Estimated Worldwide Mortality Attributed to Secondhand Tobacco Smoke Exposure, 1990-2016

Importance: The World Health Organization estimates that the 1 billion individuals who smoke worldwide contribute to the 880 000 secondhand smoke (SHS)-related deaths among individuals who do not smoke each year. A better understanding of the scale of harm of SHS to those who do not smoke could increase awareness of the consequences of smoking and help to design measures to protect individuals who do not smoke, especially children. Objective: To calculate the number of individuals who smoke associated with the death of 1 individual who died of SHS exposure both on a global scale and in various World Bank regions. Design, Setting, and Participants: In this cross-sectional epidemiologic assessment, data from Our World in Data were used to tabulate the number of individuals who smoke in each country and number of premature deaths related to SHS in that country from 1990 to 2016. The mean number of cigarettes consumed in all countries was also included in analyses. Data were collected for the following World Bank regions: North America, Latin America and the Caribbean, Europe and Central Asia, the Middle East and North Africa, sub-Saharan Africa, South Asia, and East Asia and the Pacific from 1990 and 2016. Statistical analysis was conducted in July 2019. Exposure: Secondhand smoke. Main Outcomes and Measures: The pack-year index, calculated as the number of pack-years associated with the death of 1 individual who does not smoke but was exposed to SHS, and the SHS index, calculated as the number of individuals who smoked for 24 years (ie, the mean duration of smoking) associated with the death of 1 individual who does not smoke. Results: Globally, the SHS index changed favorably, from 31.3 (95% CI, 30.6-32.0) individuals who smoked associated with the death of 1 individual who did not smoke in 1990 to 52.3 (95% CI, 51.2-53.5) individuals who smoked in 2016. There was a wide regional variation in the 2016 secondhand smoke index, from 42.6 (95% CI, 41.6-43.5) individuals who smoked in the Middle East and North Africa to 85.7 (95% CI, 83.8-87.7) individuals who smoked in North America. Worldwide, the pack-year index also changed favorably from 751.9 (95% CI, 736.3-770.7) pack-years associated with 1 death in 1990 to 1255.9 (95% CI, 1227.2-1284.4) pack-years in 2016. Conclu

Diversity-Oriented Enzymatic Synthesis of Cyclopropane Building Blocks

While biocatalysis is increasingly incorporated into drug development pipelines, it is less commonly used in the early stages of drug discovery. By engineering a protein to produce a chiral motif with a derivatizable functional handle, biocatalysts can be used to help generate diverse building blocks for drug discovery. Here we show the engineering of two variants of Rhodothermus marinus nitric oxide dioxygenase (RmaNOD) to catalyze the formation of cis- and trans-diastereomers of a pinacolboronate-substituted cyclopropane which can be readily derivatized to generate diverse stereopure cyclopropane building blocks

Diversity-Oriented Enzymatic Synthesis of Cyclopropane Building Blocks

While biocatalysis is increasingly incorporated into drug development pipelines, it is less commonly used in the early stages of drug discovery. By engineering a protein to produce a chiral motif with a derivatizable functional handle, biocatalysts can be used to help generate diverse building blocks for drug discovery. Here we show the engineering of two variants of Rhodothermus marinus nitric oxide dioxygenase (RmaNOD) to catalyze the formation of cis- and trans-diastereomers of a pinacolboronate-substituted cyclopropane which can be readily derivatized to generate diverse stereopure cyclopropane building blocks

Mutations in SCG10 Are Not Involved in Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of enteric neurons in the distal part of the colon. Several genes have been implicated in the development of this disease that together account for 20% of all cases, implying that other genes are involved. Since HSCR is frequently associated with other congenital malformations, the functional characterization of the proteins encoded by the genes involved in these syndromes can provide insights into the protein-network involved in HSCR development. Recently, we found that KBP, encoded by the gene involved in a HSCR- associated syndrome called Goldberg-Shprintzen syndrome, interacts with SCG10, a stathmin-like protein. To determine if SCG10 is involved in the etiology of HSCR, we determined SCG10 expression levels during development and screened 85 HSCR patients for SCG10 mutations. We showed that SCG10 expression increases during development but no germline mutation was found in any of these patients. In conclusion, this study shows that SCG10 is not directly implicated in HSCR development. However, an indirect involvement of SCG10 cannot be ruled out as this can be due to a secondary effect caused by its direct interactors

Supported Education and Supported Employment for Individuals at Clinical-High Risk of Psychosis:A Pilot Study

Deteriorated functioning is a part of the clinical-high risk (CHR) criteria for psychosis. Diminished social, educational and occupational functioning in the phase of late adolescence and early adulthood are associated with long-term social, economic and health consequences, which stresses the importance of early intervention to stimulate functioning. This pilot study examines the effectiveness and feasibility of the choose-get-keep model of Supported Education and Supported Employment (SEE) to improve educational and occupational functioning of individuals at CHR for a psychosis. A single blind randomized controlled pilot study combined SEE with treatment as usual (TAU) versus TAU among adolescents and early adults at CHR. School performance and job status as well as global functioning scales were assessed at twelve months. Of the 78 eligible participants, 20 individuals consented to participate in this study. At follow-up, participants in the intervention condition (n = 9) did not start an education more often than the participants in the control condition (n = 11) and the school results for both conditions were similar. However, in the intervention condition there were no school dropouts, more participants gained a job and worked longer hours. Two participants quit the intervention. This pilot study provides preliminary evidence that a SEE intervention is effective and feasible in sustaining and improving the level of both educational and occupational functioning of individuals at CHR for psychosis by supporting them in attaining, keeping and elaborating of their education or employment.</p

Supported Education and Supported Employment for Individuals at Clinical-High Risk of Psychosis:A Pilot Study

Deteriorated functioning is a part of the clinical-high risk (CHR) criteria for psychosis. Diminished social, educational and occupational functioning in the phase of late adolescence and early adulthood are associated with long-term social, economic and health consequences, which stresses the importance of early intervention to stimulate functioning. This pilot study examines the effectiveness and feasibility of the choose-get-keep model of Supported Education and Supported Employment (SEE) to improve educational and occupational functioning of individuals at CHR for a psychosis. A single blind randomized controlled pilot study combined SEE with treatment as usual (TAU) versus TAU among adolescents and early adults at CHR. School performance and job status as well as global functioning scales were assessed at twelve months. Of the 78 eligible participants, 20 individuals consented to participate in this study. At follow-up, participants in the intervention condition (n = 9) did not start an education more often than the participants in the control condition (n = 11) and the school results for both conditions were similar. However, in the intervention condition there were no school dropouts, more participants gained a job and worked longer hours. Two participants quit the intervention. This pilot study provides preliminary evidence that a SEE intervention is effective and feasible in sustaining and improving the level of both educational and occupational functioning of individuals at CHR for psychosis by supporting them in attaining, keeping and elaborating of their education or employment.</p

Budget impact of optimizing rifaximin-alpha use for the prevention of recurrent hepatic encephalopathy in The Netherlands

Aims Rifaximin-alpha as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-alpha remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-alpha as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer's perspective. Materials and methods A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness. Results Treating eligible HE patients with rifaximin-alpha in addition to lactulose saves euro4,487 and costs euro249 per patient over a 5-year period compared with lactulose monotherapy from hospital and healthcare payer's perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligible patients are currently being treated with rifaximin-alpha. Optimizing rifaximin-alpha use by treating all eligible patients with the rifaximin-alpha + lactulose could save more than 3,000 hospital admissions, almost 15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treatment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from a Dutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer's perspective. Conclusions Next to a clinical perspective, also from an economic perspective, wider prescription of rifaximin-alpha adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer's perspective, costs increase with addition of rifaximin-alpha due to relative better survival causing relatively higher drug and liver transplantation-related costs.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

The Dynamics of the Pulmonary Microbiome During Mechanical Ventilation in the Intensive Care Unit and the Association with Occurrence of Pneumonia

RATIONALE: Ventilator-associated pneumonia (VAP) is the most common nosocomial infections in patients admitted to the ICU. The adapted island model predicts several changes in the respiratory microbiome during intubation and mechanical ventilation. OBJECTIVES: We hypothesised that mechanical ventilation and antibiotic administration decrease the diversity of the respiratory microbiome and that these changes are more profound in patients who develop VAP. METHODS: Intubated and mechanically ventilated ICU-patients were included. Tracheal aspirates were obtained three times a week. 16S rRNA gene sequencing with the Roche 454 platform was used to measure the composition of the respiratory microbiome. Associations were tested with linear mixed model analysis and principal coordinate analysis. MEASUREMENTS AND MAIN RESULTS: 111 tracheal aspirates were obtained from 35 patients; 11 had VAP, 18 did not have VAP. Six additional patients developed pneumonia within the first 48 hours after intubation. Duration of mechanical ventilation was associated with a decrease in α diversity (Shannon index; fixed-effect regression coefficient (β): -0.03 (95% CI -0.05 to -0.005)), but the administration of antibiotic therapy was not (fixed-effect β: 0.06; 95% CI -0.17 to 0.30). There was a significant difference in change of β diversity between patients who developed VAP and control patients for Bray-Curtis distances (p=0.03) and for Manhattan distances (p=0.04). Burkholderia, Bacillales and, to a lesser extent, Pseudomonadales positively correlated with the change in β diversity. CONCLUSION: Mechanical ventilation, but not antibiotic administration, was associated with changes in the respiratory microbiome. Dysbiosis of microbial communities in the respiratory tract was most profound in patients who developed VAP.info:eu-repo/semantics/publishedVersio

<i>C-elegans</i> model identifies genetic modifiers of alpha-synuclein inclusion formation during aging

Inclusions in the brain containing alpha-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a &lt;i&gt;C-elegans&lt;/i&gt; model that makes it possible to monitor, in living animals, the formation of alpha-synuclein inclusions. In worms of old age, inclusions contain aggregated alpha-synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in alpha-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between alpha-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other alpha-synuclein related disorders