendroglial neoplasms.
The -1p/-19q genotype predicts chemosensitivity in oligodendroglial neoplasms, but some with intact 1p/19q also respond and not all with 1p/19q loss derive durable benefit from chemotherapy. We have evaluated the predictive and prognostic significance of pretherapy (201)Tl and (18)F-FDG SPECT and genotype in 38 primary and 10 recurrent oligodendroglial neoplasms following PCV chemotherapy. 1p/19q loss was seen in 8/15 OII, 6/15 OAII, 7/7 OIII, 3/11 OAIII and was associated with response (Fisher-Exact: P=0.000) and prolonged progression-free (log-rank: P=0.002) and overall survival (OS) (log-rank: P=0.0048). Response was unrelated to metabolism, with tumours with high or low metabolism showing response. Increased (18)F-FDG or (201)Tl uptake predicted shorter progression-free survival (PFS) in the series (log-rank: (201)Tl P=0.0097, (18)F-FDG P=0.0170) and in cases with or without the -1p/-19q genotype. Elevated metabolism was associated with shorter OS in cases with intact 1p/19q (log-rank: (18)F-FDG P=0.0077; (201)Tl P=0.0004) and shorter PFS in responders (log-rank: (18)F-FDG P=0.005; (201)Tl P=0.0132). (201)Tl uptake and 1p/19q loss were independent predictors of survival in multivariate analysis. In this initial study, (201)Tl and (18)F-FDG uptake did not predict response to PCV, but may be associated with poor survival following therapy irrespective of genotype. This may be clinically useful warranting further study.


Identification of a Candidate Streptococcus pneumoniae core genome and regions of diversity correlated with invasive pneumococcal disease.
Streptococcus pneumoniae is a leading cause of community-acquired pneumonia and gram-positive sepsis. While multiple virulence determinants have been identified, the combination of features that determines the propensity of an isolate to cause invasive pneumococcal disease (IPD) remains unknown. In this study, we determined the genetic composition of 42 invasive and 30 noninvasive clinical isolates of serotypes 6A, 6B, and 14 by comparative genomic hybridization. Comparison of the present/absent gene matrix (i.e., comparative genomic analysis [CGA]) identified a candidate core genome consisting of 1,553 genes (73% of the TIGR4 genome), 154 genes whose presence correlated with the ability to cause IPD, and 176 genes whose presence correlated with the noninvasive phenotype. Genes identified by CGA were cross-referenced with the published signature-tagged mutagenesis studies, which served to identify core and IPD-correlated genes required for in vivo passage. Among these, two pathogenicity islands, region of diversity 8a (RD8a), which encodes a neuraminidase and V-type sodium synthase, and RD10, which encodes PsrP, a protein homologous to the platelet adhesin GspB in Streptococcus gordonii, were identified. Mice infected with a PsrP mutant were delayed in the development of bacteremia and demonstrated reduced mortality versus wild-type-infected controls. Finally, the presence of seven RDs was determined to correlate with the noninvasive phenotype, a finding that suggests some RDs may contribute to asymptomatic colonization. In conclusion, RDs are unequally distributed between invasive and noninvasive isolates, RD8a and RD10 are correlated with the propensity of an isolate to cause IPD, and PsrP is required for full virulence in mice.


Synthetic Cannabinoids.
Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.


Islet cell autoantibodies in African patients with Type 1 and Type 2 diabetes in Dar es Salaam Tanzania: a cross sectional study.
The aim of the present study was to assess the occurrence of glutamic acid decarboxylase autoantibodies (GADA) and insulinoma antigen 2 autoantibodies (IA2A) among patients of African origin in Dar es Salaam, Tanzania and to compare the occurrence of autoimmune mediated Type 1 diabetes with findings previously reported from the same place and from other African diabetic populations. Two hundred and forty five patients from the diabetic clinic at Muhimbili Hospital were recruited for a cross sectional study. Patients were clinically classified into groups with Type 1 (T1D) and Type 2 diabetes (T2D); there were 94 patients with T1D and 151 with T2D. Autoantibodies for GAD and IA2 were measured with an assay based on radioligand binding. Fasting and random blood glucose, HbA1c, and C-peptide levels were also determined. Of the patients with T1D, 28 (29.8%) were GADA positive and 20 (21.3%) were IA2A positive. The overall occurrence of any autoantibody was 42.6%. The GAD and IA2 autoantibodies were detected more frequently among patients with T1D than among patients with T2D (P < 0.001). A higher autoantibody prevalence was observed with combined GADA and IA2A measurements compared to individual autoantibody measurements; 40 (42.6%) patients with T1D versus 11 (7.3%) with T2D had at least one positive autoantibody titer. There was no correlation between duration of disease and detection of autoantibodies in patients with T1D. There was a strong association with family history of diabetes among the autoantibody positive versus autoantibody negative patients with T1D (p < 0.01). The prevalence of GAD and IA2 autoantibodies among African patients with T1D in Dar es Salaam was the same as that reported previously for South Africa and Ethiopia. It was much higher than the prevalence of islet cell autoantibodies (ICA) reported from the same clinic about 15 years ago. For unknown reasons the prevalence of pancreatic related autoantibodies in this African population is lower than the prevalence found among Caucasian populations.


STAT3 oligonucleotide inhibits tumor angiogenesis in preclinical models of squamous cell carcinoma.
Signal transducer and activator of transcription 3 (STAT3) has shown to play a critical role in head and neck squamous cell carcinoma (HNSCC) and we have recently completed clinical trials of STAT3 decoy oligonucleotide in patients with recurrent or metastatic HNSCC. However, there is limited understanding of the role of STAT3 in modulating other aspects of tumorigenesis such as angiogenesis. In this study, we aimed to examine the effects of STAT3 decoy oligonucleotide on tumor angiogenesis. A STAT3 decoy oligonucleotide and small interfering RNA (siRNA) were used to inhibit STAT3 in endothelial cells in vitro and in vivo. The biochemical effects of STAT3 inhibition were examined in conjunction with the consequences on proliferation, migration, apoptotic staining, and tubule formation. Additionally, we assessed the effects of STAT3 inhibition on tumor angiogenesis using murine xenograft models. STAT3 decoy oligonucleotide decreased proliferation, induces apoptosis, decreased migration, and decreased tubule formation of endothelial cells in vitro. The STAT3 decoy oligonucleotide also inhibited tumor angiogenesis in murine tumor xenografts. Lastly, our data suggest that the antiangiogenic effects of STAT3 decoy oligonucleotide were mediatedthrough the inhibition of both STAT3 and STAT1. The STAT3 decoy oligonucleotidewas found to be an effective antiangiogenic agent, which is likely to contribute to the overall antitumor effects of this agent in solid tumors.Taken together with the previously demonstrated antitumor activity of this agent, STAT3 decoy oligonucleotide represents a promising single agent approach to targeting both the tumor and vascular compartments in various malignancies.


Development of genomic resources for the prairie vole (Microtus ochrogaster): construction of a BAC library and vole-mouse comparative cytogenetic map.
The prairie vole (Microtus ochrogaster) is a premier animal model for understanding the genetic and neurological basis of social behaviors. Unlike other biomedical models, prairie voles display a rich repertoire of social behaviors including the formation of long-term pair bonds and biparental care. However, due to a lack of genomic resources for this species, studies have been limited to a handful of candidate genes. To provide a substrate for future development of genomic resources for this unique model organism, we report the construction and characterization of a bacterial artificial chromosome (BAC) library from a single male prairie vole and a prairie vole-mouse (Mus musculus) comparative cytogenetic map. We constructed a prairie vole BAC library (CHORI-232) consisting of 194,267 recombinant clones with an average insert size of 139 kb. Hybridization-based screening of the gridded library at 19 loci established that the library has an average depth of coverage of approximately 10x. To obtain a small-scale sampling of the prairie vole genome, we generated 3884 BAC end-sequences totaling approximately 2.8 Mb. One-third of these BAC-end sequences could be mapped to unique locations in the mouse genome, thereby anchoring 1003 prairie vole BAC clones to an orthologous position in the mouse genome. Fluorescence in situ hybridization (FISH) mapping of 62 prairie vole clones with BAC-end sequences mapping to orthologous positions in the mouse genome was used to develop a first-generation genome-wide prairie vole-mouse comparative cytogenetic map. While conserved synteny was observed between this pair of rodent genomes, rearrangements between the prairie vole and mouse genomes were detected, including a minimum of five inversions and 16 inter-chromosomal rearrangements. The construction of the prairie vole BAC library and the vole-mouse comparative cytogenetic map represent the first genome-wide modern genomic resources developed for this species. The BAC library will support future genomic, genetic and molecular characterization of this genome and species, and the isolation of clones of high interest to the vole research community will allow for immediate characterization of the regulatory and coding sequences of genes known to play important roles in social behaviors. In addition, these resources provide an excellent platform for future higher resolution cytogenetic mapping and full genome sequencing.


An expressed sequence tag (EST) library from developing fruits of an Hawaiian endemic mint (Stenogyne rugosa, Lamiaceae): characterization and microsatellite markers.
The endemic Hawaiian mints represent a major island radiation that likely originated from hybridization between two North American polyploid lineages. In contrast with the extensive morphological and ecological diversity among taxa, ribosomal DNA sequence variation has been found to be remarkably low. In the past few years, expressed sequence tag (EST) projects on plant species have generated a vast amount of publicly available sequence data that can be mined for simple sequence repeats (SSRs). However, these EST projects have largely focused on crop or otherwise economically important plants, and so far only few studies have been published on the use of intragenic SSRs in natural plant populations. We constructed an EST library from developing fleshy nutlets of Stenogyne rugosa principally to identify genetic markers for the Hawaiian endemic mints. The Stenogyne fruit EST library consisted of 628 unique transcripts derived from 942 high quality ESTs, with 68% of unigenes matching Arabidopsis genes. Relative frequencies of Gene Ontology functional categories were broadly representative of the Arabidopsis proteome. Many unigenes were identified as putative homologs of genes that are active during plant reproductive development. A comparison between unigenes from Stenogyne and tomato (both asterid angiosperms) revealed many homologs that may be relevant for fruit development. Among the 628 unigenes, a total of 44 potentially useful microsatellite loci were predicted. Several of these were successfully tested for cross-transferability to other Hawaiian mint species, and at least five of these demonstrated interesting patterns of polymorphism across a large sample of Hawaiian mints as well as close North American relatives in the genus Stachys. Analysis of this relatively small EST library illustrated a broad GO functional representation. Many unigenes could be annotated to involvement in reproductive development. Furthermore, first tests of microsatellite primer pairs have proven promising for the use of Stenogyne rugosa EST SSRs for evolutionary and phylogeographic studies of the Hawaiian endemic mints and their close relatives. Given that allelic repeat length variation in developmental genes of other organisms has been linked with morphological evolution, these SSRs may also prove useful for analyses of phenotypic differences among Hawaiian mints.


Identifying walking trips from GPS and accelerometer data in adolescent females.
Studies that have combined accelerometers and global positioning systems (GPS) to identify walking have done so in carefully controlled conditions. This study tested algorithms for identifying walking trips from accelerometer and GPS data in free-living conditions. The study also assessed the accuracy of the locations where walking occurred compared with what participants reported in a diary. A convenience sample of high school females was recruited (N = 42) in 2007. Participants wore a GPS unit and an accelerometer, and recorded their out-of-school travel for 6 days. Split-sample validation was used to examine agreement in the daily and total number of walking trips with Kappa statistics and count regression models, while agreement in locations visited by walking was examined with geographic information systems. Agreement varied based on the parameters of the algorithm, with algorithms exhibiting moderate to substantial agreement with self-reported daily (Kappa = 0.33-0.48) and weekly (Kappa = 0.41-0.64) walking trips. Comparison of reported locations reached by walking and GPS data suggest that reported locations are accurate. The use of GPS and accelerometers is promising for assessing the number of walking trips and the walking locations of adolescent females.


Providing assertive community treatment for severely mentally ill patients in a rural area.
The authors' goals were to describe an assertive community treatment program developed for patients in rural South Carolina and to evaluate the effect of the program on rates of hospital utilization and cost of care. Twenty-three patients with chronic psychotic disorders living in rural areas of South Carolina were assigned to an assertive community treatment program. The patients' average number of days per year in the hospital, length of stay per admission, number of admissions per year, and estimated annual cost of care during the five years before assignment to the program and during a period from four to 26 months after assignment were compared. The intervention was associated with a 79 percent decrease in hospital days per year, a 64 percent decrease in the number of admissions per year, a 75 percent decrease in the average length of stay per admission, and a 52 percent reduction in estimated direct cost of care. Although the methods of assertive community treatment may need to be modified to suit the travel requirements and other characteristics of rural settings, the study results suggest that the model can be successfully used in rural areas.


Socioecological variables predict telomere length in wild spotted hyenas.
Telomeres are regarded as important biomarkers of ageing and serve as useful tools in revealing how stress acts at the cellular level. However, the effects of social and ecological factors on telomere length remain poorly understood, particularly in free-ranging mammals. Here, we investigated the influences of within-group dominance rank and group membership on telomere length in wild adult spotted hyenas (Crocuta crocuta). We found large effects of both factors; high-ranking hyenas exhibited significantly greater mean telomere length than did subordinate animals, and group membership significantly predicted mean telomere length within high-ranking females. We further inquired whether prey availability mediates the observed effect of group membership on telomere length, but this hypothesis was not supported. Interestingly, adult telomere length was not predicted by age. Our work shows for the first time, to the best of our knowledge, the effects of social rank on telomere length in a wild mammal and enhances our understanding of how social and ecological variables may contribute to organismal senescence.


Detecting pathway-based gene-gene and gene-environment interactions in pancreatic cancer.
Data mining and data reduction methods to detect interactions in epidemiologic data are being developed and tested. In these analyses, multifactor dimensionality reduction, focused interaction testing framework, and traditional logistic regression models were used to identify potential interactions with up to three factors. These techniques were used in a population-based case-control study of pancreatic cancer from the San Francisco Bay Area (308 cases, 964 controls). From 7 biochemical pathways, along with tobacco smoking, 26 polymorphisms in 20 genes were included in these analyses. Combinations of genetic markers and cigarette smoking were identified as potential risk factors for pancreatic cancer, including genes in base excision repair (OGG1), nucleotide excision repair (XPD, XPA, XPC), and double-strand break repair (XRCC3). XPD.751, XPD.312, and cigarette smoking were the best single-factor predictors of pancreatic cancer risk, whereas XRCC3.241*smoking and OGG1.326*XPC.PAT were the best two-factor predictors. There was some evidence for a three-factor combination of OGG1.326*XPD.751*smoking, but the covariate-adjusted relative-risk estimates lacked precision. Multifactor dimensionality reduction and focused interaction testing framework showed little concordance, whereas logistic regression allowed for covariate adjustment and model confirmation. Our data suggest that multiple common alleles from DNA repair pathways in combination with cigarette smoking may increase the risk for pancreatic cancer, and that multiple approaches to data screening and analysis are necessary to identify potentially new risk factor combinations.


Initial clinical experience with matrix detachable coils for the treatment of intracranial aneurysms.
The Matrix detachable coil is a new bioactive, bioabsorbable coil used in the endovascular embolization of intracranial aneurysms. It has a platinum core covered with a bioactive, bioabsorbable polymer (polyglycolic acid/lactide). The authors report on their initial midterm clinical experience with the first-generation Matrix detachable coil. One hundred twelve patients harboring 118 aneurysms were treated using Matrix coils. Forty-nine aneurysms (41.5%) were associated with acute subarachnoid hemorrhage (SAH). Twenty-four lesions (49%) were harbored by patients with Hunt and Hess Grade I, 11 (23.4%) by patients with Grade II, eight (16.3%) by those with Grade III, and six (12.2%) by those with Grade IV. Four aneurysms (3.4%) were harbored by patients who had presented with nonacute SAH. Sixty-five aneurysms (55%) were unruptured. Fifty-seven lesions (48.3%) were small with a small neck, 29 (24.6%) were small with a wide neck, 30 (25.4%) were large, and two (1.7%) were giant. All patients were followed up to obtain angiography and clinical outcome data. Technical complications occurred in six patients: two thromboembolic complications and four aneurysm perforations. Of these six patients, the status of two deteriorated because of aneurysm perforation and another two because of thrombus formation (morbidity 3.6%). There were five deaths--one due to rerupture after embolization. Angiography follow-up studies of 87 aneurysms were obtained. Seventy aneurysms demonstrated progressive occlusion or a stable neck (80.5%), and 17 had some degree of recanalization (19.5%). The aneurysms originally diagnosed as a neck remnant showed a 15% rate of recanalization. Matrix coils can be delivered into aneurysms with technical complications similar to those encountered using GDCs. Midterm anatomical outcomes to date have shown moderate improvement in the recanalization rate when compared with those realized using the GDC system. Because of the increased friction associated with the first-generation Matrix coil, the packing density in most aneurysms was less than that achieved with GDCs. Prolonged angiography follow-up evaluations are needed to document long-term efficacy.


Myocardial blood flow quantification for evaluation of coronary artery disease by computed tomography.
During the last decade coronary computed tomography angiography (CTA) has become the preeminent non-invasive imaging modality to detect coronary artery disease (CAD) with high accuracy. However, CTA has a limited value in assessing the hemodynamic significance of a given stenosis due to a modest specificity and positive predictive value. In recent years, different CT techniques for detecting myocardial ischemia have emerged, such as CT-derived fractional flow reserve (FFR-CT), transluminal attenuation gradient (TAG), and myocardial CT perfusion (CTP) imaging. Myocardial CTP imaging can be performed with a single static scan during first pass of the contrast agent, with monoenergetic or dual-energy acquisition, or as a dynamic, time-resolved scan during stress by using coronary vasodilator agents (adenosine, dipyridamole, or regadenoson). A number of CTP techniques are available, which can assess myocardial perfusion in both a qualitative, semi-quantitative or quantitative manner. Once used primarily as research tools, these modalities are increasingly being used in routine clinical practice. All these techniques offer the substantial advantage of combining anatomical and functional evaluation of flow-limiting coronary stenosis in the same examination that would be beneficial for clinical decision-making. This review focuses on the state-of the-art and future trends of these evolving imaging modalities in the field of cardiology for the physiologic assessments of CAD.


Comparison and Evaluation of PET/CT Image Registration.
Diagnosis, treatment planning and prognosis may be improved by combining functional data with anatomic location via PET/CT dual-modality image registration. The aim of this work is to reveal the spatial accuracy, reliability and speed of registration techniques used in GeminiTM PET/CT Imaging System, as a part of quality assurance program for clinical and research applications. A multi-layer alignment bearing source device was used to validate PET/CT intrinsic alignment, as well as a Rando a Man phantom. A series of known transformations were performed to simulate different misalignment between PET and CT images. Two semi-automated registration techniques used to correct misalignment were assessed and compared quantitatively by measuring absolute distances between the centroids of corresponding fiducial markers in the registered volumes. Comparisons between independent and cross fiducial localization indicate that fused PET/CT is superior to visual correlation of PET and CT individually in identifying registration errors. The experimental and theoretical findings confirm that PET/CT hybrid system can produce robust intrinsic image alignment and accurate PET/CT image registration with careful user interaction. The maximum spatial error in our experiments is below 4 mm, and is better than the spatial resolution of the PET scanner used. This is considered to be sufficient for most PET/CT applications.


Plant nitrogen concentration and isotopic composition in residential lawns across seven US cities.
Human drivers are often proposed to be stronger than biophysical drivers in influencing ecosystem structure and function in highly urbanized areas. In residential land cover, private yards are influenced by individual homeowner preferences and actions while also experiencing large-scale human and biophysical drivers. We studied plant nitrogen (%N) and N stable isotopic composition (δ(15)N) in residential yards and paired native ecosystems in seven cities across the US that span major ecological biomes and climatic regions: Baltimore, Boston, Los Angeles, Miami, Minneapolis-St. Paul, Phoenix, and Salt Lake City. We found that residential lawns in three cities had enriched plant δ(15)N (P < 0.03) and in six cities higher plant N (%) relative to the associated native ecosystems (P < 0.05). Plant δ(15)N was progressively depleted across a gradient of urban density classes in Baltimore and Boston (P < 0.05). Lawn fertilization was associated with depleted plant δ(15)N in Boston and Los Angeles (P < 0.05), and organic fertilizer additions were associated with enriched plant δ(15)N in Los Angeles and Salt Lake City (P < 0.04). Plant δ(15)N was significantly enriched as a function of housing age in Baltimore (r (2) = 0.27, P < 0.02), Boston (r (2) = 0.27, P < 0.01), and Los Angeles (r (2) = 0.34, P < 0.01). These patterns in plant δ(15)N and plant N (%) across these cities suggests that N sources to lawns, as well as greater rates of N cycling combined with subsequent N losses, may be important drivers of plant N dynamics in lawn ecosystems at the national scale.


Dominant effects of RET receptor misexpression and ligand-independent RET signaling on ureteric bud development.
During kidney development, factors from the metanephric mesenchyme induce the growth and repeated branching of the ureteric bud, which gives rise to the collecting duct system and also induces nephrogenesis. One signaling pathway known to be required for this process includes the receptor tyrosine kinase RET and co-receptor GFR(&agr;)-1, which are expressed in the ureteric bud, and the secreted ligand GDNF produced in the mesenchyme. To examine the role of RET signaling in ureteric bud morphogenesis, we produced transgenic mice in which the pattern of RET expression was altered, or in which a ligand-independent form of RET kinase was expressed. The Hoxb7 promoter was used to express RET throughout the ureteric bud branches, in contrast to its normal expression only at the bud tips. This caused a variable inhibition of ureteric bud growth and branching reminiscent of, but less severe than, the RET knockout phenotype. Manipulation of the level of GDNF, in vitro or in vivo, suggested that this defect was due to insufficient rather than excessive RET signaling. We propose that RET receptors expressed ectopically on ureteric bud trunk cells sequester GDNF, reducing its availability to the normal target cells at the bud tips. When crossed to RET knockout mice, the Hoxb7/RET transgene, which encoded the RET9 isoform, supported normal kidney development in some RET-/- animals, indicating that the other major isoform, RET51, is not required in this organ. Expression of a Hoxb7/RET-PTC2 transgene, encoding a ligand-independent form of RET kinase, caused the development of abnormal nodules, outside the kidney or at its periphery, containing branched epithelial tubules apparently formed by deregulated growth of the ureteric bud. This suggests that RET signaling is not only necessary but is sufficient to induce ureteric bud growth, and that the orderly, centripetal growth of the bud tips is controlled by the spatially and temporally regulated expression of GDNF and RET.


PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study.
The role of hybrid imaging using 18F-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study. This prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Västerbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umeå University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology. Twenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management. The RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI. NCT03846882 .


Management of velopharyngeal insufficiency: development of a protocol and modifications of sphincter pharyngoplasty.
Velopharyngeal closure is required for normal speech production. Incomplete velopharyngeal closure manifests as resonance disorders and nasal air escape. Management of velopharyngeal insufficiency requires a general knowledge of speech production as well as a more detailed understanding of the velopharyngeal mechanism. Comprehensive evaluation by a velopharyngeal insufficiency team includes medical assessment focusing on airway obstructive symptoms, perceptual speech analysis, and instrumental assessment, which is utilized to characterize the velopharyngeal gap. Options for intervention include speech therapy, intraoral prosthetic devices, and surgery. Surgical interventions can be categorized as palatal, palatopharyngeal, or pharyngeal procedures. The therapeutic challenge lies in achieving velopharyngeal closure during speech production while maintaining patency of the upper airway. We present our protocol for evaluation of velopharyngeal function with a focus on indications for palatoplasty and pharyngoplasty. We also discuss surgical modifications of sphincter pharyngoplasty.


The role of gamma delta T cells in haematopoietic stem cell transplantation.
Although haematopoietic stem cell transplantation (HSCT) is a potential curative treatment for haematological malignancies, it is still a procedure associated with substantial morbidity and mortality due to toxicity, graft-versus-host disease (GVHD) and relapse. Recent attempts of developing safer transplantation modalities increasingly focuses on selective cell depletion and graft engineering with the aim of retaining beneficial immune donor cells for the graft-versus-leukaemia (GVL) effect. In this context, the adoptive and especially innate effector functions of γδ T cells together with clinical studies investigating the effect of γδ T cells in relation to HSCT are reviewed. In addition to phospho-antigen recognition by the γδ T cell receptor (TCR), γδ T cells express receptors of the natural killer (NK) and natural cytotoxicity (NCR) families enabling them to recognize and kill leukaemia cells. Antigen recognition independent from the major histocompatibility complex (MHC) allows for the theoretical possibility of mediating GVL without an allogeneic response in terms of GVHD. Early studies on the impact of γδ T cells in HSCT have reported conflicting results. Recent studies, however, do suggest an overall favourable effect of high γδ T cell immune reconstitution after HSCT; patients with elevated numbers of γδ T cells had a significantly higher overall survival rate and a decreased rate of acute GVHD compared to patients with low or normal γδ T cell counts. Further research in terms of effector mechanisms, subtypes and tissue distribution during the course of HSCT is needed to assess the potentially beneficial effects of γδ T cells in this setting.


Infrequent confirmation of visual field progression.
To evaluate the effects of the repeatability criteria on the detection of change in visual fields by six progression algorithms used in standard automated perimetry. Retrospective, observational case series Fifty-one glaucoma patients, each with multiple visual fields performed between May 1990 and December 1998, were included. Each patient's set of visual fields were analyzed using the glaucoma change probability, the Early Manifest Glaucoma Trial (EMGT) algorithm, a modified glaucoma change probability score, a modified EMGT score, the Advanced Glaucoma Intervention Study algorithm, and the Collaborative Initial Glaucoma Treatment Study algorithm. The effects of repeatability on the detection of field change, the level of agreement among algorithms, as well as the number of eyes identified as changed with each algorithm, were assessed. Mean follow-up was 34 months (range, 12-87 months). The average percentage of eyes with change based on three consecutive follow-up fields was 8.2% (4.0%-12.5%). However, of those showing change on the initial follow-up, this change from baseline was observed in subsequent examinations on average in 23% (18%-33%), depending on the algorithm. When change was based on just one field, four of the six algorithms noted a significantly greater number of eyes with change. The algorithms, however, did not differ significantly when confirmation of field change required two versus three consecutive follow-up visual fields. Although current algorithms may help identify change, there are inconsistencies among them. We found that requiring repeatable change from baseline significantly reduces the number of changed eyes identified with each subsequent follow-up field. Identification and confirmation of change in visual fields plays an important role in helping to identify true glaucoma progression; however, the specific methods to do so have yet to be determined.


Major histocompatibility complex class II-expressing endothelial cells induce allospecific nonresponsiveness in naive T cells.
The role of endothelial cells (EC) in initiating a primary T cell response is of importance in clinical transplantation and autoimmunity since EC are the first allogeneic target encountered by the recipient's immune system and may display tissue-specific autoantigens in the context of an inflammatory response. In this study, we have investigated the antigen-presenting cell function of human umbilical vein-derived EC (HUVEC), depleted of constitutively major histocompatibility complex class II+ cells and induced to express class II molecules by interferon-gamma. The results show that HUVEC do not express B7 but can support proliferation by antigen-specific T cell clones. In contrast, they were unable to initiate a primary alloresponse using three independent HUVEC cultures and MHC class II-mismatched CD4+ T cells from eight donors. The response to HUVEC was reconstituted by trans-costimulation provided by DAP.3 transfectants expressing human B7.1. Coculture of peripheral blood T cells with EC expressing allogeneic DR molecules had markedly different effects on CD45RO+ and RA+ subsets. Subsequent reactivity of the RO+ T cells was unaffected by exposure to EC, indicating a neutral encounter. In contrast, culture with DR+ EC induced allospecific nonresponsiveness in RA+ T cells.


Effect of Mechanical Ventilation Mode Type on Intra- and Postoperative Blood Loss in Patients Undergoing Posterior Lumbar Interbody Fusion Surgery: A Randomized Controlled Trial.
The aim of study was to evaluate the effect of mechanical ventilation mode type, pressure-controlled ventilation (PCV), or volume-controlled ventilation (VCV) on intra- and postoperative surgical bleeding in patients undergoing posterior lumbar interbody fusion (PLIF) surgery. This was a prospective, randomized, single-blinded, and parallel study that included 56 patients undergoing PLIF and who were mechanically ventilated using PCV or VCV. A permuted block randomization was used with a computer-generated list. The hemodynamic and respiratory parameters were measured after anesthesia induction in supine position, 5 min after patients were changed from supine to prone position, at the time of skin closure, and 5 min after the patients were changed from prone to supine position. The amount of intraoperative surgical bleeding, fluid administration, urine output, and transfusion requirement were measured at the end of surgery. The amount of postoperative bleeding and transfusion requirement were recorded every 24 h for 72 h. The primary outcome was the amount of intraoperative surgical bleeding, and 56 patients were analyzed. The amount of intraoperative surgical bleeding was significantly less in the PCV group than that in the VCV group (median, 253.0 [interquartile range, 179.0 to 316.5] ml in PCV group vs. 382.5 [328.0 to 489.5] ml in VCV group; P < 0.001). Comparing other parameters between groups, only peak inspiratory pressure at each measurement point in PCV group was significantly lower than that in VCV group. No harmful events were recorded. Intraoperative PCV decreased intraoperative surgical bleeding in patients undergoing PLIF, which may be related to lower intraoperative peak inspiratory pressure.


The Vibrio parahaemolyticus Type III Secretion Systems manipulate host cell MAPK for critical steps in pathogenesis.
Vibrio parahaemolyticus is a food-borne pathogen causing inflammation of the gastrointestinal epithelium. Pathogenic strains of this bacterium possess two Type III Secretion Systems (TTSS) that deliver effector proteins into host cells. In order to better understand human host cell responses to V. parahaemolyticus, the modulation of Mitogen Activated Protein Kinase (MAPK) activation in epithelial cells by an O3:K6 clinical isolate, RIMD2210633, was investigated. The importance of MAPK activation for the ability of the bacterium to be cytotoxic and to induce secretion of Interleukin-8 (IL-8) was determined. V. parahaemolyticus deployed its TTSS1 to induce activation of the JNK, p38 and ERK MAPK in human epithelial cells. VP1680 was identified as the TTSS1 effector protein responsible for MAPK activation in Caco-2 cells and the activation of JNK and ERK by this protein was important in induction of host cell death. V. parahaemolyticus actively induced IL-8 secretion in a response mediated by TTSS1. A role for VP1680 and for the ERK signalling pathway in the stimulation of IL-8 production in epithelial cells by V. parahaemolyticus was established. Interestingly, TTSS2 inhibited IL-8 mRNA transcription at early stages of interaction between the bacterium and the cell. This study demonstrated that V. parahaemolyticus activates the three major MAPK signalling pathways in intestinal epithelial cells in a TTSS1-dependent manner that involves the TTSS1 effector VP1680. Furthermore VP1680 and JNK and ERK activation were needed for maximal cytotoxicity of the bacterium. It was shown that V. parahaemolyticus is a strong inducer of IL-8 secretion and that induction reflects a balance between the effects of TTSS1 and TTSS2. Increases in IL-8 secretion were mediated by TTSS1 and VP1680, and augmented by ERK activation. These results shed light on the mechanisms of bacterial pathogenesis mediated by TTSS and suggest significant roles for MAPK signalling during infection with V. parahaemolyticus.


Assessing impaired hypoglycemia awareness in type 1 diabetes: agreement of self-report but not of field study data with the autonomic symptom threshold during experimental hypoglycemia.
The aim of our study was to determine the agreement of two noninvasive methods, a self-report and a field study method, for the assessment of impaired hypoglycemia awareness with a gold standard criterion of hypoglycemia awareness, the autonomic symptom threshold during experimental hypoglycemia. A total of 19 type 1 diabetic patients completed a standardized questionnaire to assess impaired hypoglycemia awareness and performed a hand-held computer (HHC) study to assess their recognition of hypoglycemic episodes occurring during 24 weeks. Patients subsequently underwent a stepped hypoglycemic clamp to study responses to standardized hypoglycemia. Diagnoses of impaired hypoglycemia awareness were based on the separate self-report questions, a composite self-report score, and three different cutoff levels for the percentage of accurately recognized hypoglycemic episodes during the field study Agreement of these noninvasive measures with the hypoglycemic clamp measure were tested by calculating kappa values, sensitivity, and specificity. The composite self-report score agreed reasonably well with the hypoglycemic clamp measure (kappa 0.49, sensitivity 66.7%, and specificity 85.7%) and showed a better agreement than the separate self-report questions. The HHC criterion of impaired hypoglycemia awareness did not agree with the hypoglycemic clamp criterion at any of the cutoff levels tested. The composite self-report tested in this study is a reasonably reliable assessment method for the diagnosis of impaired hypoglycemia awareness, using the physiological definition of an absence of autonomic symptoms at a blood glucose level of 3 mmol/l. In contrast, the recognition of hypoglycemic events in everyday life as measured using the HHC method is not related to the hypoglycemic clamp criterion.


Transcranial magnetic stimulation for depression and other psychiatric disorders.
Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a possible alternative to electroconvulsive therapy for the treatment of selected patients with depression, bipolar affective disorder and schizophrenia. The aim of this study was to evaluate the evidence for the effectiveness of rTMS in mood disorders and schizophrenia. Studies were identified using MEDLINE (1966 to January 2000), EMBASE/Excerpta Medica (1980 to January 2000), Biological Abstracts and Index to Scientific and Technical Proceedings. A number of biomedical and TMS related websites were also searched. We estimated the number needed to treat to show beneficial effect of rTMS when compared with the placebo controlled group. Seven controlled trials of rTMS depression were identified. Five of these were suitable for meta-analysis and show a beneficial effect of rTMS compared to placebo, with a number needed to treat of 2-3 with a 95 % confidence interval 1.6 to 4.0, total; 81 patients. A single trial of rTMS has also been performed in mania, which shows a beneficial effect of right hemisphere stimulation when compared with left hemisphere stimulation. A controlled trial in schizophrenia failed to show any benefit of rTMS. rTMS has demonstrable beneficial effects in depression. The extent and the duration of the anti-depressant effect of rTMS has yet to be defined. There now needs to be randomized controlled trials to compare rTMS directly with standardized electroconvulsive therapy in order to take this subject forward. With regard to the treatment of other mood disorders and schizophrenia, we are at an early stage in the assessment of further studies that are needed to examine any potential role for rTMS.


A comparison of self-reported and device measured sedentary behaviour in adults: a systematic review and meta-analysis.
Sedentary behaviour (SB) is a risk factor for chronic disease and premature mortality. While many individual studies have examined the reliability and validity of various self-report measures for assessing SB, it is not clear, in general, how self-reported SB (e.g., questionnaires, logs, ecological momentary assessments (EMAs)) compares to device measures (e.g., accelerometers, inclinometers). The primary objective of this systematic review was to compare self-report versus device measures of SB in adults. Six bibliographic databases were searched to identify all studies which included a comparable self-report and device measure of SB in adults. Risk of bias within and across studies was assessed. Results were synthesized using meta-analyses. The review included 185 unique studies. A total of 123 studies comprising 173 comparisons and data from 55,199 participants were used to examine general criterion validity. The average mean difference was -105.19 minutes/day (95% CI: -127.21, -83.17); self-report underestimated sedentary time by ~1.74 hours/day compared to device measures. Self-reported time spent sedentary at work was ~40 minutes higher than when assessed by devices. Single item measures performed more poorly than multi-item questionnaires, EMAs and logs/diaries. On average, when compared to inclinometers, multi-item questionnaires, EMAs and logs/diaries were not significantly different, but had substantial amount of variability (up to 6 hours/day within individual studies) with approximately half over-reporting and half under-reporting. A total of 54 studies provided an assessment of reliability of a self-report measure, on average the reliability was good (ICC = 0.66). Evidence from this review suggests that single-item self-report measures generally underestimate sedentary time when compared to device measures. For accuracy, multi-item questionnaires, EMAs and logs/diaries with a shorter recall period should be encouraged above single item questions and longer recall periods if sedentary time is a primary outcome of study. Users should also be aware of the high degree of variability between and within tools. Studies should exert caution when comparing associations between different self-report and device measures with health outcomes. PROSPERO CRD42019118755.


Vasodilator therapy for chronic left ventricular failure.
The effects of chronic oral vasodilator therapy were studied in a group of patients with refractory congestive heart failure. Fifteen patients were treated acutely with intravenous sodium nitroprusside and sublingual isosorbide dinitrate. After continuous therapy with nitroprusside and isosorbide dinitrate for up to 72 hours the patients were then placed on isosorbide dinitrate and oral phenoxybenzamine. Hemodynamic responses to nitroprusside, isosorbide dinitrate, and phenoxybenzamine with isosorbide dinitrate were determined. After a mean follow-up of seven months, nine patients who were receiving isosorbide dinitrate and phenoxybenzamine underwent repeat hemodynamic studies. Beneficial effects of acute vasodilator therapy included a significant reduction in pulmonary capillary wedge pressure and systemic vascular resistance, and significant increases in cardiac index and stroke work index. Mean arterial blood pressure and heart rate were unchanged. During the period of chronic vasodilator administration, no other change in basic therapy with isosorbide dinitrate and phenoxybenzamine (3-21 months), the favorable effects observed acutely were maintained. All patients demonstrated symptomatic improvement with minimal side effects. The beneficial hemodynamic responses that are noted with acute vasodilator therapy in patients in advanced congestive heart failure are maintained with oral therapy on a chronic basis.


Biodiversity, distributions and adaptations of Arctic species in the context of environmental change.
The individual of a species is the basic unit which responds to climate and UV-B changes, and it responds over a wide range of time scales. The diversity of animal, plant and microbial species appears to be low in the Arctic, and decreases from the boreal forests to the polar deserts of the extreme North but primitive species are particularly abundant. This latitudinal decline is associated with an increase in super-dominant species that occupy a wide range of habitats. Climate warming is expected to reduce the abundance and restrict the ranges of such species and to affect species at their northern range boundaries more than in the South: some Arctic animal and plant specialists could face extinction. Species most likely to expand into tundra are boreal species that currently exist as outlier populations in the Arctic. Many plant species have characteristics that allow them to survive short snow-free growing seasons, low solar angles, permafrost and low soil temperatures, low nutrient availability and physical disturbance. Many of these characteristics are likely to limit species' responses to climate warming, but mainly because of poor competitive ability compared with potential immigrant species. Terrestrial Arctic animals possess many adaptations that enable them to persist under a wide range of temperatures in the Arctic. Many escape unfavorable weather and resource shortage by winter dormancy or by migration. The biotic environment of Arctic animal species is relatively simple with few enemies, competitors, diseases, parasites and available food resources. Terrestrial Arctic animals are likely to be most vulnerable to warmer and drier summers, climatic changes that interfere with migration routes and staging areas, altered snow conditions and freeze-thaw cycles in winter, climate-induced disruption of the seasonal timing of reproduction and development, and influx of new competitors, predators, parasites and diseases. Arctic microorganisms are also well adapted to the Arctic's climate: some can metabolize at temperatures down to -39 degrees C. Cyanobacteria and algae have a wide range of adaptive strategies that allow them to avoid, or at least minimize UV injury. Microorganisms can tolerate most environmental conditions and they have short generation times which can facilitate rapid adaptation to new environments. In contrast, Arctic plant and animal species are very likely to change their distributions rather than evolve significantly in response to warming.


Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 6 (STAT6) with Cell-Permeable, Phosphatase-Stable Phosphopeptide Mimics Potently Inhibits Tyr641 Phosphorylation and Transcriptional Activity.
Signal transducer and activator of transcription 6 (STAT6) transmits signals from cytokines IL-4 and IL-13 and is activated in allergic airway disease. We are developing phosphopeptide mimetics targeting the SH2 domain of STAT6 to block recruitment to phosphotyrosine residues on IL-4 or IL-13 receptors and subsequent Tyr641 phosphorylation to inhibit the expression of genes contributing to asthma. Structure-affinity relationship studies showed that phosphopeptides based on Tyr631 from IL-4Rα bind with weak affinity to STAT6, whereas replacing the pY+3 residue with simple aryl and alkyl amides resulted in affinities in the mid to low nM range. A set of phosphatase-stable, cell-permeable prodrug analogues inhibited cytokine-stimulated STAT6 phosphorylation in both Beas-2B human airway cells and primary mouse T-lymphocytes at concentrations as low as 100 nM. IL-13-stimulated expression of CCL26 (eotaxin-3) was inhibited in a dose-dependent manner, demonstrating that targeting the SH2 domain blocks both phosphorylation and transcriptional activity of STAT6.


Genetic testing of children for adult-onset conditions: opinions of the British adult population and implications for clinical practice.
This study set out to explore the attitudes of a representative sample of the British public towards genetic testing in children to predict disease in the future. We sought opinions about genetic testing for adult-onset conditions for which no prevention/treatment is available during childhood, and about genetic 'carrier' status to assess future reproductive risks. The study also examined participants' level of agreement with the reasons professional organisations give in favour of deferring such testing. Participants (n=2998) completed a specially designed questionnaire, distributed by email. Nearly half of the sample (47%) agreed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. This runs contrary to professional guidance about genetic testing in children. Testing for carrier status was supported by a larger proportion (60%). A child's future ability to decide for her/himself if and when to be tested was the least supported argument in favour of deferring testing.


Calbindin d28k overexpression protects striatal neurons from transient focal cerebral ischemia.
Increased intracellular calcium accumulation is known to potentiate ischemic injury. Whether endogenous calcium-binding proteins can attenuate this injury has not been clearly established, and existing data are conflicting. Calbindin D28K (CaBP) is one such intracellular calcium buffer. We investigated whether CaBP overexpression is neuroprotective against transient focal cerebral ischemia. Bipromoter, replication-incompetent herpes simplex virus vectors that encoded the genes for cabp and, as a reporter gene, lacZ were used. Sprague-Dawley rats received bilateral striatal injections of viral vector 12 to 15 hours before ischemia onset. With the use of an intraluminal occluding suture, animals were subjected to 1 hour of middle cerebral artery occlusion followed by 47 hours of reperfusion. Brains were harvested and stained with X-gal (to visualize beta-galactosidase, the gene product of lacZ). The number of remaining virally transfected, X-gal-stained neurons in both the ischemic and contralateral striata were counted and expressed as the percentage of surviving neurons in the ischemic striatum relative to the contralateral nonischemic striatum. Striatal neuron survivorship among cabp-injected animals was 53.5+/-4.1% (n=10) versus 26.8+/-5.4% among those receiving lacZ (n=9) (mean+/-SEM; P<0.001). We conclude that viral vector-mediated overexpression of CaBP leads to neuroprotection in this model of central nervous system injury. This is the first demonstration that CaBP overexpression protects neurons in a focal stroke model.


Group music performance causes elevated pain thresholds and social bonding in small and large groups of singers.
Over our evolutionary history, humans have faced the problem of how to create and maintain social bonds in progressively larger groups compared to those of our primate ancestors. Evidence from historical and anthropological records suggests that group music-making might act as a mechanism by which this large-scale social bonding could occur. While previous research has shown effects of music making on social bonds in small group contexts, the question of whether this effect 'scales up' to larger groups is particularly important when considering the potential role of music for large-scale social bonding. The current study recruited individuals from a community choir that met in both small (n = 20 - 80) and large (a 'megachoir' combining individuals from the smaller subchoirs n = 232) group contexts. Participants gave self-report measures (via a survey) of social bonding and had pain threshold measurements taken (as a proxy for endorphin release) before and after 90 minutes of singing. Results showed that feelings of inclusion, connectivity, positive affect, and measures of endorphin release all increased across singing rehearsals and that the influence of group singing was comparable for pain thresholds in the large versus small group context. Levels of social closeness were found to be greater at pre- and post-levels for the small choir condition. However, the large choir condition experienced a greater change in social closeness as compared to the small condition. The finding that singing together fosters social closeness - even in large contexts where individuals are not known to each other - is consistent with evolutionary accounts that emphasize the role of music in social bonding, particularly in the context of creating larger cohesive groups than other primates are able to manage.


Development of Sound Localization Strategies in Children with Bilateral Cochlear Implants.
Localizing sounds in our environment is one of the fundamental perceptual abilities that enable humans to communicate, and to remain safe. Because the acoustic cues necessary for computing source locations consist of differences between the two ears in signal intensity and arrival time, sound localization is fairly poor when a single ear is available. In adults who become deaf and are fitted with cochlear implants (CIs) sound localization is known to improve when bilateral CIs (BiCIs) are used compared to when a single CI is used. The aim of the present study was to investigate the emergence of spatial hearing sensitivity in children who use BiCIs, with a particular focus on the development of behavioral localization patterns when stimuli are presented in free-field horizontal acoustic space. A new analysis was implemented to quantify patterns observed in children for mapping acoustic space to a spatially relevant perceptual representation. Children with normal hearing were found to distribute their responses in a manner that demonstrated high spatial sensitivity. In contrast, children with BiCIs tended to classify sound source locations to the left and right; with increased bilateral hearing experience, they developed a perceptual map of space that was better aligned with the acoustic space. The results indicate experience-dependent refinement of spatial hearing skills in children with CIs. Localization strategies appear to undergo transitions from sound source categorization strategies to more fine-grained location identification strategies. This may provide evidence for neural plasticity, with implications for training of spatial hearing ability in CI users.


External validation of diagnostic models to estimate the risk of malignancy in adnexal masses.
To externally validate and compare the performance of previously published diagnostic models developed to predict malignancy in adnexal masses. We externally validated the diagnostic performance of 11 models developed by the International Ovarian Tumor Analysis (IOTA) group and 12 other (non-IOTA) models on 997 prospectively collected patients. The non-IOTA models included the original risk of malignancy index (RMI), three modified versions of the RMI, six logistic regression models, and two artificial neural networks. The ability of the models to discriminate between benign and malignant adnexal masses was expressed as the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and likelihood ratios (LR(+), LR(-)). Seven hundred and forty-two (74%) benign and 255 (26%) malignant masses were included. The IOTA models did better than the non-IOTA models (AUCs between 0.941 and 0.956 vs. 0.839 and 0.928). The difference in AUC between the best IOTA and the best non-IOTA model was 0.028 [95% confidence interval (CI), 0.011-0.044]. The AUC of the RMI was 0.911 (difference with the best IOTA model, 0.044; 95% CI, 0.024-0.064). The superior performance of the IOTA models was most pronounced in premenopausal patients but was also observed in postmenopausal patients. IOTA models were better able to detect stage I ovarian cancer. External validation shows that the IOTA models outperform other models, including the current reference test RMI, for discriminating between benign and malignant adnexal masses.


The refined crystal structure of an eel pout type III antifreeze protein RD1 at 0.62-A resolution reveals structural microheterogeneity of protein and solvation.
RD1 is a 7-kDa globular protein from the Antarctic eel pout Lycodichthys dearborni. It belongs to type III of the four types of antifreeze proteins (AFPs) found in marine fishes living at subzero temperatures. For type III AFP, a potential ice-binding flat surface has been identified and is imbedded with side chains capable of making hydrogen bonds with a specific lattice plane on ice. So far, all crystallographic studies on type III AFPs were carried out using the Atlantic ocean pout Macrozoarces americanus as the source organism. Here we present the crystal structure of a type III AFP from a different zoarcid fish, and at an ultra-high resolution of 0.62 A. The protein fold of RD1 comprises a compact globular domain with two internal tandem motifs arranged about a pseudo-dyad symmetry. Each motif of the "pretzel fold" includes four short beta-strands and a 3(10) helix. There is a novel internal cavity of 45 A(3) surrounded by eight conserved nonpolar residues. The model contains several residues with alternate conformations, and a number of split water molecules, probably caused by alternate interactions with the protein molecule. After extensive refinement that includes hydrogen atoms, significant residual electron densities associated with the electrons of peptides and many other bonds could be visualized.


Emerging potential benefits of modulating NAD+ metabolism in cardiovascular disease.
Nicotinamide adenine dinucleotide (NAD+) and related metabolites are central mediators of fuel oxidation and bioenergetics within cardiomyocytes. Additionally, NAD+ is required for the activity of multifunctional enzymes, including sirtuins and poly(ADP-ribose) polymerases that regulate posttranslational modifications, DNA damage responses, and Ca2+ signaling. Recent research has indicated that NAD+ participates in a multitude of processes dysregulated in cardiovascular diseases. Therefore, supplementation of NAD+ precursors, including nicotinamide riboside that boosts or repletes the NAD+ metabolome, may be cardioprotective. This review examines the molecular physiology and preclinical data with respect to NAD+ precursors in heart failure-related cardiac remodeling, ischemic-reperfusion injury, and arrhythmias. In addition, alternative NAD+-boosting strategies and potential systemic effects of NAD+ supplementation with implications on cardiovascular health and disease are surveyed.


Factors Influencing Adherence to Standard Precautions Scale: A psychometric validation.
Despite the mandated use of standard precaution guidelines to limit infection transmission in health-care settings, adherence by health-care professionals is suboptimal. There is currently no psychometrically-validated scale to assess influences on workers' adherence. After the data collection was conducted, Michinov et al. (2016) published a questionnaire to determine sociocognitive determinants of adherence to Standard Precautions. The aim of the present study was to develop and test the psychometric properties of such a scale. Forty nine items were derived from interviews with 29 nurses and tested across two studies. Study 1 was a repeated-measures survey using principal components analysis with data from 363 participants; a 29 item, five factor solution was extracted with good to acceptable internal reliabilities (α = .61-.85). Data from 122 of the original participants retested at 4 weeks showed intraclass correlations of .69-.84. Study 2, which was 6 months later, used confirmatory factor analysis with data from a second sample of 384 participants, and supported the five factor structure of leadership, justification, culture/practice, contextual cues, and judgement. The Factors Influencing Adherence to Standard Precautions Scale has good psychometric properties and stability across time and samples. The scale is suitable for use with nurses, and its validation with other health-care professionals and trainees is important in order to tailor effective interventions to promote adherence.


Multifactorial effects of ambient temperature, precipitation, farm management, and environmental factors determine the level of generic Escherichia coli contamination on preharvested spinach.
A repeated cross-sectional study was conducted to identify farm management, environment, weather, and landscape factors that predict the count of generic Escherichia coli on spinach at the preharvest level. E. coli was enumerated for 955 spinach samples collected on 12 farms in Texas and Colorado between 2010 and 2012. Farm management and environmental characteristics were surveyed using a questionnaire. Weather and landscape data were obtained from National Resources Information databases. A two-part mixed-effect negative binomial hurdle model, consisting of a logistic and zero-truncated negative binomial part with farm and date as random effects, was used to identify factors affecting E. coli counts on spinach. Results indicated that the odds of a contamination event (non-zero versus zero counts) vary by state (odds ratio [OR] = 108.1). Odds of contamination decreased with implementation of hygiene practices (OR = 0.06) and increased with an increasing average precipitation amount (mm) in the past 29 days (OR = 3.5) and the application of manure (OR = 52.2). On contaminated spinach, E. coli counts increased with the average precipitation amount over the past 29 days. The relationship between E. coli count and the average maximum daily temperature over the 9 days prior to sampling followed a quadratic function with the highest bacterial count at around 24°C. These findings indicate that the odds of a contamination event in spinach are determined by farm management, environment, and weather factors. However, once the contamination event has occurred, the count of E. coli on spinach is determined by weather only.


Real-Time Chemical Analysis of E-Cigarette Aerosols By Means Of Secondary Electrospray Ionization Mass Spectrometry.
Chemical analysis of aerosols collected from electronic cigarettes (ECs) has shown that these devices produce vapors that contain harmful and potentially harmful compounds. Conventional analytical methods used for the analysis of electronic cigarettes do not reflect the actual composition of the aerosols generated because they usually neglect the changes in the chemical composition that occur during the aerosol generation process and after collection. The aim of this work was to develop and apply a method for the real-time analysis of electronic cigarette aerosols, based on the secondary electrospray ionization technique coupled to high-resolution mass spectrometry, by mimicking the "vaping" process. Electronic cigarette aerosols were successfully analyzed and quantitative differences were found between the liquids and aerosols. Thanks to the high sensitivity shown by this method, more than 250 chemical substances were detected in the aerosols, some of them showing a high correlation with the operating power of the electronic cigarettes. The method also allows proper quantification of several chemical components such as alkaloids and flavor compounds.


Effectiveness of school-based smoking prevention curricula: systematic review and meta-analysis.
To assess effectiveness of school-based smoking prevention curricula keeping children never-smokers. Systematic review, meta-analysis. MEDLINE (1966+), EMBASE (1974+), Cinahl, PsycINFO (1967+), ERIC (1982+), Cochrane CENTRAL, Health Star, Dissertation Abstracts, conference proceedings. pooled analyses, fixed-effects models, adjusted ORs. Risk of bias assessed with Cochrane Risk of Bias tool. 50 randomised controlled trials (RCTs) of school-based smoking curricula. Never-smokers age 5-18 (n=143,495); follow-up ≥6 months; all countries; no date/language limitations. Information, social influences, social competence, combined social influences/competence and multimodal curricula. Remaining a never-smoker at follow-up. Pooling all curricula, trials with follow-up ≤1 year showed no statistically significant differences compared with controls (OR 0.91 (0.82 to 1.01)), though trials of combined social competence/social influences curricula had a significant effect on smoking prevention (7 trials, OR 0.59 (95% CI 0.41 to 0.85)). Pooling all trials with longest follow-up showed an overall significant effect in favour of the interventions (OR 0.88 (0.82 to 0.95)), as did the social competence (OR 0.65 (0.43 to 0.96)) and combined social competence/social influences curricula (OR 0.60 (0.43 to 0.83)). No effect for information, social influences or multimodal curricula. Principal findings were not sensitive to inclusion of booster sessions in curricula or to whether they were peer-led or adult-led. Differentiation into tobacco-only or multifocal curricula had a similar effect on the primary findings. Few trials assessed outcomes by gender: there were significant effects for females at both follow-up periods, but not for males. RCTs of baseline never-smokers at longest follow-up found an overall significant effect with average 12% reduction in starting smoking compared with controls, but no effect for all trials pooled at ≤1 year. However, combined social competence/social influences curricula showed a significant effect at both follow-up periods. Cochrane Tobacco Review Group CD001293.


PCR amplification and direct sequencing of gyrB genes with universal primers and their application to the detection and taxonomic analysis of Pseudomonas putida strains.
Degenerate PCR primers, UP-1 and UP-2r, for the amplification of DNA gyrase subunit B genes (gyrB) were designed by using consensus amino acid sequences of gyrases from Escherichia coli, Pseudomonas putida, and Bacillus subtilis. In addition to the degenerate sequences, these primers have sequences at the 5' end which allow direct sequencing of amplified PCR products. With these primers, DNA segments of the predicted size were amplified from a variety of gram-negative and gram-positive genera. The nucleotide sequences of the amplified gyrB DNA from three P. putida strains were determined directly from the amplified fragments. The base substitution frequency of gyrB between the strains of P. putida was much higher than that of the 16S rRNA gene. With a specific set of PCR primers, it was possible to amplify gyrB fragments selectively from P. putida or its subgroups. The direct sequencing method of gyrB developed in this study provides a rapid and convenient system for bacterial identification, taxonomic analysis, and monitoring of bacteria in the natural environment.


The RNA-binding protein HOS5 and serine/arginine-rich proteins RS40 and RS41 participate in miRNA biogenesis in Arabidopsis.
MicroRNAs are a class of small regulatory RNAs that are generated from primary miRNA (pri-miRNA) transcripts with a stem-loop structure. Accuracy of the processing of pri-miRNA into mature miRNA in plants can be enhanced by SERRATE (SE) and HYPONASTIC LEAVES 1 (HYL1). HYL1 activity is regulated by the FIERY2 (FRY2)/RNA polymerase II C-terminal domain phosphatase-like 1 (CPL1). Here, we discover that HIGH OSMOTIC STRESS GENE EXPRESSION 5 (HOS5) and two serine/arginine-rich splicing factors RS40 and RS41, previously shown to be involved in pre-mRNA splicing, affect the biogenesis of a subset of miRNA. These proteins are required for correct miRNA strand selection and the maintenance of miRNA levels. FRY2 dephosphorylates HOS5 whose phosphorylation status affects its subnuclear localization. HOS5 and the RS proteins bind both intronless and intron-containing pri-miRNAs. Importantly, all of these splicing-related factors directly interact with both HYL1 and SE in nuclear splicing speckles. Our results indicate that these splicing factors are directly involved in the biogenesis of a group of miRNA.