Doctor of Philosophy / This thesis is concerned with an examination and re-assessment of the establishment, operation and management of the Female and Male Orphan Schools, in the first half of the nineteenth century in New South Wales. The chaplains and governors in the early penal settlement were faced with a dilemma, as they beheld the number of children who were ‘orphaned’, neglected, abandoned and destitute. In order to understand the reasons why these children were in necessitous circumstances, the thesis seeks to examine the situations of the convict women, who were the mothers of these children. Governors Philip Gidley King and Lachlan Macquarie respectively in 1801 and 1819 established the Schools, which provided elementary education, training and residential care within a religious setting. Researching the motives underlying the actions of these men has been an important part of the thesis. An examination of the social backgrounds of some of the children admitted to these Schools has been undertaken, in order to provide a greater understanding of the conditions under which the children were living prior to their admissions. Information about family situations, and the social problems encountered by parents that led them to place their children in the Schools, have been explored. The avenues open to the girls and boys when they left the Schools, has formed part of the study. Some children were able to be reunited with family members, but the majority of them were apprenticed. A study of the nature of these apprenticeships, has led to a greater understanding of employment opportunities for girls and boys at that time. In 1850 the Schools were amalgamated into the Protestant Orphan School at Parramatta. By examining the governance and operation of the Schools during their last two decades as separate entities, we have more knowledge about and understanding of these two colonial institutions. It is the conclusion of this thesis that some of the harsher judgements of revisionist social historians need to be modified. It was the perception that more social disorder would occur if action was not taken to ‘rescue’ the ‘orphaned’ children, usually of convict parentage. However genuine charity, philanthropy and concern was displayed for the children in grave physical and moral danger. The goals of the founders were not always reached in the Orphan Schools, nevertheless they performed an invaluable service in the lives of many children.

In this work we have addressed the complex problem of recovery for concurrent failures in a distributed computing environment. We have proposed a new checkpointing and recovery approach that enables each process to restart from its recent checkpoint and therefore guarantees least amount of recomputation to be done after recovery. The proposed new approach deals effectively with orphan and lost messages. We have introduced two new ideas. The value of the common checkpointing interval is such that it requires to log only the messages sent in the recent checkpoints of the processes. The lost messages are always determined a priori by the initiator process in parallel to the normal distributed computation. Thereby, it does not delay the recovery approach in anyway.

Religious identity, self-concept, and resilience are considered the three main components that contribute to adolescents' life developmental tasks. The purpose of the current study is to examine the effect of psycho-educational group intervention on religious identity, self-concept, and resilience among 94 Malaysian female orphan adolescents. Participants, aged between 14 and 17 years (early adolescence), were selected from four different orphanages in Malaysia. Using a quasi-experimental design, these participants completed two sets of pretests and post-tests on demographic information, the Muslim Religious Personality Inventory (MRPI), the Tennessee Self-Concept Scale-2 (TSCS-2), and the Singaporean Youth Resilience Scale (SYRESS). The data was analyzed using both Pearson Correlation and Multivariate Analysis of Covariance (MANCOVA). Findings found a positive relationship among three constructs--religious identity, self-concept, and resilience. Given the types of orphans in this study, there was no significant difference between true and social orphans on their religious identity, self-concept, and resilience scores. The results also showed that the psycho-educational group intervention did have a significant effect on the treatment group's score of religious identity, self-concept, and resilience tasks over a four-week session. The change of religious identity, self-concept, and resilience suggests that this intervention group is sufficient to be effective in female orphans who are participating in this study while providing new perspectives for group worker practitioners, caregivers, institutional principals, and Pertubuhan Kebajikan Anak Yatim Malaysia (PEYATIM).

Bakgrund: Strategier för att upprätta ett system för finansiering av särläkemedel, d.v.s. läkemedel för behandling av sällsynta sjukdomar, pågår. Målet är att individer med störst behov ska prioriteras utan att resurser till större individgrupper minskas. Problem föreligger dock vid fördelning av resurserna, då dessa redan är begränsade, och att särläkemedel medför mycket höga kostnader. Syfte: Syftet med detta examensarbete är att redovisa hur olika intressenter i Sverige bedömer i vilken omfattning särläkemedel skall användas, vem som skall bära kostnaderna, och hur prioriteringar bör göras för att skapa ett ekonomiskt utrymme för deras användning. Som modelläkemedel har Cerezyme® (ett läkemedel mot Gaucher’s sjukdom) använts. Metod: För att finna svar på min frågeställning gjordes datainsamling genom sökningar i följande databaser: Tandvård- och läkemedelsverket, Fass, Google och PubMed. För att studera prioritering exemplifierades arbetet genom en fallstudie av Cerezyme®. Resultat: Undersökningarna visade att prioriteringar sker genom kostnadsberäkningar av QALY (quality-adjusted life year) tillsammans med människovärdesprincipen, kostnadseffektivitetsprincipen, samt behovs- och solidaritetsprincipen. Utifrån dessa grunder handlägger TLV (Tandvård- och läkemedelsförmånsverket) för innefattande av läkemedelsförmån. TLV valde den 8 mars, 2012, att utesluta Cerezyme® ur läkemedelsförmånen på grund av för höga kostnader per patient och år. Detta överklagades av tillverkaren, Genzyme, men förvaltningsrätten avslog överklagandet den 30 april, 2012. Genzyme valde att överklaga domen, vilket kammarrätten sedan beviljade genom inhibering av TLV:s beslut tills en slutgiltig dom för Cerezyme® fastslagits. TLV överklagade återigen, vilket också avslogs. Cerezyme® finns inom förmån tills vidare. Slutsats: Det råder idag stora olikheter kring rätten att få behandling gällande särläkemedel beroende på patientens geografiska lokalisering, är det synnerligen viktigt att se över finansiering och prioritering av dessa behandlingar. / The choice of my thesis is based on orphan drugs, which individuals with rare diseases use as treatment, diagnostics or to prevent the progress of the disease. In order to get a classification as an orphan drug, the drug must be used for a condition that affects 5 or less of 10 000 individuals, based on the European classification. The clinical trials for this type of medicines are as every medical trial, expensive and orphan drugs have the smallest patient groups. Therefore there is no justification to the pharmaceutical companies in development in orphan drugs. This project is made by a case study and answer survey, and the literature research was based on articles written in English or Swedish, and articles older than 2000 were excluded.The purpose of this thesis is to evaluate how priorities of resources are made, to fund expensive drugs, in Sweden. Tandvårds- och läkemedelsförmånsverket (TLV) has the authority to decide whether different kind of medicines are subjects to the Swedish pharmaceutical benefits, which are funding a great amount of medicines. The thesis is based on evaluations from various stakeholder, Swedish laws and previous research in priority.Sweden is financing the orphan drugs in three ways. Orphan drugs included in Swedish pharmaceutical benefits are funded by customs fee to 2200 SEK, and the rest of the costs are financed by the state through the council counties. Orphan drugs in hospitalization are financed by the hospital, clinic or the county where the patient is registered. The orphan drugs which are prescribed but still excluded from the benefits are financed either by the patient, county or the hospital. The investigation of pricing and financial proposition of orphan drugs in Sweden is delayed but still in progress, and are expected to be presented in April, 2014.TLV make the decisions regarding pharmaceutical benefits through calculations of QALY’s and by three ethical grounds or principles. The principles stand for human dignity, cost-effectiveness, solidarity and needs. TLV could either approve the drug, which makes the drug included to pharmaceutical benefits, or disapprove the drug and makes it unavailable through state funding. TLV decided to exclude Cerezyme® from the Swedish pharmaceutical benefits. The decisions were made of calculations of QALY’s, which was calculated much higher costs than previously approved by TLV. The manufacturers of Cerezyme® did not agree with TLV’s decision, and went to higher courts. The recent decision of higher courts was to re-include Cerezyme® from pharmaceutical benefits, which makes the drug available to patients in desperate need again.Processes of different kinds of orphan drugs to include these to pharmaceutical benefits are not treated equally. Depending of the state of the disease, prevalence and geographic location, are patients treated variously. This is a major problem in management of orphan drugs, and should be prevented as soon as possible. All citizens should on equal terms, have access to same health care, this through Swedish Health Care laws.

Evaluating Drugs for Rare Diseases (DRDs) for the purpose of reimbursement and beyond represents a tremendous challenge for most health care priorities. A consensus is set about the irrelevance of cost e ectiveness analysis to evaluate such drugs. The appeal for multi criteria decision aid models seems reasonable as the evaluation of DRDs is indeed multifaceted. However, the application of MCDA for the purpose of evaluating DRDs is yet primitive and simplistic. The present work tries to tackle the issue of evaluating DRDs from a decision maker angle by adopting an innovative robust ordinal regression MCDA method, UTADIS-GMS, that helps the decision maker discern between the DRDs based on their multi criteria value.

The opportunistic pathogen Pseudomonas aeruginosa utilizes a variety of virulence factors to infect a wide range of hosts. Virulence genes in this organism are many times controlled by two-component regulatory systems consisting of a sensor histidine kinase and a response regulator giving them high importance in research. Orphan response regulators consist of genes that have been proposed to be a response regulator but have not been studied to determine if they do work in a two-component regulatory system or not. Investigating these orphan response regulators could potentially lead to the finding of another regulator of virulence genes. Non-polar deletions were designed using splicing of genomic segments by overlapping extension. A variety of phenotypic assays, liquid-killing assays with the nematode C. elegans, and virulence assays with macrophages were utilized to determine if these orphans were different from the wild-type strain PAO1. If attenuated, these genes can be further studied to find new and novel regulators of virulence in Pseudomonas aeruginosa.

Magister Artium (Child and Family Studies) - MA(CFS) / Kinship foster care in South Africa, whereby orphaned and vulnerable children (OVC) are being cared for by their biological relatives, is increasing. The significant increase in kinship foster care has a strong correlation to the high rates of HIV/AIDS-related deaths, resulting in a high prevalence of children who are vulnerable and orphaned. Social workers are mandated to seek alternative care placements for such OVC, prioritising kinship care as opposed to foster care with non-biological families. However, such kinship foster care, in which children are likely to be placed in the care of their grandparents, as common practice in South Africa, is not without challenges relating to family dynamics, especially when foster children become teenagers.

The blockchain technology promises innovation by moving away from conventional centralized architectures, where trust is placed in a small number of actors, to a decentralized environment where a collection of actors must work together to maintain consensus in the overall system. Blockchain offers security and pseudo-anonymity to its adopters, through the use of various cryptographic methods. While much attention has focused on creating new applications that make use of this technology, equal importance must be given to studying naturally occurring phenomena in existing blockchain ecosystems and mitigating their effects where harmful. In this dissertation, we develop a novel open-source log-to-file system that provides the ability to record information relevant to events as they take place in live blockchain networks. Specifically, our open-source software facilitates in-situ measurements on full nodes in the live Bitcoin and Bitcoin Cash blockchain networks. This measurement framework sheds new light on many phenomena that were previously unknown or scarcely studied. First, we examine the presence and impact of churn, namely nodes joining and leaving, on the behavior of the Bitcoin network. Our data analysis over a two-month period shows that a large number of Bitcoin nodes churn at least once. We perform statistical distribution fitting to this churn and emulate it in our measurement nodes to evaluate the impact of churn on the performance of the Bitcoin protocol. From our experiments, we find that blocks received by churning nodes experience as much as five times larger propagation delay than those received by non-churning nodes. We introduce and evaluate a novel synchronization scheme to mitigate such effects on the performance of the protocol. Our empirical evaluation shows that blocks received by churning nodes that synchronize their mempools with peers have roughly half the delay in propagation experienced by those that do not synchronize their mempools. We next evaluate and compare the performance of three block relay protocols, namely the default protocol, and the more recent compact block and Graphene protocols. This evaluation is conducted over full nodes running the Bitcoin Unlimited client (which is used in conjunction with the Bitcoin Cash network). We find that in most scenarios, the Graphene block relay protocol outperforms the other two in terms of the block propagation delay and the amount of total communication associated with block relay. An exception is when nodes churn frequently and spend a significant fraction of time off the network, in which case the compact block relay protocol performs best. In-depth analyses reveal subtle inefficiencies of the protocols. Thus, in the case of frequent churns, the Graphene block relay protocol performs as many as two extra round-trips of communication to recover information necessary to reconstruct blocks. Likewise, an inspection of the compact block relay protocol indicates that the full transactions included in the initial block message are either unnecessary or insufficient for the successful reconstruction of blocks. Finally, we investigate the occurrence of orphan transactions which are those whose parental income sources are missing at the time that they are processed. These transactions typically languish in a local buffer until they are evicted or all their parents are discovered, at which point they may be propagated further. Our data reveals that slightly less than half of orphan transactions end up being included in the blockchain. Surprisingly, orphan transactions tend to have fewer parents on average than non-orphan transactions, and their missing parents have a lower fee, a larger size, and a lower transaction fee per byte than all other received transactions. Moreover, the network overhead incurred by these orphan transactions can be significant when using the default orphan memory pool size (i.e., 100 transactions), although this overhead can be made negligible if the pool size is simply increased to 1,000 transactions. In summary, this dissertation demonstrates the importance of characterizing the inner behavior of the peer-to-peer network underlying a blockchain. While our results primarily focus on the Bitcoin network and its variants, this work provides foundations that should prove useful for studying and characterizing other blockchains.

As sequencing technology has taken off since the late 1990's, a unique phenomenon has been observed repeatedly: genes with little to no conservation across species. For a while, the predominant theory that arose to explain these genes was duplication and subsequent evolution of conserved genes. While this theory can explain some, still many genes have now been proven to arrive de novo - from previously non-coding DNA. This work further investigates the origins of these de novo evolved genes and their practical application relevance in crop biotechnology. This work demonstrates the dynamic nature of plant mitochondrial genomes between even closely related species, and the integral role of mitochondrial genomes in the origin of de novo orphan genes in plants. To better understand the functional potential of plant orphan genes, the network of the orphan gene Qua Quine Starch (QQS) is further elucidated. This analysis demonstrates the broad functionality of an orphan gene as a "fine-tuning knob" in many plant pathways. Further, QQS' role in protein and starch allocation and plant defense is tied to the Nuclear Factor Y subunit C4 (NF-YC4) transcription factor - this knowledge leads us to manipulate expression of native NF-YC4 transcription factors in important crop species to successfully increase seed protein, increase broad disease resistance, and expedite maturation in soybean. A key goal in biotechnology is creating non-transgenic plants with advantageous traits. To accomplish this, the CRISPR-CAS9 system was used to target and delete repressive cis-regulatory elements in the GmNF-YC4-1 promoter sequence. This has allowed us to modify the activity of GmNF-YC4-1 and thus increase soybean seed protein, making it possible to get a non-transgenic plant by segregating out the CRISPR-CAS9 T-DNA and keeping the regulatory deletion. Overall, this work uncovers a novel mechanism of orphan gene evolution and uses the study of the orphan gene QQS to develop important crop biotechnology.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第24558号 / 薬科博第175号 / 新制||薬科||19(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 土居 雅夫, 教授 竹島 浩, 教授 中山 和久 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM