Search

Treated-wastewater (TW) irrigation transfers antibiotic-resistant bacteria (ARB) to soil, but persistence of these bacteria is generally low due to resilience of the soil microbiome. Nonetheless, wastewater-derived bacteria and associated antibiotic resistance genes (ARGs) may persist below detection levels and potentially proliferate under copiotrophic conditions. To test this hypothesis, we exposed soils from microcosm, lysimeter, and field experiments to short-term enrichment in copiotroph-stimulating media. In microcosms, enrichment stimulated growth of multidrug-resistant Escherichia coli up to 2 weeks after falling below detection limits. Lysimeter and orchard soils irrigated in-tandem with either freshwater or TW were subjected to culture-based, qPCR and shotgun metagenomic analyses prior, and subsequent, to enrichment. Although native TW- and freshwater-irrigated soil microbiomes and resistomes were similar to each other, enrichment resulted in higher abundances of cephalosporin- and carbapenem-resistant Enterobacteriaceae and in substantial differences in the composition of microbial communities and ARGs. Enrichment stimulated ARG-harboring Bacillaceae in the freshwater-irrigated soils, whereas in TWW-irrigated soils, ARG-harboring γ-proteobacterial families Enterobacteriaceae and Moraxellaceae were more profuse. We demonstrate that TW-derived ARB and associated ARGs can persist at below detection levels in irrigated soils and believe that similar short-term enrichment strategies can be applied for environmental antimicrobial risk assessment in the future.

Living cells perform sophisticated computations that guide them toward discrete states. Synthetic genetic circuits are powerful tools for programing these computations, where transcription-regulatory networks and DNA recombination are the two dominant paradigms for implementing these systems. While each strategy exhibits unique strengths and weaknesses, integrating both into one seamless design framework would enable advanced gene circuit designs intractable with either approach alone. Here, we present Computation via Recombinase Assisted Transcriptional Effectors (CREATE), which leverages site-specific recombination to perform robust logic on discreet computational layers and programmable transcription factors that connect these layers, allowing individual calculations to contribute toward larger operations. We demonstrate the functionality of CREATE by producing sophisticated circuits using a simple plug- and-play framework, including 189 2-input-3-output circuits, modular digital-to-analog signal converters, a 2-bit multiplier circuit, and a digital and analog mixed-signal generator. This work establishes CREATE as a versatile platform for programming complex signal processing systems capable of high-fidelity logic computation and tunable control over circuit output levels.One-Sentence SummaryWe present a minimal and robust genetic circuit platform for programming cells with sophisticated signal processing capabilities.

Alphaviruses (genus Alphavirus; family Togaviridae) are a medically relevant family of viruses that include chikungunya virus and Mayaro virus. Infectious cDNA clones of these viruses are necessary molecular tools to understand viral biology. Traditionally, rescuing virus from an infectious cDNA clone requires propagating plasmids in bacteria, which can result in mutations in the viral genome due to bacterial toxicity or recombination and requires specialized equipment and knowledge to propagate the bacteria. Here, we present an alternative- rolling circle amplification (RCA), an in vitro technology. We demonstrate that the viral yield of transfected RCA product is comparable to midiprepped plasmid, albeit with a slight delay in kinetics. RCA, however, is cheaper and less time-consuming. Further, sequential RCA did not introduce mutations into the viral genome, subverting the need for glycerol stocks and retransformation. These results indicate that RCA is a viable alternative to traditional plasmid-based approaches to viral rescue.

Contains fulltext : 282658.pdf (Publisher’s version ) (Open Access) IMPORTANCE: The Global Burden of Disease study conducted between 1990 and 2016, based on a global study of 195 countries and territories, identified Parkinson disease (PD) as the fastest growing neurological disorder when measured using death and disability. Most people affected by PD live in low- and middle-income countries (LMICs) and experience large inequalities in access to neurological care and essential medicines. This Special Communication describes 6 actions steps that are urgently needed to address global disparities in PD. OBSERVATIONS: The adoption by the 73rd World Health Assembly (WHA) of resolution 73.10 to develop an intersectoral global action plan on epilepsy and other neurological disorders in consultation with member states was the stimulus to coordinate efforts and leverage momentum to advance the agenda of neurological conditions, such as PD. In April 2021, the Brain Health Unit at the World Health Organization convened a multidisciplinary, sex-balanced, international consultation workshop, which identified 6 workable avenues for action within the domains of disease burden; advocacy and awareness; prevention and risk reduction; diagnosis, treatment, and care; caregiver support; and research. CONCLUSIONS AND RELEVANCE: The dramatic increase of PD cases in many world regions and the potential costs of PD-associated treatment will need to be addressed to prevent possible health service strain. Across the board, governments, multilateral agencies, donors, public health organizations, and health care professionals constitute potential stakeholders who are urged to make this a priority.

Objective:To determine the clinical effect of continuous hemoperfusion with Cytosorb associated with standard Continuous Renal Replacement Therapy on hemodynamics and on clinically relevant outcome parameters in children with septic shock.Design:Retrospective analysis.Setting:Pediatric intensive care unit.Patients:Eight consecutive children with septic shock who received hemoperfusion with Cytosorb while on Continuous Renal Replacement Therapy.Interventions:Continuous hemoperfusion with Cytosorb (adsorber was changed every 24 h).Measurements and main results:Vasoactive-Inotropic Score was measured before and after the extracorporeal blood purification treatment. Bedside refractory septic shock score was calculated before the onset of the extracorporeal blood purification treatment. Time course of cytokines interleukin-6, interleukin-10, and tumor necrosis factor–alpha was measured at Time 0, then every 12 h until the end of blood purification treatment (72 or 96 h). Pediatric intensive care unit survival in our cohort was 90%. Median bedside refractory septic shock score was 2.1. Patients showed improved Vasoactive-Inotropic Score following blood purification (pre: 40.00 post: 8.89 p = 0.0076). Measurement of cytokines level showed a significant reduction of interleukin-6 plasma levels (7977.27–210.18 pg/mL, p = 0.0077) and interleukin-10 plasma levels (from 687.19 to 36.95 pg/mL, p = 0.0180). In those patients with detectable tumor necrosis factor–alpha plasma level, its reduction was not significant ( p = 0.138). The median removal ratio was 80% for interleukin-6, 90% for interleukin-10, and 29% for tumor necrosis factor–alpha.Conclusion:The use of Cytosorb in combination with Continuous Renal Replacement Therapy as blood purification strategy in pediatric septic shock is associated with a rapid hemodynamic stabilization in the first 48 h of treatment and a significant reduction of interleukin-6 and interleukin-10.

Dear editor,Digoxin is a cardioactive drug with a narrow therapeutic window. Severe intoxication may require urgent treatment. The clinical picture is represented by dangerous dysrhythmias and the ...

SARS-CoV-2 emerged in 2019 as a devastating viral pathogen with no available preventative or treatment to control what led to the current global pandemic. The continued spread of the virus and increasing death toll necessitate the development of effective antiviral treatments to combat this virus. To this end, we evaluated a new class of organometallic complexes as potential antivirals. Our findings demonstrate that two pentamethylcyclopentadienyl (Cp*) rhodium piano stool complexes, Cp*Rh(1,3-dicyclohexylimidazol-2-ylidene)Cl2 (complex 2) and Cp*Rh(dipivaloylmethanato)Cl (complex 4), have direct virucidal activity against SARS-CoV-2. Subsequent in vitro testing suggests that complex 4 is the more stable and effective complex and demonstrates that both 2 and 4 have low toxicity in Vero E6 and Calu-3 cells. The results presented here highlight the potential application of organometallic complexes as antivirals and support further investigation into their activity.

Alphaviruses (genusAlphavirus; familyTogaviridae) are a medically relevant family of viruses that include chikungunya virus, Eastern equine encephalitis virus, and the emerging Mayaro virus. Infectious cDNA clones of these viruses are necessary molecular tools to understand viral biology and to create effective vaccines. The traditional approach to rescuing virus from an infectious cDNA clone requires propagating large amounts of plasmids in bacteria, which can result in unwanted mutations in the viral genome due to bacterial toxicity or recombination and requires specialized equipment and knowledge to propagate the bacteria. Here, we present an alternative to the bacterial-based plasmid platform that uses rolling circle amplification (RCA), anin vitrotechnology that amplifies plasmid DNA using only basic equipment. We demonstrate that the use of RCA to amplify plasmid DNA is comparable to the use of a midiprepped plasmid in terms of viral yield, albeit with a slight delay in virus recovery kinetics. RCA, however, has lower cost and time requirements and amplifies DNA with high fidelity and with no chance of unwanted mutations due to toxicity. We show that sequential RCA reactions do not introduce mutations into the viral genome and, thus, can replace the need for glycerol stocks or bacteria entirely. These results indicate that RCA is a viable alternative to traditional plasmid-based approaches to viral rescue.ImportanceThe development of infectious cDNA clones is critical to studying viral pathogenesis and for developing vaccines. The current method for propagating clones in bacteria is limited by the toxicity of the viral genome within the bacterial host, resulting in deleterious mutations in the viral genome, which can only be detected through whole-genome sequencing. These mutations can attenuate the virus, leading to lost time and resources and potentially confounding results. We have developed an alternative method of preparing large quantities of DNA that can be directly transfected to recover infectious virus without the need for bacteria by amplifying the infectious cDNA clone plasmid using rolling circle amplification (RCA). Our results indicate that viral rescue from an RCA product produces a viral yield equal to bacterial-derived plasmid DNA, albeit with a slight delay in replication kinetics. The RCA platform, however, is significantly more cost and time-efficient compared to traditional approaches. When the simplicity and costs of RCA are combined, we propose that a shift to an RCA platform will benefit the field of molecular virology and could have significant advantages for recombinant vaccine production.

This Data in Brief contains results from three different survey logistic regression models comparing risks of self-reported diagnoses of cardiovascular and pulmonary diseases among smokers of menthol and non-menthol cigarettes. Analyses employ data from National Health and Nutrition Examination Survey (NHANES) cycles administered between 1999 and 2012, combined and in subsets. Raw data may be downloaded from the National Center for Health Statistics. Results were not much affected by which covariates were included in the models, but depended strongly on the NHANES cycles included in the analysis. All three models returned elevated risk estimates for three endpoints when they were run in individual NHANES cycles (congestive heart failure in 2001–02; hypertension in 2003–04; and chronic obstructive pulmonary disease in 2005–06), and all three models returned null results for these endpoints when data from 1999–2012 were combined.

Though available evidence is relatively consistent in showing no additional health effects among smokers due to menthol in cigarettes, two studies reported conflicting results for stroke risk using different subsets of NHANES data. We investigated reasons for the differences in these reports by analyzing NHANES cycles conducted between 1999 and 2012, combined and in subsets. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) from three different survey logistic regression models compare risk of reported stroke diagnoses among menthol and non-menthol cigarette smokers. Depending on timeframe, about 1150 to 8000 U.S. adults (aged ≥ 20 years) who smoked on ≥ 1 of the last 30 days had complete data for cigarette type and all covariates included in each model. Results were not much affected by which covariates were included in the models, but depended strongly on the NHANES cycles included in the analysis. Using NHANES 1999–2012 data combined, AORs and 95% CIs for stroke comparing menthol with non-menthol cigarette smokers were 0.95 (95% CI: 0.65, 1.37), 0.85 (95% CI: 0.59, 1.23) or 0.86 (95% CI: 0.59, 1.25). Collectively, findings illustrate the need for fully reporting research and analytical methods, especially when analyses are meant to develop evidence intended for regulatory decision-making.

Usutu virus (USUV; Flavivirus) has caused massive die-offs in birds across Europe since the 1950s. Although rare, severe neurologic disease in humans has been reported. USUV is genetically related to West Nile virus (WNV) and shares an ecological niche, suggesting it could spread from Europe to the Americas. USUV's risk of transmission within the United States is currently unknown. To this end, we exposed field-caught Aedes japonicus, Culex pipiens pipiens, and Culex restuans-competent vectors for WNV-to a recent European isolate of USUV. While infection rates for each species varied from 7%-21%, no dissemination or transmission was observed. These results differed from a 2018 report by Cook and colleagues, who found high dissemination rates and evidence of transmission potential using a different USUV strain, U.S. mosquito populations, temperature, and extrinsic incubation period. Future studies should evaluate the impact of these experimental conditions on USUV transmission by North American mosquitoes.

Wastewater (WW) reuse is expected to be increasingly indispensable in future water management to mitigate water scarcity. However, this increases the risk of antibiotic resistance (AR) dissemination via irrigation. Herein, a conventional (chlorination) and an advanced oxidation process (heterogeneous photocatalysis (HPC)) were used to disinfect urban WW to the same target of Escherichia coli

Dear Editor,Deferasirox (DFR) is an oral chelator used in transfusion-dependent patients with hematological diseases [1]. Recommended dosage is 20–30 mg/kg/d, but some patients require doses >30 mg...

Eltrombopag is an oral thrombopoietin receptor agonist approved for the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP), who are more than 1 year old, and show poor response to first-line therapy. ITP is a hematological disorder characterized by isolated thrombocytopenia in the absence of secondary causes or disorders. Eltrombopag is generally well tolerated in the pediatric population; therefore, therapeutic drug monitoring (TDM) is not usually performed in clinical practice.We presented the case study of a 3-year-old girl with chronic ITP. She arrived in the pediatric intensive care unit with acute liver failure due to eltrombopag toxicity despite taking the standard drug dosage. A very high eltrombopag plasma concentration, indicating drug toxicity, was found through TDM. The patient also carried the allelic variations that are involved in drug metabolism [CYP2C8 and UDP glucuronosyltransferase (UGT) 1A1 (UGT1A1)] and drug cellular transportation [ABCG2 (ATP-binding cassette G2)]. This observation highlights the importance of using TDM and pharmacogenetic approaches to manage patients' unusual complications associated with standard pharmacological treatment regimens.

Reuse of municipal wastewater is a growing global trend, but currently there is lack of consensus regarding the potential dissemination of antibiotic resistance elements by treated wastewater irrigation. We tracked intI1, a proxy for anthropogenic pollution, and an assemblage of antibiotic resistance genes associated with mobile elements and/or wastewater (blaGES, blaOXA2, blaOXA10, blaTEM, blaCTX-M-32 and qnrS) in treated wastewater effluents, effluent stabilization reservoirs, and along irrigation water-soil-crop continua in experimental lysimeters and large-scale commercial fields. While several of the targeted antibiotic resistance genes were profuse in effluents, there was almost no correlation between gene abundance in irrigation water and those detected in soil, and no evidence of systematic gene transfer to irrigated soil or crops. In contrast, soil intI1 abundance correlated strongly to irrigation water levels in lysimeters and sandy field soils, but this was not the case for clay-rich soils or for most of the analyzed crops, suggesting that intI1 may not always be a reliable marker for tracking the impact of treated wastewater irrigation. We hypothesize that "ecological boundaries" expedited by biotic and abiotic factors constrain dissemination of antibiotic resistance elements, and assert that a more holistic perception of these factors is crucial for understanding and managing antibiotic resistance dissemination.

Adverse drug reactions occur at a high rate in hospitalized children, frequently due to antiepileptic drug administration. Phenytoin is a commonly used drug, and its metabolism is mediated by a specific cytochrome-P450 isoform, CYP2C9, which is encoded by a polymorphic gene. It is worth noting that very frequently administered drugs, such as proton pump inhibitors, compete with phenytoin for CYP2C19-mediated metabolism. Here we describe a case of phenytoin intoxication in a child with defective CYP2C9, after omeprazole administration.

In Parkinson's disease, intracellular α-synuclein (α-syn) inclusions form in neurons and are referred to as Lewy bodies. These aggregates spread through the brain following a specific pattern leading to the hypothesis that neuron-to-neuron transfer is critical for the propagation of Lewy body pathology. Here we review recent studies employing pre-formed fibrils generated from recombinant α-syn to evaluate the uptake, trafficking, and release of α-syn fibrils. We outline methods of internalization as well as cell surface receptors that have been described in the literature as regulating α-syn fibril uptake. Pharmacological and genetic studies indicate endocytosis is the primary method of α-syn internalization. Once α-syn fibrils have crossed the plasma membrane they are typically trafficked through the endo-lysosomal system with autophagy acting as the dominant method of α-syn clearance. Interestingly, both chaperone-mediated autophagy and macroautophagy have been implicated in the degradation of α-syn, although it remains unclear which system is chiefly responsible for the removal of α-syn fibrils. The major hallmark of α-syn spreading is the templating of misfolded properties onto healthy protein resulting in a conformational change; we summarize the evidence indicating misfolded α-syn can seed endogenous α-syn to form new aggregates. Finally, recent studies demonstrate that cells release misfolded and aggregated α-syn and that these processes may involve different chaperones. Nonetheless, the exact mechanism for the release of fibrillar α-syn remains unclear. This review highlights what is known, and what requires further clarification, regarding each step of α-syn transmission.

A large-scale comprehensive survey of indicator bacteria, pathogen viruses, coliphages, microbial source tracking (MST) indicators, and antibiotic resistance genes was carried out in the Sh...

Dear editor,There are four venomous species of viper distributed in different geographic regions of Italy, Vipera aspis, Vipera berus, Vipera ammodytes and Vipera ursinii. Neurological signs follow...

Dear Editor,Although, most spiders in Italy basically have venom that is harmless to humans, one must consider some potentially dangerous species. Latrodectus tredecimguttatus (Rossi, 1790), also k...

Array comparative genomic hybridization (aCGH) testing can diagnose chromosomal microdeletions and duplications too small to be detected by conventional cytogenetic techniques. We need to consider which patients are more likely to receive a diagnosis from aCGH testing versus patients that have lower likelihood and may benefit from broader genome wide scanning. We retrospectively reviewed charts of a population of 200 patients, 117 boys and 83 girls, who underwent aCGH testing in Genetics Clinic at Rhode Island hospital between 1 January/2008 and 31 December 2010. Data collected included sex, age at initial clinical presentation, aCGH result, history of seizures, autism, dysmorphic features, global developmental delay/intellectual disability, hypotonia and failure to thrive. aCGH analysis revealed abnormal results in 34 (17%) and variants of unknown significance in 24 (12%). Patients with three or more clinical diagnoses had a 25.0% incidence of abnormal aCGH findings, while patients with two or fewer clinical diagnoses had a 12.5% incidence of abnormal aCGH findings. Currently, we provide families with a range of 10–30% of a diagnosis with aCGH testing. With increased clinical complexity, patients have an increased probability of having an abnormal aCGH result. With this, we can provide individualized risk estimates for each patient.

Plasmids harboring

Wastewater is among the most important reservoirs of antibiotic resistance in urban environments. The abundance of carbon sources and other nutrients, a variety of possible electron acceptors such as oxygen or nitrate, the presence of particles onto which bacteria can adsorb, or a fairly stable pH and temperature are examples of conditions favouring the remarkable diversity of microorganisms in this peculiar habitat. The wastewater microbiome brings together bacteria of environmental, human and animal origins, many harbouring antibiotic resistance genes (ARGs). Although numerous factors contribute, mostly in a complex interplay, for shaping this microbiome, the effect of specific potential selective pressures such as antimicrobial residues or metals, is supposedly determinant to dictate the fate of antibiotic resistant bacteria (ARB) and ARGs during wastewater treatment. This paper aims to enrich the discussion on the ecology of ARB&ARGs in urban wastewater treatment plants (UWTPs), intending to serve as a guide for wastewater engineers or other professionals, who may be interested in studying or optimizing the wastewater treatment for the removal of ARB&ARGs. Fitting this aim, the paper overviews and discusses: i) aspects of the complexity of the wastewater system and/or treatment that may affect the fate of ARB&ARGs; ii) methods that can be used to explore the resistome, meaning the whole ARB&ARGs, in wastewater habitats; and iii) some frequently asked questions for which are proposed addressing modes. The paper aims at contributing to explore how ARB&ARGs behave in UWTPs having in mind that each plant is a unique system that will probably need a specific procedure to maximize ARB&ARGs removal. Keywords: Antibiotic resistance monitoring, SWOT analysis, Wastewater treatment optimization

Cardiovascular disease (CVD) biomarkers of biological effect (BoBE), including hematologic biomarkers, serum lipid-related biomarkers, other serum BoBE, and one physiological biomarker, were evaluated in adult cigarette smokers (SMK), smokeless tobacco consumers (STC), and non-consumers of tobacco (NTC). Data from adult males and females in the US National Health and Nutrition Examination Survey and a single site, cross-sectional study of healthy US males were analyzed and compared. Within normal clinical reference ranges, statistically significant differences were observed consistently for fibrinogen, C-reactive protein (CRP), hematocrit, mean cell volume, mean cell hemoglobin, hemoglobin, white blood cells, monocytes, lymphocytes, and neutrophils in comparisons between SMK and NTC; for CRP, white blood cells, monocytes, and lymphocytes in comparisons between SMK and STC; and for folate in comparisons with STC and NTC. Results provide evidence for differences in CVD BoBE associated with the use of different tobacco products, and provide evidence of a risk continuum among tobacco products and support for the concept of tobacco harm reduction.

An age-stratified, cross-sectional study was conducted in the US among healthy adult male cigarette smokers, moist snuff consumers, and non-tobacco consumers to evaluate cardiovascular biomarkers of biological effect (BoBE). Physiological assessments included flow-mediated dilation, ankle-brachial index, carotid intima-media thickness and expired carbon monoxide. Approximately one-half of the measured serum BoBE showed statistically significant differences; IL-12(p70), sICAM-1 and IL-8 were the BoBE that best differentiated among the three groups. A significant difference in ABI was observed between the cigarette smokers and non-tobacco consumer groups. Significant group and age effect differences in select biomarkers were identified.

Quantitative risk assessment (QRA), a scientific, evidence-based analytical process that combines chemical and biological data to quantify the probability and potential impact of some defined risk, is used by regulatory agencies for decision-making. Thus, in tobacco product regulation, specifically in substantial equivalence (SE) evaluations, QRA can provide a useful, practical, and efficient approach to address questions that might arise regarding human health risk and potential influence on public health. In SE reporting, when differences in product characteristics may necessitate the determination of whether a new product raises different questions of public health, the results from QRA are a valuable metric. An approach for QRA in this context is discussed, which is modeled after the methodology for assessment of constituent mixtures by the US Environmental Protection Agency for environmental Superfund site assessment. Given the intent in both cases is an assessment of the public health impact resulting from the totality of exposure to a mixture of constituents, the application is appropriate. Although some uncertainties in the information incorporated may exist, relying on the most appropriate of the available data increases the confidence and decreases the uncertainty in the risk characterization using this data-driven methodology.

Cognitive impairment can impair driving skills and safety, and given the fact that persons with MCI can develop cognitive deficits in several cognitive domains it is important to address driving safety. The goal of the clinician is to identify potentially unsafe drivers without unnecessarily restricting safe drivers, and this chapter focuses on evaluating patients in this gray area. The office exam can be be broadened to address cognitive and functional assessments that may reflect on driving safety, and the clinician may advise the patient and family to have a comprehensive driving assessment by a driving rehabilitation specialist. Clinicians need to be well informed about state law regarding the evaluation of driving safety in order to maintain privacy while adhering to highest standards of public safety.

There are no large-scale, carefully designed cohort studies that provide evidence on whether menthol cigarette use is associated with a differential risk of initiating and/or progressing to increased smoking. However, questions of whether current menthol cigarette smokers initiated smoking at a younger age or are more likely to have transitioned from non-daily to daily cigarette use compared to non-menthol smokers can be addressed using cross-sectional data from U.S. government surveys. Analyses of nationally representative samples of adult and youth smokers indicate that current menthol cigarette use is not associated with an earlier age of having initiated smoking or greater likelihood of being a daily versus non-daily smoker. Some surveys likewise provide information on cigarette type preference (menthol versus non-menthol) among youth at different stages or trajectories of smoking, based on number of days smoked during the past month and/or cigarettes smoked per day. Prevalence of menthol cigarette use does not appear to differ among new, less experienced youth smokers compared to established youth smokers. While there are limitations with regard to inferences that can be drawn from cross-sectional analyses, these data do not suggest any adverse effects for menthol cigarettes on measures of initiation and progression to increased smoking.

Previously published studies provide somewhat inconsistent evidence on whether menthol in cigarettes is associated with increased dependence. The National Health and Nutrition Examination Survey, National Survey on Drug Use and Health, National Health Interview Survey, and Tobacco Use Supplement to the Current Population Survey collect data on current cigarette type preference and primary measures of dependence, and thus allow examination of whether menthol smokers are more dependent than non-menthol smokers. Analyses based on combined data from multiple administrations of each of these four nationally representative surveys, using three definitions for current smokers (i.e., smoked ⩾1 day, ⩾10 days and daily during the past month), consistently demonstrate that menthol smokers do not report smoking more cigarettes per day than non-menthol smokers. Moreover, two of the three surveys that provide data on time to first cigarette after waking indicate no difference in urgency to smoke among menthol compared to non-menthol smokers, while the third suggests menthol smokers may experience a greater urgency to smoke; estimates from all three surveys indicate that menthol versus non-menthol smokers do not report a higher Heaviness of Smoking Index. Collectively, these findings indicate no difference in dependence among U.S. smokers who use menthol compared to non-menthol cigarettes.

To evaluate the safety and effectiveness of ultrasound-guided left brachiocephalic vein cannulation in infants and children with underlying bleeding conditions.Retrospective cohort.PICU of a tertiary pediatric hospital.Thirty-four patients requiring central venous catheterization from January 2011 to January 2012.None.Two pediatric intensivists, experienced in ultrasound-guided vessel cannulation, performed the ultrasound catheterization of the left brachiocephalic vein. Ultrasound equipment consisted of a standard ultrasound monitor with a linear 6-13 MHz probe. The ultrasound monitor was set on a resolution with a depth of 1.8 cm for infants and 2.2 cm for children. The "in-plane" technique was used for all patients. Thirty-four catheterizations were performed. Patient median age was 12.5 months (5.75-63.5 mo) and median weight was 9.25 kg (7-16.25 kg). The population of infants and children analyzed was composed of 25 patients with hematologic disorder (73%) treated with hematopoietic stem cell transplantation, five patients (15%) supported with extracorporeal membrane oxygenation for viral pneumonias, and four patients (12%) with uremic hemolytic syndrome. A 4F catheter was used in 79% of cases. Left brachiocephalic vein cannulation was successful in all 34 patients. Median time needed for cannulation was 350 seconds (277.5-450 s). The overall complication rate was 9% (3 of 34) and consisted of difficulty in advancing the guidewire after having pierced the vein. The time required for catheter positioning and complications was not associated with both lower body weight and body surface area of the patients (p0.05). Mean central venous catheter duration was 32 ± 4 days.Data reported in this retrospective study confirm the safety and effectiveness of ultrasound-guided left brachiocephalic vein catheterization in infants and children with underlying bleeding disorders.

Sir,We read with great interest the retrospective study by Claudet et al., on the consideration hyperglycemia as risk factor for high-grade envenomations after European viper bites (Vipera spp.) in...

To investigate whether cadmium has an independent role in diseases associated with tobacco consumption, epidemiology data were reviewed, biomonitoring data were analyzed, and probabilistic risk assessment (PRA) was performed. Results from previous epidemiology studies have indicated that there are adverse health effects potentially in common between cadmium exposure and tobacco consumption. Analysis of publically available biomonitoring data showed that blood (B-Cd) and urine (U-Cd) cadmium were higher in cigarette smokers compared with smokeless tobacco (SLT) consumers, and B-Cd and U-Cd in SLT consumers were not significantly different than in non-consumers of tobacco. Comparison with previously established biomonitoring equivalent (BE) values indicated that B-Cd and U-Cd in the majority of these cigarette smokers and SLT consumers did not exceed the blood and urine BEs. Results of the PRA showed that the mean hazard estimate was below a generally accepted regulatory threshold for SLT consumers, but not for cigarette smokers. In total, this evaluation indicated that cadmium exposures in tobacco consumers differed by product category consumed; cadmium in tobacco may not be associated with tobacco consumption related diseases; if cadmium in tobacco contributes to tobacco consumption related diseases, differences in hazard and/or risk may exist by product category.

The objective of this study was to investigate possible correlations between the preload index global end-diastolic volume (GEDV) and the indexes of cardiac function, cardiac index, and stroke volume index in critically ill pediatric patients. The aim was to evaluate whether GEDV may help in the decision-making process concerning volume loading.Prospective clinical study.Pediatric intensive care unit of the Bambino Gesù Children's Research Hospital.Seventy patients, 40 male and 30 female, mean age 62 +/- 41 months (range 5-156 months), divided into six groups: group A, hemorrhagic shock, ten cases; group B, head injury, 21 cases; group C, septic shock, ten cases; group D, encephalitis, ten cases; group E, respiratory failure, nine cases; group F, cardiogenic shock, ten cases.All patients received volumetric hemodynamic monitoring following initial resuscitation and every 4 hrs thereafter or whenever a hemodynamic deterioration was suspected. During the cumulative in-hospital stay, a total 1,184 sets of measurements were done.Findings are consistent with a statistically significant linear correlation of GEDV with cardiac index and stroke volume index in hemorrhagic shock (group A) (R2 = .647, p.0001; R2 = .738, p.0001) and cardiogenic shock (group F) (R2 = .645, p.0001; R2 = .841, p.0001).GEDV may potentially be a useful guide to treatment in preload-dependent conditions, such as hemorrhagic and cardiogenic shock. In the other groups where there is little relationship between preload and cardiac function indexes, the influence of non-preload-dependent mechanisms on cardiac output is certainly more significant.

A randomized, multi-center study of adult cigarette smokers switched to tobacco-heating cigarettes, snus or ultra-low machine yield tobacco-burning cigarettes (50/group) was conducted, and subjects’ experience with the products was followed for 24 weeks. Differences in biomarkers of tobacco exposure between smokers and never smokers at baseline and among groups relative to each other and over time were assessed. Results indicated reduced exposure to many potentially harmful constituents found in cigarette smoke following product switching. Findings support differences in exposure from the use of various tobacco products and are relevant to the understanding of a risk continuum among tobacco products. Trial registration:ClinicalTrials.gov identifier: NCT02061917.

A study was conducted to evaluate biomarkers of biological effect and physiological assessments related to cardiovascular disease (CVD) among adult male cigarette smokers (SMK), moist snuff consumers (MSC) and non-consumers of tobacco (NTC). Additionally, biomarkers of tobacco and tobacco smoke exposure (BoE) were measured in spot urines and are reported here. Except for the BoE to nicotine and NNK, BoE were generally greater in SMK compared with MSC, and BoE were generally not different in comparisons of MSC and NTC. Results demonstrated that MSC had lower systemic exposures to many harmful and potentially harmful constituents than SMK, which is consistent with epidemiological data that indicate a differential in CVD risk between these groups.

In this paper we consider a problem of best approximation in lp, 1 < p ≤ ∞. Lethp denote the best p-approximation of h ∈ Rn from a closed, convex set K of Rn 1 < p < ∞, h ∉ K, and let h∞* be the strict uniform approximation of h from K. We prove that if K satisfies locally a geometrical property, fulfilled by any polyhedral set of Rn, then lim sup p→∞ p||hp - h∞*|| < ∞.

A diode-pumped Tm-Ho:YAG laser, widely tunable at around 2090 nm, was fabricated and used to perform high-resolution spectroscopy of several molecular absorption lines of HBr and CO/sub 2/. The laser source was then frequency locked, using the fringe side locking technique, to the H/sup 79/Br P(12) transition at 2097.222 nm and to the CO/sub 2/ P(22) transition at 2087.844 nm. The obtained laser frequency stabilities evaluated by monitoring the error signal of the control loop were /spl sim/30 kHz root mean square (rms) values, with both the molecular frequency references. Additional frequency stability measurements were performed by monitoring the beat note between two independently stabilized Tm-Ho:YAG lasers. The two-sample frequency deviation of the beat frequency below 200 kHz was measured over different integration times of interest in Lidar and differential absorption Lidar system applications.

Let J be an open interval and denote by SΠ the set of all the splines of degree at most n−1 with simple knots in Π, a countably infinite set of points in J, n⩾2. In this paper, we prove that there exists a unique best φ-approximation to a continuous function in Lφ(J) from SΠ, where φ:[0,∞)↦[0,∞) is a convex function that generalizes the pth-power functions, p⩾1.

In this paper we present recent results obtained on the generation of ultra-high repetition rate optical pulse trains at 1.5 μm in asynchronously frequency-modulated Er–Yb : glass lasers. Nearly transform-limited pulse trains at either single or dual carrier wavelength with repetition rates up to ∼20 GHz are generated by means of an external fiber Bragg grating. These pulse trains are of great potential interest for soliton-based optical transmission systems.

A randomized, multi-center study was conducted to assess potential improvement in health status measures, as well as changes in biomarkers of tobacco exposure and biomarkers of biological effect, in current adult cigarette smokers switched to tobacco-heating cigarettes, snus or ultra-low machine yield tobacco-burning cigarettes (50/group) evaluated over 24 weeks. Study design, conduct and methodology are presented here along with subjects’ disposition, characteristics, compliance and safety results. This design and methodology, evaluating generally healthy adult smokers over a relatively short duration, proved feasible. Findings from this randomized study provide generalized knowledge of the risk continuum among various tobacco products. Trial registration:ClinicalTrials.gov identifier: NCT02061917.

A randomized, multi-center study of adult cigarette smokers switched to tobacco-heating cigarettes, snus or ultra-low machine yield tobacco-burning cigarettes (50/group) for 24 weeks was conducted. Evaluation of biomarkers of biological effect (e.g. inflammation, lipids, hypercoaguable state) indicated that the majority of consistent and statistically significant improvements over time within each group were observed in markers of inflammation. Consistent and statistically significant differences in pairwise comparisons between product groups were not observed. These findings are relevant to the understanding of biomarkers of biological effect related to cigarette smoking as well as the risk continuum across various tobacco products. Trial registration:ClinicalTrials.gov identifier: NCT02061917.

A novel and compact Er-Yb:glass laser was developed with single-frequency output power >10 mW in a wavelength range from 1531 to 1547 nm. The laser output was efficiently frequency doubled at 770.1 nm in a single-pass periodically poled lithium niobate waveguide and a second harmonic power in excess of 15 /spl mu/W was achieved, with an internal conversion efficiency of /spl sim/220% W/sup -1/. This frequency-doubled beam was used for high-resolution saturated spectroscopy of the /sup 39/K 4S/sub 1/2 /-4P/sub 1/2 / absorption line. The best resolved crossover peak showed 16% line contrast and 10-MHz linewidth. In a second experiment, working at the fundamental frequency, saturation spectroscopy of /sup 13/C/sub 2/H/sub 2/ was achieved using a low-pressure gas cell inside a build-up cavity. The measured absorption dip has 3% line contrast and 1.2 MHz linewidth. Both the atomic and molecular saturated lines are very well suited for frequency locking in order to establish accurate frequency standards in the optical communication band.

A novel and compact diode-pumped Er–Yb:glass laser, with single-frequency output power up to 20 mW in a wavelength range from 1531 to 1547 nm, was frequency stabilized against sub-Doppler rovibrational transitions of 13C2H2. The non-linear wavelength-modulation spectroscopy technique was used to lock the laser frequency to the molecular lines. The stability of the developed optical frequency standard was mainly dominated by a white frequency-noise contribution, which sets the Allan deviation at a level of σy(τ)=2×10−11τ−1/2 for integration times in the range of 0.01 s .

We developed a low-noise, single-frequency Tm–Ho:YAG laser tunable in the wavelength interval between 2087 and 2099 nm. To suppress both amplitude and frequency fluctuations the laser has been stabilised by two different control loops. Intensity noise has been effectively reduced using a feedback loop acting on the pump diode current, based on a biquadratic bandpass filter, which provides up to 17 dB suppression at the relaxation oscillation peak. Absolute frequency stabilisation has been achieved by locking the oscillator to the P(12) absorption line of the HBr molecule at 2097.2 nm using the fringe side locking technique, obtaining a long-term frequency stability better than 32 kHz over an observation time of 60 min. This stabilised source is aimed to injection seeding of a coherent lidar system for high precision measurements of wind velocity.

Dear Editor, Dr. Peters et al. [1] presented in your journal an interesting case regarding a subcapsular hematoma of the kidney after a cardiac catheterization in an adult patients and its clinical management. This complication, albeit rare in adults [2], is of great interest in children with congenital heart disease undertaking diagnostic or interventional catheterizations [3–5] and it should be considered in the differential diagnosis when managing ‘‘apparently’’ spontaneous perirenal hematomas in this selected population. We describe a case of a ‘‘late onset’’ retroperitoneal hematoma in a 7 months old child discovered in the fourth postoperative day (POD) after a cardiac operation, discussing the possible differential diagnosis and treatment options. A 7 months old child, weighting 7 kg, affected by a pulmonary atresia with intact ventricular septum treated with a systemic-pulmonary shunt early after birth, was admitted in the pediatric cardiac surgery unit for the intervention of bidirectional cavo-pulmonary anstomosis (Glenn operation). An angiographic evaluation, scheduled the day before surgery, was performed with a percutaneous catheterization from the left femoral vein. The access to the vessel was easily obtained under ultrasound guidance and a 5 French sheath with a 0.35 guidewire (Terumo, Tokyo, Japan) was used. The child was heparinized for the diagnostic procedure (100 UI/Kg) to reach an Activated Clotting Time of 180–200 s. Catheterization was performed under fluoroscopic guidance and resulted apparently uneventful. The following day the patient successfully underwent to the scheduled cardiac operation and was discharged from the PICU in the second POD. Anticoagulant therapy with warfarin was suddenly started according to the institutional protocol. In the fourth POD, the child presented vomiting and diaphoresis. Clinical examination revealed an important left flank pain and a tense abdomen. Blood tests showed: increased levels of the C reactive protein (C-RP) (15 mg/l), white blood cells (WBC) count (18 9 10/ mm), a marked reduction of the haemoglobin concentration with an international normalized ratio (INR) F. De Sanctis Department of Anesthesia and Intensive Care Medicine, ‘‘La Sapienza’’ University, II Faculty of Medicine, Sant’ Andrea Hospital, Rome, Italy

In Italy viper bites represent an uncommon event, though envenomation can cause severe complications, more in children than adults, because of dose/body size ratio. We present a case series within a selected population: 10 Italian cases (from Rome surroundings) of viperbites requiring PICU admission, over a 5-year interval. Five children showed a systemic involvement, whereas the remaining patients showed a damage. All were managed and closely monitored in an ICU setting. Relevant clinical findings and therapeutic approach, ICU course and complications have been recorded. Age range was 3-15 years with mean age of 6,9 (SD±4,58) years; 2 patients needed respiratory support beyond oxygen supplementation. Most patients underwent fluid loading, while hemodynamic support was given to4/10. Median PICU stay was 60 hours (IQR=24.0-75.5). No mortality was reported. Indications and precautions for administration of antivenom in the last years have been reviewed: early treatment seems to reduce mortality/morbidity, though representing a threat for children. Current recommendations for the treatment of viper envenomation have been described, based on a literature's review and the application of these knowledges to clinical reality of our PICUs. Therefore, paediatric patients with systemic or rapidly evolving symptoms should be monitored carefully for the development of bite-related complications in an ICU setting mostly in younger children.

A detailed experimental analysis of the amplitude noise in high-repetition-rate picosecond pulse trains generated by spectral filtering of a frequency-modulated Er-Yb:glass laser is reported. Two distinct sources of noise are identified, and stabilization techniques for noise suppression are proposed and experimentally demonstrated. Intensity noise suppression of ∼20 dB, corresponding to less than 2% residual amplitude fluctuations of the pulse train, has been achieved at repetition rates of 2.5 GHz and 5 GHz with pulse durations of ∼50 ps.