Towards real-time understanding of processes in pharmaceutical powder technology

There is a need for better understanding of the processes and new ideas to develop traditional pharmaceutical powder manufacturing procedures. Process analytical technology (PAT) has been developed to improve understanding of the processes and establish methods to monitor and control processes. The interest is in maintaining and even improving the whole manufacturing process and the final products at real-time. Process understanding can be a foundation for innovation and continuous improvement in pharmaceutical development and manufacturing. New methods are craved for to increase the quality and safety of the final products faster and more efficiently than ever before. The real-time process monitoring demands tools, which enable fast and noninvasive measurements with sufficient accuracy. Traditional quality control methods have been laborious and time consuming and they are performed off line i.e. the analysis has been removed from process area. Vibrational spectroscopic methods are responding this challenge and their utilisation have increased a lot during the past few years. In addition, other methods such as colour analysis can be utilised in noninvasive real-time process monitoring. In this study three pharmaceutical processes were investigated: drying, mixing and tabletting. In addition tablet properties were evaluated. Real-time monitoring was performed with NIR and Raman spectroscopies, colour analysis, particle size analysis and compression data during tabletting was evaluated using mathematical modelling. These methods were suitable for real-time monitoring of pharmaceutical unit operations and increase the knowledge of the critical parameters in the processes and the phenomena occurring during operations. They can improve our process understanding and therefore, finally, enhance the quality of final products.

Talking About Time in Russian and Finnish

In this study I look at what people want to express when they talk about time in Russian and Finnish, and why they use the means they use. The material consists of expressions of time: 1087 from Russian and 1141 from Finnish. They have been collected from dictionaries, usage guides, corpora, and the Internet. An expression means here an idiomatic set of words in a preset form, a collocation or construction. They are studied as lexical entities, without a context, and analysed and categorized according to various features. The theoretical background for the study includes two completely different approaches. Functional Syntax is used in order to find out what general meanings the speaker wishes to convey when talking about time and how these meanings are expressed in specific languages. Conceptual metaphor theory is used for explaining why the expressions are as they are, i.e. what kind of conceptual metaphors (transfers from one conceptual domain to another) they include. The study has resulted in a grammatically glossed list of time expressions in Russian and Finnish, a list of 56 general meanings involved in these time expressions and an account of the means (constructions) that these languages have for expressing the general meanings defined. It also includes an analysis of conceptual metaphors behind the expressions. The general meanings involved turned out to revolve around expressing duration, point in time, period of time, frequency, sequence, passing of time, suitable time and the right time, life as time, limitedness of time, and some other notions having less obvious semantic relations to the others. Conceptual metaphor analysis of the material has shown that time is conceptualized in Russian and Finnish according to the metaphors Time Is Space (Time Is Container, Time Has Direction, Time Is Cycle, and the Time Line Metaphor), Time Is Resource (and its submapping Time Is Substance), Time Is Actor; and some characteristics are added to these conceptualizations with the help of the secondary metaphors Time Is Nature and Time Is Life. The limits between different conceptual metaphors and the connections these metaphors have with one another are looked at with the help of the theory of conceptual integration (the blending theory) and its schemas. The results of the study show that although Russian and Finnish are typologically different, they are very similar both in the needs of expression their speakers have concerning time, and in the conceptualizations behind expressing time. This study introduces both theoretical and methodological novelties in the nature of material used, in developing empirical methodology for conceptual metaphor studies, in the exactness of defining the limits of different conceptual metaphors, and in seeking unity among the different facets of time. Keywords: time, metaphor, time expression, idiom, conceptual metaphor theory, functional syntax, blending theory

Methodological and Empirical Advances in the Quantitative Analysis of Spontaneous Responses in Psychophysiological Time Series

The aim of the present study was to advance the methodology and use of time series analysis to quantify dynamic structures in psychophysiological processes and thereby to produce information on spontaneously coupled physiological responses and their behavioral and experiential correlates. Series of analyses using both simulated and empirical cardiac (IBI), electrodermal (EDA), and facial electromyographic (EMG) data indicated that, despite potential autocorrelated structures, smoothing increased the reliability of detecting response coupling from an interindividual distribution of intraindividual measures and that especially the measures of covariance produced accurate information on the extent of coupled responses. This methodology was applied to analyze spontaneously coupled IBI, EDA, and facial EMG responses and vagal activity in their relation to emotional experience and personality characteristics in a group of middle-aged men (n = 37) during the administration of the Rorschach testing protocol. The results revealed new characteristics in the relationship between phasic end-organ synchronization and vagal activity, on the one hand, and individual differences in emotional adjustment to novel situations on the other. Specifically, it appeared that the vagal system is intimately related to emotional and social responsivity. It was also found that the lack of spontaneously synchronized responses is related to decreased energetic arousal (e.g., depression, mood). These findings indicate that the present process analysis approach has many advantages for use in both experimental and applied research, and that it is a useful new paradigm in psychophysiological research. Keywords: Autonomic Nervous System; Emotion; Facial Electromyography; Individual Differences; Spontaneous Responses; Time Series Analysis; Vagal System

Effect of waiting time on health outcomes and service utilization : A prospective randomized study on patients admitted to hospital for hip or knee replacement

Although the principle of equal access to medically justified treatment has been promoted by official health policies in many Western health care systems, practices do not completely meet policy targets. Waiting times for elective surgery vary between patient groups and regions, and growing problems in the availability of services threaten equal access to treatment. Waiting times have come to the attention of decision-makers, and several policy initiatives have been introduced to ensure the availability of care within a reasonable time. In Finland, for example, the treatment guarantee came into force in 2005. However, no consensus exists on optimal waiting time for different patient groups. The purpose of this multi-centre randomized controlled trial was to analyse health-related quality of life, pain and physical function in total hip or knee replacement patients during the waiting time and to evaluate whether the waiting time is associated with patients health outcomes at admission. This study also assessed whether the length of waiting time is associated with social and health services utilization in patients awaiting total hip or knee replacement. In addition, patients health-related quality of life was compared with that of the general population. Consecutive patients with a need for a primary total hip or knee replacement due to osteoarthritis were placed on the waiting list between August 2002 and November 2003. Patients were randomly assigned to a short waiting time (maximum 3 months) or a non-fixed waiting time (waiting time not fixed in advance, instead the patient followed the hospitals routine practice). Patients health-related quality of life was measured upon being placed on the waiting list and again at hospital admission using the generic 15D instrument. Pain and physical function were evaluated using the self-report Harris Hip Score for hip patients and a scale modified from the Knee Society Clinical Rating System for knee patients. Utilization measures were the use of home health care, rehabilitation and social services, physician visits and inpatient care. Health and social services use was low in both waiting time groups. The most common services used while waiting were rehabilitation services and informal care, including unpaid care provided by relatives, neighbours and volunteers. Although patients suffered from clear restrictions in usual activities and physical functioning, they seemed primarily to lean on informal care and personal networks instead of professional care. While longer waiting time did not result in poorer health-related quality of life at admission and use of services during the waiting time was similar to that at the time of placement on the list, there is likely to be higher costs of waiting by people who wait longer simply because they are using services for a longer period. In economic terms, this would represent a negative impact of waiting. Only a few reports have been published of the health-related quality of life of patients awaiting total hip or knee replacement. These findings demonstrate that, in addition to physical dimensions of health, patients suffered from restrictions in psychological well-being such as depression, distress and reduced vitality. This raises the question of how to support patients who suffer from psychological distress during the waiting time and how to develop strategies to improve patients initiatives to reduce symptoms and the burden of waiting. Key words: waiting time, total hip replacement, total knee replacement, health-related quality of life, randomized controlled trial, outcome assessment, social service, utilization of health services

Management of multi-scale forest resource data over time

During the last decades there has been a global shift in forest management from a focus solely on timber management to ecosystem management that endorses all aspects of forest functions: ecological, economic and social. This has resulted in a shift in paradigm from sustained yield to sustained diversity of values, goods and benefits obtained at the same time, introducing new temporal and spatial scales into forest resource management. The purpose of the present dissertation was to develop methods that would enable spatial and temporal scales to be introduced into the storage, processing, access and utilization of forest resource data. The methods developed are based on a conceptual view of a forest as a hierarchically nested collection of objects that can have a dynamically changing set of attributes. The temporal aspect of the methods consists of lifetime management for the objects and their attributes and of a temporal succession linking the objects together. Development of the forest resource data processing method concentrated on the extensibility and configurability of the data content and model calculations, allowing for a diverse set of processing operations to be executed using the same framework. The contribution of this dissertation to the utilisation of multi-scale forest resource data lies in the development of a reference data generation method to support forest inventory methods in approaching single-tree resolution.

Stiffer Optical Tweezers through Real-Time Feedback Control

This thesis integrates real-time feedback control into an optical tweezers instrument. The goal is to reduce the variance in the trapped bead s position, -effectively increasing the trap stiffness of the optical tweezers. Trap steering is done with acousto-optic deflectors and control algorithms are implemented with a field-programmable gate array card. When position clamp feedback control is on, the effective trap stiffness increases 12.1-times compared to the stiffness without control. This allows improved spatial control over trapped particles without increasing the trapping laser power.

Power Aware Real Time Scheduling in Constrained Devices

Real-time scheduling algorithms, such as Rate Monotonic and Earliest Deadline First, guarantee that calculations are performed within a pre-defined time. As many real-time systems operate on limited battery power, these algorithms have been enhanced with power-aware properties. In this thesis, 13 power-aware real-time scheduling algorithms for processor, device and system-level use are explored.

Time to rest : Signals in shoot apex developmental transitions underlying dormancy

Vuodenajat rytmittävät monivuotisten kasvien elämää pohjoisella pallonpuoliskolla, jolla varmin merkki lähestyvästä talvikaudesta on asteittain lyhenevä päivänpituus. Kun päivänpituus on lyhentynyt tiettyyn raja-arvoon saakka, kasvu hiipuu ja kasvin kehityksessä tapahtuu suuria muutoksia. Väitöskirjatyössäni tutkittiin mekanismeja, jotka liittyvät pituuskasvun päättymiseen, silmujen lepotilan kehittymiseen ja kärkisilmun muodostumiseen hybridihaavan ja koivuntaimilla lyhyen päivänpituuden seurauksena kasvihuoneolosuhteissa. Vain lepotilaiset silmut selviytyvät luonnossa ankaran talvikauden yli, joten etenkin lepotilan kehittymisen tutkiminen on keskeistä pyrittäessä selvittämään monivuotisille kasveille tyypillisen kasvutavan mekanismeja. Jo pitkään on tiedetty, että täysikasvuiset lehdet vastaanottavat tiedon päivänpituudesta ja lähettävät signaaleja varren johtojänteissä ylöspäin kohti kasvin kärkiosaa. Sen sijaan varren kärjen ja kärkikasvupisteen roolia lepotilan kehittymisessä on selvitetty vain vähän. Kuitenkin juuri kärkikasvupisteen selviytyminen vuodesta toiseen on tärkeää, koska sen jakautumiskykyiset solukot tuottavat kasvin maanpäälliset osat. Tässä työssä tehdyissä varttamiskokeissa osoitettiin, että varren kärki ei ainoastaan vastaanota signaaleja lehdistä ja ajoita toimintaansa niiden mukaan, vaan myös kärjellä itsellään on aktiivinen rooli lepotilan kehittymisessä. Erityisesti kiinnitettiin huomiota kärkikasvupisteen eri alueiden, ns. apikaalimeristeemin ja rib-meristeemin erilaisiin tehtäviin ja pääteltiin, että molemmat vaikuttavat lepotilan kehittymiseen. Kokeissa käytettiin normaalien hybridihaapojen lisäksi siirtogeenisiä hybridihaapoja, jotka eivät lopeta kasvuaan lyhyt päivä –olosuhteissa. Siirtogeeniset hybridihaavat ilmensivät voimakkaasti fytokromi A -nimistä valon vastaanottajamolekyyliä rib-meristeemin alueella, mikä saattoi osaltaan vaikuttaa poikkeavaan pituuskasvukäyttäytymiseen. Myös useiden lepotilan kehittymiseen liittyvien geenien ilmenemisessä havaittiin poikkeavuuksia verrattuna ei-siirtogeenisiin kontrolleihin, joiden silmuissa kehittyi lepotila lyhyt päivä –altistuksen seurauksena. Väitöskirjatyössäni havaittiin, että myös kaasumainen kasvihormoni etyleeni toimii viestinvälittäjänä silmujen lepotilan kehittymisessä ja vaikuttaa etenkin lepotilan oikeaan ajoittumiseen. Etyleenillä huomattiin olevan määräävä rooli päätesilmun muodostumisessa: siirtogeeniset koivut, jotka eivät aisti etyleeniä, eivät muodostaneet päätesilmua. Silti siirtogeeniset koivut vaipuivat lepotilaan, joskin myöhemmin kuin ei-siirtogeeniset kontrollit. Tämän perusteella todettiin, että lepotilan ja päätesilmun kehittyminen ovat erillisiä kehitystapahtumia, vaikka ne saattavatkin ajoittua osaksi päällekkäin.

Children and adolescents in full-time special education : an epidemiological and magnetic resonance imaging study

The need for special education (SE) is increasing. The majority of those whose problems are due to neurodevelopmental disorders have no specific aetiology. The aim of this study was to evaluate the contribution of prenatal and perinatal factors and factors associated with growth and development to later need for full-time SE and to assess joint structural and volumetric brain alterations among subjects with unexplained, familial need for SE. A random sample of 900 subjects in full-time SE allocated into three levels of neurodevelopmental problems and 301 controls in mainstream education (ME) provided data on socioeconomic factors, pregnancy, delivery, growth, and development. Of those, 119 subjects belonging to a sibling-pair in full-time SE with unexplained aetiology and 43 controls in ME underwent brain magnetic resonance imaging (MRI). Analyses of structural brain alterations and midsagittal area and diameter measurements were made. Voxel-based morphometry (VBM) analysis provided detailed information on regional grey matter, white matter, and cerebrospinal fluid (CSF) volume differences. Father’s age ≥ 40 years, low birth weight, male sex, and lower socio-economic status all increased the probability of SE placement. At age 1 year, one standard deviation score decrease in height raised the probability of SE placement by 40% and in head circumference by 28%. At infancy, the gross motor milestones differentiated the children. From age 18 months, the fine motor milestones and those related to speech and social skills became more important. Brain MRI revealed no specific aetiology for subjects in SE. However, they had more often ≥ 3 abnormal findings in MRIs (thin corpus callosum and enlarged cerebral and cerebellar CSF spaces). In VBM, subjects in full-time SE had smaller global white matter, CSF, and total brain volumes than controls. Compared with controls, subjects with intellectual disabilities had regional volume alterations (greater grey matter volumes in the anterior cingulate cortex bilaterally, smaller grey matter volume in left thalamus and left cerebellar hemisphere, greater white matter volume in the left fronto-parietal region, and smaller white matter volumes bilaterally in the posterior limbs of the internal capsules). In conclusion, the epidemiological studies emphasized several factors that increased the probability of SE placement, useful as a framework for interventional studies. The global and regional brain MRI findings provide an interesting basis for future investigations of learning-related brain structures in young subjects with cognitive impairments or intellectual disabilities of unexplained, familial aetiology.

Spirometric studies on the adult general population of Helsinki : bronchodilation responses, determinants, and intrasession repeatability of FEV1, FEV6, FVC, and forced expiratory time

Spirometry is the most widely used lung function test in the world. It is fundamental in diagnostic and functional evaluation of various pulmonary diseases. In the studies described in this thesis, the spirometric assessment of reversibility of bronchial obstruction, its determinants, and variation features are described in a general population sample from Helsinki, Finland. This study is a part of the FinEsS study, which is a collaborative study of clinical epidemiology of respiratory health between Finland (Fin), Estonia (Es), and Sweden (S). Asthma and chronic obstructive pulmonary disease (COPD) constitute the two major obstructive airways diseases. The prevalence of asthma has increased, with around 6% of the population in Helsinki reporting physician-diagnosed asthma. The main cause of COPD is smoking with changes in smoking habits in the population affecting its prevalence with a delay. Whereas airway obstruction in asthma is by definition reversible, COPD is characterized by fixed obstruction. Cough and sputum production, the first symptoms of COPD, are often misinterpreted for smokers cough and not recognized as first signs of a chronic illness. Therefore COPD is widely underdiagnosed. More extensive use of spirometry in primary care is advocated to focus smoking cessation interventions on populations at risk. The use of forced expiratory volume in six seconds (FEV6) instead of forced vital capacity (FVC) has been suggested to enable office spirometry to be used in earlier detection of airflow limitation. Despite being a widely accepted standard method of assessment of lung function, the methodology and interpretation of spirometry are constantly developing. In 2005, the ATS/ERS Task Force issued a joint statement which endorsed the 12% and 200 ml thresholds for significant change in forced expiratory volume in one second (FEV1) or FVC during bronchodilation testing, but included the notion that in cases where only FVC improves it should be verified that this is not caused by a longer exhalation time in post-bronchodilator spirometry. This elicited new interest in the assessment of forced expiratory time (FET), a spirometric variable not usually reported or used in assessment. In this population sample, we examined FET and found it to be on average 10.7 (SD 4.3) s and to increase with ageing and airflow limitation in spirometry. The intrasession repeatability of FET was the poorest of the spirometric variables assessed. Based on the intrasession repeatability, a limit for significant change of 3 s was suggested for FET during bronchodilation testing. FEV6 was found to perform equally well as FVC in the population and in a subgroup of subjects with airways obstruction. In the bronchodilation test, decreases were frequently observed in FEV1 and particularly in FVC. The limit of significant increase based on the 95th percentile of the population sample was 9% for FEV1 and 6% for FEV6 and FVC; these are slightly lower than the current limits for single bronchodilation tests (ATS/ERS guidelines). FEV6 was proven as a valid alternative to FVC also in the bronchodilation test and would remove the need to control duration of exhalation during the spirometric bronchodilation test.

Quantifying Time Awake Posturographically

This thesis focuses on the issue of testing sleepiness quantitatively. The issue is relevant to policymakers concerned with traffic- and occupational safety; such testing provides a tool for safety legislation and -surveillance. The findings of this thesis provide guidelines for a posturographic sleepiness tester. Sleepiness ensuing from staying awake merely 17 h impairs our performance as much as the legally proscribed blood alcohol concentration 0.5 does. Hence, sleepiness is a major risk factor in transportation and occupational accidents. The lack of convenient, commercial sleepiness tests precludes testing impending sleepiness levels contrary to simply breath testing for alcohol intoxication. Posturography is a potential sleepiness test, since clinical diurnal balance testing suggests the hypothesis that time awake could be posturographically estimable. Relying on this hypothesis this thesis examines posturographic sleepiness testing for instrumentation purposes. Empirical results from 63 subjects for whom we tested balance with a force platform during wakefulness for maximum 36 h show that sustained wakefulness impairs balance. The results show that time awake is posturographically estimable with 88% accuracy and 97% precision which validates our hypothesis. Results also show that balance scores tested at 13:30 hours serve as a threshold to detect excessive sleepiness. Analytical results show that the test length has a marked effect on estimation accuracy: 18 s tests suffice to identify sleepiness related balance changes, but trades off some of the accuracy achieved with 30 s tests. The procedure to estimate time awake relies on equating the subject s test score to a reference table (comprising balance scores tested during sustained wakefulness, regressed against time awake). Empirical results showed that sustained wakefulness explains 60% of the diurnal balance variations, whereas the time of day explains 40% of the balance variations. The latter fact implies that time awake estimations also must rely on knowing the local times of both test and reference scores.