Dynamic changes during the treatment of pancreatic cancer

This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments. When an unusual drug response was detected, an extensive RNA sequencing analysis was employed to establish novel mechanisms of action of this drug. Organoid cell cultures were employed to identify possible antigens associated with the tumor and the patient\u27s T-cells were expanded against one of these antigens. Similar and identical T-cell receptor sequences were observed in the initial biopsy and the expanded T-cell population. Immunotherapy treatment failed to shrink the tumor, which had undergone an epithelial to mesenchymal transition prior to therapy. A warm autopsy of the metastatic lung tumor permitted an extensive analysis of tumor heterogeneity over five years of treatment and surgery. This detailed analysis of the clinical descriptions, imaging, pathology, molecular and cellular evolution of the tumors, treatments, and responses to chemotherapy, targeted therapies, and immunotherapies, as well as attempts at the development of personalized medical treatments for a single patient should provide a valuable guide to future directions in cancer treatment

Quality improvement in primary care: the essential guide

This book provides readers with an invaluable set of tools to convert the endless challenges for quality and myriad opportunities for improvement into meaningful and useful change. It begins by considering how to manage primary care organisations in order to improve quality of care. Patient perspectives on quality are examined initially, moving onto market mechanisms and commissioning which are increasingly being used as levers for change. It also considers how general practices are regulated and held accountable for the quality of the services they provide. All doctors work within teams, organisations and the wider health system. How these are designed and managed greatly determines individual and team effectiveness. Reflecting on this, leadership, management and the right organisational culture are reviewed. Prompts for personal reflection are included throughout the book, enabling practitioners to use personal experiences to transform the services provided. It also explores various techniques used for assessing and measuring quality of care, commonly used quality improvement frameworks along with the burgeoning sciences of process control, systems and spread. Quality Improvement in Primary Care is a highly practical introductory primer for quality improvement, relevant to every individual working and learning in primary healthcare and the wider health service

The Quality and Outcomes Framework – transforming the face of primary care in the UK

Background: Introduced in 2004 in the UK National Health Service and costing approximately £1billion per annum the Quality and Outcomes Framework (QOF) continues to provoke controversy as the largest natural experiment in pay for performance (P4P) of its kind. The accumulating evidence has important findings for practitioners and policy makers. Methods: Secondary analysis of research literature examining the impact of P4P and QOF on health and care. Results: Trend analysis suggests that improvements in indicators are only partly attributable to the QOF. More comprehensive data recording explains some of this increase. While the quality of chronic disease management in incentivised domains has improved, the opportunity costs of QOF are largely unevaluated. The evidence for a “street lamp” effect whereby the care of non-incentivised diseases is neglected is limited. Practices vary in rates of “exception-reporting” (exclusions from the denominator) but there is little evidence of ‘gaming’. QOF has effected role revision, promoting nurses with extended roles, salaried medical grades and healthcare assistants. Whereas the QOF may have added to nurses’ job satisfaction, doctors express reservations concerning fractured continuity of care, “tick box medicine” and the invasiveness of computerised protocols. Little is known of how users view P4P. Opportunity costs are largely unevaluated. Conclusions: The QOF has contributed to improvements in quality of primary care, but at considerable cost. P4P illustrates the law of unintended policy consequences, transforming general practice in unexpected ways. Further research is needed to track QOF’s impact on nursing roles, continuity of care and the patient experience

Clinical Trial Designs for the Testing of OTC Products for Dentine Hypersensitivity-A Systematic Review

Aim: The aim of the present study was to review the papers in the published literature and to compare the clinical trial methodology used in these studies to evaluate the products for Dentine Hypersensitivity (DH) based on the previously recommended guidelines of Holland, et al. (1997). Material and Methods: A systematic search was conducted on PubMed and Embase for double blind randomized placebo-controlled clinical studies conducted over ≥6 weeks assessing the efficacy of OTC products for the treatment of DH in otherwise healthy adult subjects with reported and diagnosed DH. Results: A total of 35 studies were included in this review from an initial search of 882 titles. All the included studies complied with the guidelines in terms of study design, duration, subject selection, adequate control(s) and subject instructions. 91% of studies used a sample size of ≥ 25 per arm. Most studies (91%) complied with the minimum required number of teeth to be test ed except in two studies. All the studies used an objective assessment however only two studies (22.8%) included a subjective evaluation to an everyday stimulus when evaluating DH. Only two studies included assessment of the impact of DH treatment on the participants’ Quality of Life (QoL). Most studies did not include a recommended specific run in/wash period (10 studies [28.5%]) or a follow up period following the cessation of the study (2 studies [5.7%]). All studies reported the reduction of DH as a percentage reduction from baseline values. None of the studies reported a total relief of pain irrespective of the in- tervention(s) evaluated although there were mean reductions in both test and control groups. Conclusions: All of the included studies reported a significant statistical reduction of pain in both the test and control groups, although none of the studies reported the complete absence of the pain response following any of the interventions at the end of the studies. Overall, most studies complied with the recommendations from the Holland, et al. guidelines however, there is still a need to include both a run in/wash out and follow up periods in future studies. Furthermore, it may be recommended to include a subjective evaluation of the treatment outcome to overall sensitivity from day to day activities as well as the effect on the QoL (person-centered approach) in future studies. None of the included studies reported the complete absence of the pain response following any of the interventions at the end of the studies

The Index Of Narrative Microstructure: A Clinical Tool For Analyzing School-Age Children's Narrative Performances

Purpose: This research was conducted to develop a clinical tool-the Index of Narrative Microstructure (INMIS)-that would parsimoniously account for important microstructural aspects of narrative production for school-age children. The study provides field test age- and grade-based INMIS values to aid clinicians in making normative judgments about microstructural aspects of pupils' narrative performance. Method: Narrative samples using a single-picture elicitation context were collected from 250 children age 5-12 years and then transcribed and segmented into T-units. A T-unit consists of a single main clause and any dependent constituents. The narrative transcripts were then coded and analyzed to document a comprehensive set of microstructural indices. Results: Factor analysis indicated that narrative microstructure consisted of 2 moderately related factors. The Productivity factor primarily comprised measures of word output, lexical diversity, and T-unit output. The Complexity factor comprised measures of syntactic organization, with mean length of T-units in words and proportion of complex T-units loading most strongly. Principal components analysis was used to provide a linear combination of 8 variables to approximate the 2 factors. Formulas for calculating a student's performance on the 2 factors using 8 narrative measures are provided. Conclusions: This study provided a method for professionals to calculate INMIS scores for narrative Productivity and Complexity for comparison against field test data for age (5- to 12-year-old) or grade (kindergarten to Grade 6) groupings. INMIS scores complement other tools in evaluating a child's narrative performance specifically and language abilities more generally.Communication Sciences and Disorder

Populations dynamics in Northern Eurasian forests: a long-term perspective from Northeast Asia

The ‘Northern Eurasian Greenbelt’ (NEG) is the northern forest zone stretching from the Japanese Archipelago to Northern Europe. The NEG has created highly productive biomes for humanity to exploit since the end of the Pleistocene. This research explores how the ecological conditions in northern Eurasia contributed to and affected human migrations and cultural trajectories by synthesizing the complimentary viewpoints of environmental archaeology, Geographic Information Science (GIS), genetics and linguistics. First, the environmental archaeology perspective raises the possibility that the NEG functioned as a vessel fostering people to develop diverse cultures and engage in extensive cross-cultural exchanges. Second, geographical analysis of genomic data on mitochondrial DNA using GIS reveals the high probability that population dynamics in the southeastern NEG promoted the peopling of the Americas at the end of the Pleistocene. Finally, a linguistic examination of environmental- and landscape-related vocabulary of the proto-Turkic language groups enables the outline of their original cultural landscape and natural conditions, demonstrating significant cultural spheres, i.e. from southern Siberia to eastern Inner Mongolia during Neolithization. All of these results combine to suggest that the ecological complex in the southern edge of the NEG in northeast Asia played a significant role in peopling across the continents during prehistory.- Introduction: Northern Eurasian Greenbelt - Methodology: synthesizing environmental archaeology, genetic-geography and linguistics - Environmental archaeology: socio-ecological background of the NEG -- Long hunting–gathering traditions -- Environmental setting -- Hypothesis: the NEG as a trans-continental cultural system - A genetic–geographical perspective -- Cultural, physical and bio-geographical evidence -- Supporting archaeological evidence -- The genomic evidence -- Discussion - Historical linguistics: the origin of the Turkic family and its early dispersal via the NEG -- The Proto-Turkic homeland -- Proto-Turkic vocabulary of the natural and cultural environments -- Early Turkic migrations and cultural transmission via the NEG - Early Turkic migrations and cultural transmission via the NE

Biogeochemical Cycling in a Headwater Stream and Riparian Zone

Several teams of researchers at multiple universities are currently measuring annual and seasonal fluxes of carbon dioxide and other greenhouses gases (nitrous oxide and methane) in riparian wetlands and upland forests in the Tenderfoot Creek Experimental Forest (TCEF), a subalpine watershed in the Little Belt Mountains, Montana. In the current thesis, the author characterized the geochemistry and stable carbon isotope composition of shallow groundwater, soil water, and stream water in upper Stringer Creek, near sites that are being investigated for gas chemistry and microbial studies. It was hypothesized that if methanogenesis were a dominant process in the riparian wetlands of upper Stringer Creek, then this should impart a characteristic signal in the measured stable isotopic composition of dissolved inorganic carbon in shallow groundwater. For the most part, the major solute composition of shallow groundwater in upper Stringer Creek was similar to that of the stream. However, several wells completed in wetland soil had highly elevated concentrations of Fe2+ and Mn2+ which were absent in the well-oxygenated surface water. Use of sediment pore-water samplers (peepers) demonstrated a rapid increase in Fe2+ and Mn2+ with depth, most feasibly explained by microbial reduction of Fe- and Mn-oxide minerals. In general, the pH of shallow groundwater was lower than that of the stream. Since concentrations of CO2 in the groundwater samples were consistently greater than atmospheric pCO2, exchange of CO2 gas across the stream/air interface occurred in one direction, from stream to air. Evasion of CO2 partly explains the higher pH values in the stream. Microbial processes involving breakdown of organic carbon, including aerobic respiration, anaerobic respiration, and methanogenesis, explain the occurrence of excess CO2 in the groundwater. In general, the isotopic composition of total dissolved inorganic carbon (DIC) decreased with increasing DIC concentration, consistent with aerobic and/or anaerobic respiration being the dominant metabolic process in shallow groundwater. However, a minority of wells contained high DIC concentrations that were anomalously heavy in u13C, and these same wells had elevated concentrations of dissolved methane. It is concluded that the wells with isotopically-heavier DIC have likely been influenced by acetoclastic methanogenesis. Results from shallow groundwater wells and one of the peeper samplers suggest a possible link between methanogenesis and bacterial iron reduction

Bacterial expression of two human aryl sulfotransferases

The effect of replacing a single codon in the N-terminal of human aryl sulfotransferase (HAST) 1 and 3 with one that is more commonly found in E. coli genes was assessed. The pKK233-2 E. coli expression vector was employed and the polymerase chain reaction (PCR) was used to introduce the 5' nucleotide substitution, at the same time maintaining the fidelity of the amino acid sequence. The data indicates that this change had a minimal effect on protein production, subcellular localization or, in the case of HAST3, catalytic activity. In general, the pKK233-2 E. coli vector has been less than optimal for expressing human sulfotransferase cDNAs. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved

The Relationship between both Partial and Complete Denture Wearers and the Presence of Oral Malodour and the Effect of Denture Cleansers on the Oral Microbiota

Oral malodour may be considered a substantial concern for a sizeable percentage of the general population and as such it is important for clinicians to identify the causes of oral malodour, to treat the problem effectively. Aim: The aim of the present study was therefore to review the published literature on the presence and perception of oral malodour (halitosis) in patients wearing both removable partial or complete dentures and the effect of denture cleansers on the oral microbiota. Materials & Methods: A comprehensive electronic search of databases such as PUBMED, Cochrane, Google Scholar, EmBase and Web of Science was performed up to February 2016. Results: 55 potentially relevant reports were identified with six studies included in the review. Of the six included papers, only one study was randomised, and five studies were either non-randomised controlled clinical trials or, quasi randomised trials. The results from these studies would suggest that there was an indirect association between the presence and perception of oral malodour in both RPD and complete denture wearing patients. Conclusions: The strength of evidence was however insufficient to draw any definitive conclusions on a potential correlation of oral malodour in patients with RPDs