Predicting adverse events during therapy for HIV and hepatitis C : the role of ITPase activity and ITPA genotype

The general aim of this thesis is to investigate the influence of the ITPA genetic SNPs 94C>A and 124+21A>C and the activity of the enzyme ITPase on the occurrence of adverse events during treatment for the infectious diseases HCV and HIV. While ITPA SNPs were previously found to be protective against hemolytic anemia during therapy with ribavirin for HCV, it is not clear to what extent other SNPs contribute to ITPase activity. Therefore, in Chapter 2, ITPase activity is compared with ITPA genotype for prediction of anemia during ribavirin use for HCV. In HIV-infected patients the ITPase activity in erythrocytes was found to be decreased compared to a population not infected with HIV. As leukocytes are the main target cells for HIV-infection, in Chapter 3 the expression of the ITPase protein in leukocytes and leukocyte subpopulations is explored in association with ITPA genotype. The results in HIV-infected patients are compared to a non-HIV infected population. As the current therapy for HIV is highly effective, the main obstacle for treatment nowadays is adverse events during cART. In Chapter 4, we investigate the association of ITPase activity and ITPA genotype with the occurrence of adverse events during combination antiretroviral therapy for HIV. One of the most important adverse drug events during tenofovir use is nephrotoxicity. In order to test if ITPase activity and ITPA genotype could be used as a biomarker to predict nephrotoxicity during tenofovir use for HIV,these parameters are determined and compared in HIV-infected patients with and without nephrotoxicity, in Chapter 5. Other important aspects brought on by the current effective HIV therapy, are long term consequences of cART and increasing diseases of older age, one of them being cardiovascular diseases. The association of ITPase activity and ITPA genotype with the occurrence of cardiovascular diseases and metabolic events during cART for HIV-infection is further explored in Chapter 6. To further unravel effects caused by HIV-infection itself and effects caused by cART, in Chapter 7, basic cell metabolomics of untreated HIV-infected patients are compared to a control population (the effect of HIV-infection). In addition metabolomics data prior to start of cART were compared to 12 months of therapy successfully suppressing HIV replication (the effect of cART). In Chapter 8 the results of these studies are discussed with respect to future perspectives

Improving the responsiveness of Kitwe City Council to the needs of the stakeholders

This report is centred on the responsiveness of the KCC to the needs of the stakeholders in the city. It arose from the 2nd SINPA workshop at which a strategy for building capacity within the KCC was developed. Responsiveness was identified at this workshop as a priority area where capacity building was required in the KCC. The report has highlighted the importance of responsiveness in urban governance and the critical role that participatory decision making plays in good urban governance. It has defined responsiveness as the extend to which the KCC operates in a demand oriented manner and also the extent to which KCC performs satisfactorily in the eyes of the stakeholders. Therefore, the core of the work is centered on investigating the extent to which the KCC programmes and activities are rooted in the needs and priorities of the stakeholders. The main stakeholders have been identified as: the residents of the city; the business community and the NGOs. The TORs of the report were: (1) To identify and assess the existing structures vis-a vis responsiveness and to what extent they work in identifying the needs and priorities of the stakeholders and whether these are used in development planning by the KCC and; (2) To formulate recommendations to improve the existing structures or recommend new ones where necessary and to suggest ways in which SINPA Zambia can contribute to follow-up

До питання про особливості методу правового регулювання відностин у сфері державних закупівель

В статті розглянуто особливості методу правового регулювання відносин у сфері державних закупівель, здійснено аналіз науково-теоретичної розробки цього питання, окреслено основні актуальні на сьогоднішній день проблемні моменти, які стримують розвиток та вдосконалення державних закупівель,, сформульовано основні напрямки розвитку подальших досліджень формування концепції методу правового регулювання відносин у галузі державних закупівель. Ключові слова: державні закупівлі, тендер, метод правового регулювання.В статье рассмотрены особенности метода правового регулирования отношений в сфере государственных закупок, осуществлено анализ научно-теоретической разработки этого вопроса, очерчено основные актуальные на сегодняшний день проблемные моменты, которые сдерживают развитие и усовершенствование государственных закупок, сформулировано основные направления развития дальнейших исследований формирования концепции метода правового регулирования отношений в отрасли государственных закупок. Ключевые слова: государственные закупки, тендер, метод правового регулирования.The article highlights the peculiarities of the legal regulation method of state purchases; analysis of theoretical examination of this issue. The author outlines a string of problems which restrain development and improvement of procurement; states direction of further research of the legal regulation method of state purchases conception. Key words: state procurement, tender, legal regulation method

Analisi quantitativa del desh: Silver Index, un nuovo parametro radiologico per la diagnosi di idrocefalo cronico dell'adulto

RIASSUNTO Background In base alla difficoltà diagnostica della malattia e ad una mancanza di esame in grado di fornire la certezza di questa, il nostro obbiettivo è stato quello di trovare un nuovo indicatore diagnostico per la malattia di idrocefalo cronico dell’adulto idiopatico, che fosse il piu’accurato possibile, non invasivo, agevole e senza la richiesta di ulteriori esami e costi per il paziente. A tale scopo ci siamo concentrati sul desh (Disproportionately Enlarged Subarachnoidspace Hydrocephalus) studiato in RNM, e abbiamo voluto verificare se le alterazioni degli spazi liquorali descritte in questo, fossero valutabili anche in immagine TC. Materiali e metodi Abbiamo messo a confronto due popolazioni, A e B. Ai pazienti della prima, in numero di 29, giunti al nostro ambulatorio nel periodo compreso tra Marzo 2013 a Settembre 2014, è stato attribuito diagnosi di iNPH probabile in seguito a valutazione clinica con con assegnazione di score nell’ ambito della sfera cognitiva (tramite MMSE “mini mental state examination”), della deambulazione (tramite 3 meters timed up and go test) e della minzione (Incontinence Questionnaire-Short Form - ICIQ-SF), ad effettuazione di tap test, drenaggio liquorale continuo e TC, secondo le linee guida attuali (Japanese society guidelines). Abbiamo escluso pazienti con forme di idrocefalo cronico dell’adulto secondarie. Questi pazienti sono stati sottoposti poi ad intervento di derivazione ventricolo-peritoneale (con applicazione di valvola Codman Medos) a cui hanno risposto con parziale regressione clinica come auspicato. Nell’ indagine diagnostica TC, oltre ai classici parametri valutati, quali ventricolomegalia ed indice di Evans, abbiamo studiato su un’ immagine TC, in sezione coronale ottenuta tramite un sistema di ricostruzione multiplanare (Multi-Planar-Reconstruction – MPR), lo spazio liquorale della scissura silviana e quello compreso tra il punto piu craniale della circonvoluzione frontale superiore e la falce cerebrale e calcolato il valore delle rispettive aree e del loro rapporto a cui abbiamo sttribuito il nome di Silver Inex. Il tracciamento e calcolo delle aree e del silver index è sato permesso grazie ad un software di nome Synedra. Abbiamo calcolato poi il Silver Index in tutti i pazienti del gruppo A e costruito una curva statistica ROC con AUC per individuare il valore cut-off che corrispondesse a maggiore sensibilità e specificità. Valore soglia oltre al quale in base al nostro obbiettivo il paziente avesse la malattia, sotto al quale invece no. Abbiamo cosi messo a confronto la mediana del silver index con quella calcolata in una popolazione di riferimento (Gruppo B), di 26 pazienti, a cui è stata fata una TC per traumi minori e che non avevano iNPH, per valutare tramite un grafico box-blot se vi fosse una correlazione statisticamente significativa tra Silver Index e la malattia. Risultati Il valore cut-off trovato per il silver index è di 0.37550 per una sensibilità di di 0.828 ed una specificità di 0.962 Abbiamo costruito un grafico drop-box vedendo che la differenza del valore di Silver Index tra i Gruppo A e quello B era statisticamente significativa permettendo di concludere che esiste una correlazione tra Silver Index e la malattia (p-value > 0001). Silver Index risulta un buon indicatore, con sensibilità e specificità molto elevata. Inoltre, in un ulteriore studio, sempre su cotruzione drop-box, abbiamo preso due sottogruppi della popolazione A; il primo con almeno una sintomatologia della triade di Hakim & Admas, il secondo con tutti e tre i sintomi presenti. Abbiamo voluto cosi verificare se esistesse una correlazione statisticamente significativa tra il silver index e la gravità di malattia confrontando il valore tra i due sottogruppi. Il risultato ha dimostrato che non esiste rorrelazione statisticamente significativa tra il silver index e la gravità di malattia (p-value < 0,727). Conclusione e Prospettive per il futuro Dai risultati ottenuti con il nostro studio, possiamo definire il silver index come un nuovo parametro radiologico per la diagnosi di idrocefalo cronico dell’ adulto ed ipotizzare che in futuro potrebbe entrare far parte degli esami diagnostici di primo livello per questa patologia. Infatti l’indice presenta sensibilità e specificità molto elevate. Rappresenta una metodologia di studio del DESH molto agevole in pazienti con sospetto idrocefalo cronico dell’adulto idiopatico. Diventerebbe di grande ausilio non solo per il neurochirurgo, ma anche per il neurologo a cui il paziente di solito si rivolge per la clinica che si presenta. Permetterebbe cosi di porre una diagnosi piu’ accurata, precoce e senza costi ed esami aggiuntivi. Ricordiamo che diagnosi tempestiva significa anche eventuale intervento di derivazione ventricolo - peritoneale piu’ precoce, quindi migliore outcome postchirurgico e qualità di vita del paziente. I limiti di questo studio consistono nella sua natura retrospettiva e nell’uso di un software privo ancora di approvazione FDA-CE per utilizzo sanitario. L’ eventuale approvazione futura per un suo utilizzo clinico richiede ancora uno studio multicentrico di natura prospettiva. Molto interessante e gia in fase di elaborazione nel nostro gruppo, risulta anche il quesito e la ricerca di una eventuale correlazione statisticamente significativa tra valore di silver index e miglior outcome postichirurgico

Tydi-lang: A Language for Typed Streaming Hardware

Transferring composite data structures with variable-length fields often requires designing non-trivial protocols that are not compatible between hardware designs. When each project designs its own data format and protocols the ability to collaborate between hardware developers is diminished, which is an issue especially in the open-source community. Because the high-level meaning of a protocol is often lost in translation to low-level languages when a custom protocol needs to be designed, extra documentation is required, the interpretation of which introduces new opportunities for errors. The Tydi specification (Tydi-spec) was proposed to address the above issues by codifying the composite and variable-length data structures in a type and providing a standard protocol to transfer typed data among hardware components. The Tydi intermediate representation (Tydi-IR) extends the Tydi-spec by defining typed interfaces, typed components, and connections among typed components. In this paper, we propose Tydi-lang, a high-level hardware description language (HDL) for streaming designs. The language incorporates Tydi-spec to describe typed streams and provides templates to describe abstract reusable components. We also implement an open-source compiler from Tydi-lang to Tydi-IR. We leverage a Tydi-IR to VHDL compiler, and also present a simulator blueprint to identify streaming bottlenecks. We show several Tydi-lang examples to translate high-level SQL to VHDL to demonstrate that Tydi-lang can efficiently raise the level of abstraction and reduce design effort.Comment: 8 pages and 1 page of reference, 4 figures, 4 table

An Intermediate Representation for Composable Typed Streaming Dataflow Designs

Tydi is an open specification for streaming dataflow designs in digital circuits, allowing designers to express how composite and variable-length data structures are transferred over streams using clear, data-centric types. These data types are extensively used in a many application domains, such as big data and SQL applications. This way, Tydi provides a higher-level method for defining interfaces between components as opposed to existing bit and byte-based interface specifications. In this paper, we introduce an open-source intermediate representation (IR) which allows for the declaration of Tydi's types. The IR enables creating and connecting components with Tydi Streams as interfaces, called Streamlets. It also lets backends for synthesis and simulation retain high-level information, such as documentation. Types and Streamlets can be easily reused between multiple projects, and Tydi's streams and type hierarchy can be used to define interface contracts, which aid collaboration when designing a larger system. The IR codifies the rules and properties established in the Tydi specification and serves to complement computation-oriented hardware design tools with a data-centric view on interfaces. To support different backends and targets, the IR is focused on expressing interfaces, and complements behavior described by hardware description languages and other IRs. Additionally, a testing syntax for the verification of inputs and outputs against abstract streams of data, and for substituting interdependent components, is presented which allows for the specification of behavior. To demonstrate this IR, we have created a grammar, parser, and query system, and paired these with a backend targeting VHDL.Comment: arXiv admin note: substantial text overlap with arXiv:2212.1200