Evaluation of proactive therapeutic drug monitoring application in infliximab users in ulcerative colitis

Objective: To evaluate the application of proactive pro-drug therapy (TDM) at week six in users of infliximab therapy in ulcerative colitis patients and to analyze the need for further disease optimization. Method: This is a retrospective analysis that will be carried out simultaneously at the Hospital de Clínicas de Passo Fundo and at the Endoclin Diagnostic Center in the city of Passo Fundo, with secondary data collection between January 2020 and May 2022. The sample included patients from both sexes, regardless of age, who are being followed up in the services mentioned above, by signing the informed Free and Clarified Consent Term. Results: 63.2% of patients required optimization of their treatment based on the serum level assessment at week six. Conclusion: Proactive TDM performed at week six benefits patients in order to complete indications for treatment to avoid lack of drug response and complications from the disease. (AU)

Melanoma Originating from the Dura-Mater: A Case Report and Review of the Literature.

Melanomas originating from the dura-mater are extremely rare tumors. The diagnosis is complex, and usually only made after excluding other entities. The prognosis is poor, with average free-disease survival of 20 months, after treatment with complete surgical excision and adjuvant therapy. We report the case of a 41-year-old asymptomatic patient, presenting with a subcutaneous mass in the left parieto-occipital region, later diagnosed as a primary dura mater melanoma. Treatment included complete microsurgical excision, radiotherapy and adjuvant immunotherapy. Therefore, due to the rare nature of the disease and its high lethality, correct diagnosis and treatment are medical challenges.

AANA Journal Course-Residual Neuromuscular Blockade: Evidence-Based Recommendations to Improve Patient Outcomes.

Neuromuscular blocking drugs are administered to facilitate endotracheal intubation and induce paralysis to allow surgeons access to their anatomical target. Traditionally, qualitative measures; such as tactile observation of fade by a peripheral nerve stimulator, are used to assess the extent of the patient's recovery after receiving the neuromuscular blocking agent. Use of these qualitative measures; however, can contribute to high rates of residual neuromuscular blockade (RNMB), placing patients at risk of serious postoperative adverse events. Such adverse events include the need for tracheal reintubation, impaired oxygen and ventilation, increased risk of aspiration and pneumonia, pharyngeal dysfunction, and delayed discharge from the postanesthesia care unit. This problem of RNMB is exacerbated by the use of traditional drugs to reverse the neuromuscular blockade, such as the acetylcholinesterase inhibitor neostigmine. This course will examine the current limitations of qualitative neuromuscular monitoring, introduce the reader to acceleromyography, and outline the advantages of monitoring neuromuscular blockade during the perioperative period. In addition, this course will review the contemporary neuromuscular antagonists, including the newer neuromuscular antagonist sugammadex.

Two-Way Chemical Communication between Artificial and Natural Cells.

Artificial cells capable of both sensing and sending chemical messages to bacteria have yet to be built. Here we show that artificial cells that are able to sense and synthesize quorum signaling molecules can chemically communicate with V. fischeri, V. harveyi, E. coli, and P. aeruginosa. Activity was assessed by fluorescence, luminescence, RT-qPCR, and RNA-seq. Two potential applications for this technology were demonstrated. First, the extent to which artificial cells could imitate natural cells was quantified by a type of cellular Turing test. Artificial cells capable of sensing and in response synthesizing and releasing N-3-(oxohexanoyl)homoserine lactone showed a high degree of likeness to natural V. fischeri under specific test conditions. Second, artificial cells that sensed V. fischeri and in response degraded a quorum signaling molecule of P. aeruginosa (N-(3-oxododecanoyl)homoserine lactone) were constructed, laying the foundation for future technologies that control complex networks of natural cells.

An in vitro selection for small molecule induced switching RNA molecules.

The selection of RNA and DNA aptamers now has a long history. However, the ability to directly select for conformational changes upon ligand binding has remained elusive. These difficulties have stymied attempts at making small molecule responsive strand displacement circuitry as well as synthetic riboswitches. Herein we present a detailed strand displacement based selection protocol to directly select for RNA molecules with switching activity. The library was based on a previously selected thiamine pyrophosphate riboswitch. The fully in vitro methodology gave sequences that showed strong strand displacement activity in the presence of thiamine pyrophosphate. Further, the selected sequences possessed riboswitch activity similar to that of natural riboswitches. The presented methodology should aid in the design of more complex, environmentally responsive strand displacement circuitry and in the selection of riboswitches responsive to toxic ligands.

In Vitro Selection for Small-Molecule-Triggered Strand Displacement and Riboswitch Activity.

An in vitro selection method for ligand-responsive RNA sensors was developed that exploited strand displacement reactions. The RNA library was based on the thiamine pyrophosphate (TPP) riboswitch, and RNA sequences capable of hybridizing to a target duplex DNA in a TPP regulated manner were identified. After three rounds of selection, RNA molecules that mediated a strand exchange reaction upon TPP binding were enriched. The enriched sequences also showed riboswitch activity. Our results demonstrated that small-molecule-responsive nucleic acid sensors can be selected to control the activity of target nucleic acid circuitry.

Predictors of mother-child interaction quality and child attachment security in at-risk families.

Child healthy development is largely influenced by parent-child interaction and a secure parent-child attachment is predictively associated with positive outcomes in numerous domains of child development. However, the parent-child relationship can be affected by several psychosocial and socio-demographic risk factors that undermine its quality and in turn play a negative role in short and long term child psychological health. Prevention and intervention programs that support parenting skills in at-risk families can efficiently reduce the impact of risk factors on mother and child psychological health. This study examines predictors of mother-child interaction quality and child attachment security in a sample of first-time mothers with psychosocial and/or socio-demographic risk factors. Forty primiparous women satisfying specific risk criteria participated in a longitudinal study with their children from pregnancy until 18 month of child age. A multiple psychological and socioeconomic assessment was performed. The Emotional Availability Scales were used to measure the quality of emotional exchanges between mother and child at 12 months and the Attachment Q-Sort served as a measure of child attachment security at 18 months. Results highlight both the effect of specific single factors, considered at a continuous level, and the cumulative risk effect of different co-occurring factors, considered at binary level, on mother-child interaction quality and child attachment security. Implication for the selection of inclusion criteria of intervention programs that support parenting skills in at-risk families are discussed.

Integrating artificial with natural cells to translate chemical messages that direct E. coli behaviour.

Previous efforts to control cellular behaviour have largely relied upon various forms of genetic engineering. Once the genetic content of a living cell is modified, the behaviour of that cell typically changes as well. However, other methods of cellular control are possible. All cells sense and respond to their environment. Therefore, artificial, non-living cellular mimics could be engineered to activate or repress already existing natural sensory pathways of living cells through chemical communication. Here we describe the construction of such a system. The artificial cells expand the senses of Escherichia coli by translating a chemical message that E. coli cannot sense on its own to a molecule that activates a natural cellular response. This methodology could open new opportunities in engineering cellular behaviour without exploiting genetically modified organisms.

Measuring riboswitch activity in vitro and in artificial cells with purified transcription-translation machinery.

We present a simple method to measure the real-time activity of riboswitches with purified components in vitro and inside of artificial cells. Typically, riboswitch activity is measured in vivo by exploiting ß-galactosidase encoding constructs with a putative riboswitch sequence in the untranslated region. Additional in vitro characterization often makes use of in-line probing to explore conformational changes induced by ligand binding to the mRNA or analyses of transcript lengths in the presence and absence of ligand. However, riboswitches ultimately control protein levels and often times require accessory factors. Therefore, an in vitro system capable of monitoring protein production with fully defined components that can be supplemented with accessory factors would greatly aid riboswitch studies. Herein we present a system that is amenable to such analyses. Further, since the described system can be easily reconstituted within compartments to build artificial, cellular mimics with sensing capability, protocols are provided for building sense-response systems within water-in-oil emulsion compartments and lipid vesicles. Only standard laboratory equipment and commercially available material are exploited for the described assays, including DNA, purified transcription-translation machinery, i.e., the PURE system, and a spectrofluorometer.

Piecing Together Cell-like Systems.

Several laboratories are pursuing the synthesis of cellular systems from different directions, including those that begin with simple chemicals to those that exploit existing cells. The methods that begin with nonliving components tend to focus on mimicking specific features of life, such as genomic replication, protein synthesis, sensory systems, and compartment formation, growth, and division. Conversely, the more prevalent synthetic biology approaches begin with something that is already alive and seek to impart new behavior on existing cells. Here we discuss advances in building cell-like systems that mimic key features of life with defined components.

Fluorescent proteins and in vitro genetic organization for cell-free synthetic biology.

To facilitate the construction of cell-free genetic devices, we evaluated the ability of 17 different fluorescent proteins to give easily detectable fluorescence signals in real-time from in vitro transcription-translation reactions with a minimal system consisting of T7 RNA polymerase and E. coli translation machinery, i.e., the PUREsystem. The data were used to construct a ratiometric fluorescence assay to quantify the effect of genetic organization on in vitro expression levels. Synthetic operons with varied spacing and sequence composition between two genes that coded for fluorescent proteins were then assembled. The resulting data indicated which restriction sites and where the restriction sites should be placed in order to build genetic devices in a manner that does not interfere with protein expression. Other simple design rules were identified, such as the spacing and sequence composition influences of regions upstream and downstream of ribosome binding sites and the ability of non-AUG start codons to function in vitro.

Cell-like systems with riboswitch controlled gene expression.

Synthetic riboswitches can be used to control protein expression under fully defined conditions in vitro, in water-in-oil emulsions, and in vesicles. The developed system could serve as a foundation for the construction of cellular mimics that respond to molecules of our choosing.

Machine-related injuries in the US mining industry and priorities for safety research.

Researchers at the National Institute for Occupational Safety and Health studied mining accidents that involved a worker entangled in, struck by, or in contact with machinery or equipment in motion. The motivation for this study came from the large number of severe accidents, i.e. accidents resulting in a fatality or permanent disability, that are occurring despite available interventions. Accident descriptions were taken from an accident database maintained by the United States Department of Labor, Mine Safety and Health Administration, and 562 accidents that occurred during 2000-2007 fit the search criteria. Machine-related accidents accounted for 41% of all severe accidents in the mining industry during this period. Machinery most often involved in these accidents included conveyors, rock bolting machines, milling machines and haulage equipment such as trucks and loaders. The most common activities associated with these accidents were operation of the machine and maintenance and repair. The current methods to safeguard workers near machinery include mechanical guarding around moving components, lockout/tagout of machine power during maintenance and backup alarms for mobile equipment. To decrease accidents further, researchers recommend additional efforts in the development of new control technologies, training materials and dissemination of information on best practices.

Heterogeneous electron transfer of a two-centered heme protein: redox and electrocatalytic properties of surface-immobilized cytochrome C(4).

The recombinant diheme cytochrome c(4) from the psycrophilic bacterium Pseudoalteromonas haloplanktis TAC 125 and its Met64Ala and Met164Ala variants, which feature a hydroxide ion axially bound to the heme iron at the N- and C-terminal domains, respectively, were found to exchange electrons efficiently with a gold electrode coated with a SAM of 11-mercapto-1-undecanoic acid. The mutation-induced removal of the redox equivalence of the two heme groups and changes in the net charge of the protein lobes yield two-centered protein systems with unprecedented properties in the electrode-immobilized state. The heterogeneous and intraheme electron transfer processes were characterized for these species in which the high- and low-potential heme groups are swapped over in the bilobal protein framework and experience a constrained (M64A) and unconstrained (M164A) orientation toward the electrode. The reduction thermodynamics for the native and mutated hemes were measured for the first time for a diheme cytochrome c. In the diffusing regime, they reproduce closely those for the corresponding centers in single-heme class-I cytochromes c, despite the low sequence identity. Larger differences are observed in the thermodynamics of the immobilized species and in the heterogeneous electron transfer rate constants. T-dependent kinetic measurements show that the proteins are positioned approximately 7 A from the HOOC-terminated SAM-coated electrode. Protein-electrode orientation and efficient intraheme ET enable the His,OH(-)-ligated heme A of the immobilized Met64Ala variant to carry out the reductive electrocatalysis of molecular oxygen. This system therefore constitutes a novel two-centered heme-based biocatalytic interface to be exploited for "third-generation" amperometric biosensing.

Dermatitis in the mining industry: incidence, sources, and time loss.

Occupational skin diseases and disorders are the most commonly reported nontrauma-related category of occupational illness in the United States, and mining has one of the highest incidence rates among all industries. The authors' objective in this study was to describe mining industry dermatitis incidence, sources of exposure, and resultant time lost from work. The authors reviewed Mine Accident, Injury and Illness Reports. From 1983 to 2002, the Mine Safety and Health Administration reported 975 cases of dermatitis in mines across the United States and its territories. Average annual incidence was 14.4 cases per 100 000 employees. Upper extremities and multiple body regions were most commonly involved. Twenty-five percent of miners with dermatitis lost at least 1 day of work. Exposure to plants, trees, and vegetation accounted for 24% of all cases. A greater understanding of this condition will assist health professionals in focusing on appropriate intervention strategies to reduce the occurrence of dermatitis and its associated morbidity in mine workers.

[Mortality among workers in a cigarette factory in Lucca (Tuscany)]. / Studio di mortalità degli addetti alla manifattura del tabacco di Lucca.

Aim of the present cohort study was to evaluate the mortality pattern among workers in a cigar and cigarette factory in Lucca, Italy. The study followed 2341 workers (1585 women and 756 men) registered in the company payrolls and employed for at least six months from 1 January 1960 through 1 January 1994. Follow-up was between the start of employment in the factory and 1 June 2002 (totally 74363,5 person-years). For both sexes, all-causes mortality was lower than expected (men: SMR= 0.8; CI95% 0.7-0.9; 158 deaths; women: SMR= 0.9; CI95% 0.8-1.0; 584 deaths) and no excess of mortality was reported for all malignant neoplasms. Among female workers, the frequency of deaths from pleural cancer was elevated at a statistically significant level (SMR= 6.0; CI95% 2.4-12.6; 5 deaths). One death for pleural cancer also occurred among men versus 0.4 expected. All women deceased from pleural cancer had been working in tobacco manufacturing for at least 30 years. The excess of pleural neoplasms reported in this study suggests the opportunity to evaluate the risk due to asbestos use in many manifacturing industries, especially where steam was used for extractive or warming purpose.

Everyday numerical abilities in Alzheimer's disease.

The present study investigated everyday numerical abilities in a group of 21 patients affected by mild to moderate dementia of Alzheimer's type (DAT). Though patients did not differ from a control group in standard laboratory tests tapping transcoding, number comparison, simple calculation, and estimation, they showed significant difficulties in numerical tasks embedded in an everyday context, such as handling money, a bus schedule, or a television program. Patients' difficulties were attributed to those multiple cognitive demands which are inherent to real situations as compared to well-structured abstract paper-and-pencil tasks. Overall, the study suggests that the examination of numerical abilities in DAT patients should go beyond abstract paper-and-pencil tasks which can only partially reflect the actual numerical skills in DAT and should therefore include also tasks simulating everyday life situations. Assessment of everyday numerical skills may be crucial in planning adequate support for patients, for example in handling money, but also in designing targeted training programs.