Agents anti-infectieux et fonction réna!e: vers des posologies sur mesure [Antimicrobial agents and renal elimination: towards individual dosage adjustment?].

The efficacy and safety of anti-infective treatments are associated with the drug blood concentration profile, which is directly correlated with a dosing adjustment to the individual patient's condition. Dosing adjustments to the renal function recommended in reference books are often imprecise and infrequently applied in clinical practice. The recent generalisation of the KDOQI (Kidney Disease Outcome Quality Initiative) staging of chronically impaired renal function represents an opportunity to review and refine the dosing recommendations in patients with renal insufficiency. The literature has been reviewed and compared to a predictive model of the fraction of drug cleared by the kidney based on the Dettli's principle. Revised drug dosing recommendations integrating these predictive parameters are proposed.

Date adjustment tools : Date rollover and Individual date adjustment

Learning Management Systems (LMSs) have become a larger part of teaching and learning in the modern world. Therefore has Moodle, a free and open source e-learning tool surfaced and gained a lot of attraction and downloads. A purpose of this study has been to develop a new local plugin in Moodle with guidelines from Magnus Eriksson and Tsedey Terefe. A purpose for this project has also been to build a plugin which has the functions Date rollover and Individual date adjustment. Mid Sweden University (Miun) stated that WebCT/Blackboard was in use before Moodle and some other LMSs and the dissatisfaction with WebCT/Blackboard was rife, however some teachers liked it. Therefore WebCT/Blackboard was abandoned and Moodle was embraced. The methods of gaining information has generally been web based sources and three interviews, likewise called user tests. Programs and other aids that have been used include but are not limited to: Google Drive, LTI Provider, Moodle, Moodle documentation, Notepad++, PHP and XAMPP. The plugin has been implemented as a local plugin. The result has shown that the coded plugin, Date adjustment tools could be improved and that it was changed. In the plugin, support for old American English dates were added and the code for using the two functions “Date rollover” and “Individual date adjustment” were rewritten to not interfere with one another. A conclusion to draw from the result is that the plugin has been improved from Terefe’s implementation, although more work can be made with the plugin Date adjustment tools.

Pienyrittäjän velkajärjestely

Laki yksityishenkilön velkajärjestelystä (VJL, 57/1993) muuttui 1.1.2015. Yksityiset elinkeinon- ja ammatinharjoittajat saivat aiemmin velkajärjestelyn yksityistalouden veloille, mutta uutta on se, että myös elinkeinotoiminnan velkoja voidaan järjestellä samassa yhteydessä. Yksityishenkilön velkajärjestelyä ei voi hakea pelkästään yrityksen velkoihin. Jotta elinkeinon- ja ammatinharjoittaja voisi saada velkajärjestelyn, yritystoiminnan pitää olla pienimuotoista ja perustua yrittäjän omaan työpanokseen. Laki ei koske yhtiömuotoisia yrityksiä, joten ne rajataan tämän tutkimuksen ulkopuolelle. Tässä tutkimuksessa selvitetään, miten velkajärjestelylaki kohtelee pienyrittäjää. Velkajärjestelylakiin tuli 30 muutosta, mutta keskityn tutkimuksessani pienyrittäjän kannalta merkityksellisiin seikkoihin. Toisena tutkimustehtävänä on selvittää pienyrittäjän epäonnistumisen syitä ja seurauksia. Työn tutkimuksellinen lähestymistapa on kvalitatiivinen eli laadullinen ja aineistonkeräystapana käytettiin puolistrukturoituja haastatteluja. Tutkimusaineistoa kerättiin haastattelemalla epäonnistumisen kokeneita yrittäjiä tammi-maaliskuussa 2015. Teoriaosuudessa perehdytään alan kirjallisuuteen, tuomioistuimen oikeustapaukseen ja hallituksen esityksiin. Johtopäätöksenä voidaan todeta, että velkajärjestelylain muutos mahdollistaa ammatin- ja elinkeinonharjoittajien pääsyn velkajärjestelyyn ja velkajärjestelyssä voidaan tietyin edellytyksin järjestellä elinkeinotoiminnasta syntyneet velat. Menettely on kevyempi ja edullisempi kuin yrityssaneeraus. Lakimuutos on historiallinen insolvenssioikeuden alalla ja se asettaa elinkeinon- ja ammatinharjoittajat tasavertaiseen asemaan muiden velallisten kanssa ottaen huomioon elinkeinotoiminnan velkojen järjestelylle asettamat erityispiirteet. Velkajärjestelyn edellytykset ovat pienyrittäjälle hyvin tiukat, eli olettavasti moni velallinen ei hakeudu velkajärjestelyyn. Käytäntö osoittaa, onko säännöstö niin tiukka, etteivät yksityiset elinkeinon- ja ammatinharjoittajat hae velkajärjestelyä, vaan lopettavat mieluummin liiketoimintansa.

Talouden hallinta ja talousneuvonta ylivelkaantumisen estämisessä

Tutkielman tavoitteena oli saada näkemys kunnallisten talous- ja velkaneuvontatoimistojen antaman talousneuvonnan toimivuudesta ylivelkaantumisen estämisessä sekä mahdollisista kehitystarpeista. Tutkielmassa käsitellään talousneuvonnan perustana oleva lainsäädäntö, tasapainoisen talouden perusteita sekä velkaantumisen syitä. Varsinainen tutkimus tehtiin internetin kautta toteutetulla kunnallisille talous- ja velkaneuvojille suunnatulla kyselyllä. Kyselyllä selvitettiin muun muassa, kuinka paljon talousneuvontaa annetaan, minkälaista tuo annettu neuvonta on ja annetaanko neuvontaa yrittäjille. Lisäksi haluttiin saada selville talous- ja velkaneuvojien käyttämä talousneuvontaprosessi. Tutkimustuloksista ilmenee, että vaikka talous- ja velkaneuvonnasta annettu laki painottaa talousneuvontaa, talous- ja velkaneuvojien tyypilliset työtehtävät liittyvät yksityishenkilön velkajärjestelyyn. Varsinaista talousneuvontaa annetaan kohtuullisen vähän. Suurin osa talous- ja velkaneuvojista oli sitä mieltä, että talousneuvonnalla voidaan kokonaan tai osittain estää ylivelkaantuminen. Yli puolet talous- ja velkaneuvojista ei antaisi talousneuvontaa yrittäjille, mutta pääsyy kieltäytymiselle oli kuitenkin resurssipula. Talousneuvonnan antamisen tueksi tulisi saada koulutusta, materiaalia sekä konkreettisia välineitä, kuten atk-ohjelmia. Velkaantuminen on pysyvä osa markkinataloutta ja yhteiskunnan tulee kantaa siitä vastuu. Tärkeintä olisi kuitenkin saada ihmiset motivoitumaan oman taloudellisen tilanteen hoitamiseen.

First-Line Chemotherapy with Anthracycline and Taxane Combination in Metastatic Breast Cancer. Detection of bone metastases with TRACP 5b

Background: In Finland, breast cancer (BC) is the most common cancer among women, and prostate cancer (PC) that among men. At the metastatic stage both cancers remain essentially incurable. The goals of therapy include palliation of symptoms, improvement or maintenance of quality of life (QoL), delay of disease progression, and prolongation of survival. Balancing between efficacy and toxicity is the major challenge. With increasing costs of new treatments, appropriate use of resources is paramount. When new treatment regimes are introduced into clinical practice a comprehensive assessment of clinical benefit, adverse effects and cost is necessary. Both BC and PC show a predilection to metastasize to bone. Bone metastases cause significant morbidity impairing the patients´ QoL. Diagnosis of bone metastases relies mainly on radiological methods, which however lack optimal sensitivity and specificity. New tools are needed for detection and follow-up of bone metastases. Aims: Anthracyclines and taxanes are effective chemotherapeutic agents in the treatment of metastatic breast cancer (MBC) with different mechanisms of action. Therefore, evaluation of the combination of anthracyclines with taxanes was a justifiable approach in the treatment of MBC patients. We assessed the efficacy, toxicity, cost of treatment and QoL of BC patients treated with first-line chemotherapy for metastatic disease with the combination epirubicin and docetaxel. We also evaluated the diagnostic potential of tartrate-resistant acid phosphatase 5b (TRACP 5b) and carboxyterminal telopeptides of type I collagen (ICTP) in the diagnosis of bone metastases in BC and TRACP 5b in PC patients. Results: The combination of epirubicin and docetaxel was effective in this phase II study, but required individual dose adjustment to avoid neutropenic infections, and the use of growth factors to maintain a feasible dose level. The response rate was 54 % (95 % CI 37-71) and the median overall survival (OS) was 26 months. Of the patients, 87 % were treated for infections. The treatment of adverse events required additional use of health resources mainly due to neutropenic infections, thereby raising direct treatment costs by 20 %. Despite adverse events, the global QoL was not significantly compromised during the treatment. Clinically evident acute cardiac toxicity was not observed. The combination of serum TRACP 5b and ICTP was at least equally sensitive and specific in detection of of bone metastases as commonly used total alkaline phosphatise (tALP) in BC patients. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC patients. Conclusions: Treatment with epirubicin and docetaxel showed high efficacy in first-line chemotherapy of MBC. The relatively high incidence of neutropenic infections requiring hospitalization increased the treatment costs. Despite adverse events, the global QoL of the patients was not significantly compromised. The combination of TRACP 5b and ICTP showed similar activity as tALP in detecting bone metastases in MBC. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC.

Automatisierte Flüssigchromatographie mit Säulenschaltung und Ultraviolettspektroskopie oder Massenspektrometrie für therapeutisches Drug Monitoring von Antipsychotika und Antidepressiva

Therapeutisches Drug Monitoring (TDM) wird zur individuellen Dosiseinstellung genutzt, um die Effizienz der Medikamentenwirkung zu steigern und das Auftreten von Nebenwirkungen zu senken. Für das TDM von Antipsychotika und Antidepressiva besteht allerdings das Problem, dass es mehr als 50 Medikamente gibt. Ein TDM-Labor muss dementsprechend über 50 verschiedene Wirkstoffe und zusätzlich aktive Metaboliten messen. Mit der Flüssigchromatographie (LC oder HPLC) ist die Analyse vieler unterschiedlicher Medikamente möglich. LC mit Säulenschaltung erlaubt eine Automatisierung. Dabei wird Blutserum oder -plasma mit oder ohne vorherige Proteinfällung auf eine Vorsäule aufgetragen. Nach Auswaschen von störenden Matrixbestandteilen werden die Medikamente auf einer nachgeschalteten analytischen Säule getrennt und über Ultraviolettspektroskopie (UV) oder Massenspektrometrie (MS) detektiert. Ziel dieser Arbeit war es, LC-Methoden zu entwickeln, die die Messung möglichst vieler Antipsychotika und Antidepressiva erlaubt und die für die TDM-Routine geeignet ist. Eine mit C8-modifiziertem Kieselgel gefüllte Säule (20 µm 10x4.0 mm I.D.) erwies sich in Vorexperimenten als optimal geeignet bezüglich Extraktionsverhalten, Regenerierbarkeit und Stabilität. Mit einer ersten HPLC-UV-Methode mit Säulenschaltung konnten 20 verschiedene Psychopharmaka einschließlich ihrer Metabolite, also insgesamt 30 verschiedene Substanzen quantitativ erfasst werden. Die Analysenzeit betrug 30 Minuten. Die Vorsäule erlaubte 150 Injektionen, die analytische Säule konnte mit mehr als 300 Plasmainjektionen belastet werden. Abhängig vom Analyten, musste allerdings das Injektionsvolumen, die Flussrate oder die Detektionswellenlänge verändert werden. Die Methode war daher für eine Routineanwendung nur eingeschränkt geeignet. Mit einer zweiten HPLC-UV-Methode konnten 43 verschiedene Antipsychotika und Antidepressiva inklusive Metaboliten nachgewiesen werden. Nach Vorreinigung über C8-Material (10 µm, 10x4 mm I.D.) erfolgte die Trennung auf Hypersil ODS (5 µm Partikelgröße) in der analytischen Säule (250x4.6 mm I.D.) mit 37.5% Acetonitril im analytischen Eluenten. Die optimale Flussrate war 1.5 ml/min und die Detektionswellenlänge 254 nm. In einer Einzelprobe, konnten mit dieser Methode 7 bis 8 unterschiedliche Substanzen gemessen werden. Für die Antipsychotika Clozapin, Olanzapin, Perazin, Quetiapin und Ziprasidon wurde die Methode validiert. Der Variationskoeffizient (VK%) für die Impräzision lag zwischen 0.2 und 6.1%. Im erforderlichen Messbereich war die Methode linear (Korrelationskoeffizienten, R2 zwischen 0.9765 und 0.9816). Die absolute und analytische Wiederfindung lagen zwischen 98 und 118 %. Die für das TDM erforderlichen unteren Nachweisgrenzen wurden erreicht. Für Olanzapin betrug sie 5 ng/ml. Die Methode wurde an Patienten für das TDM getestet. Sie erwies sich für das TDM als sehr gut geeignet. Nach retrospektiver Auswertung von Patientendaten konnte erstmalig ein möglicher therapeutischer Bereich für Quetiapin (40-170 ng/ml) und Ziprasidon (40-130 ng/ml) formuliert werden. Mit einem Massenspektrometer als Detektor war die Messung von acht Neuroleptika und ihren Metaboliten möglich. 12 Substanzen konnten in einem Lauf bestimmt werden: Amisulprid, Clozapin, N-Desmethylclozapin, Clozapin-N-oxid, Haloperidol, Risperidon, 9-Hydroxyrisperidon, Olanzapin, Perazin, N-Desmethylperazin, Quetiapin und Ziprasidon. Nach Vorreinigung mit C8-Material (20 µm 10x4.0 mm I.D.) erfolgte die Trennung auf Synergi MAX-RP C12 (4 µm 150 x 4.6 mm). Die Validierung der HPLC-MS-Methode belegten einen linearen Zusammenhang zwischen Konzentration und Detektorsignal (R2= 0,9974 bis 0.9999). Die Impräzision lag zwischen 0.84 bis 9.78%. Die für das TDM erforderlichen unteren Nachweisgrenzen wurden erreicht. Es gab keine Hinweise auf das Auftreten von Ion Suppression durch Matrixbestandteile. Die absolute und analytische Wiederfindung lag zwischen 89 und 107 %. Es zeigte sich, dass die HPLC-MS-Methode ohne Modifikation erweitert werden kann und anscheinend mehr als 30 verschiedene Psychopharmaka erfasst werden können. Mit den entwickelten flüssigchromatographischen Methoden stehen neue Verfahren für das TDM von Antipsychotika und Antidepressiva zur Verfügung, die es erlauben, mit einer Methode verschiedene Psychopharmaka und ihre aktiven Metabolite zu messen. Damit kann die Behandlung psychiatrischer Patienten insbesondere mit Antipsychotika verbessert werden.

Pharmacogenetics in palliative care

Response to analgesics, anticancer pharmacotherapy and pharmacotherapy of other cancer related symptoms vary broadly between individuals. Age, disease, comorbidities, concomitant medication, organ function and patients' compliance may partly explain the differences. However, the focus of ongoing research has shifted towards genomic variants of phase I and II drug metabolizing enzymes with one important goal being an individual dose adjustment according to a patient's genotype. Polymorphisms of the cytochrome P 450 2D6 influence the metabolism of many drugs including the analgesics codeine, tramadol, hydrocodone and oxycodone, as well as the metabolism of tricyclic antidepressants and the anticancer drug tamoxifen. Other candidate genes such as (opioid)-receptors, transporters and other molecules important for pharmacotherapy in pain management are discussed. Although pharmacogenetics as a diagnostic tool has the potential to improve patient therapy, study results are often equivocal and limited by small sample sizes and often by their retrospective design. Well designed studies are needed to demonstrate superiority of pharmoacogenetics to conventional dosing regimes.

The treatment of spasticity with Delta9-tetrahydrocannabinol in persons with spinal cord injury

STUDY DESIGN: Open label study to determine drug dose for a randomized double-blind placebo-controlled parallel study. OBJECTIVES: To assess the efficacy and side effects of oral Delta(9)-tetrahydrocannabinol (THC) and rectal THC-hemisuccinate (THC-HS) in SCI patients. SETTING: REHAB Basel, Switzerland. METHOD: Twenty-five patients with SCI were included in this three-phase study with individual dose adjustment, each consisting of 6 weeks. Twenty-two participants received oral THC open label starting with a single dose of 10 mg (Phase 1, completed by 15 patients). Eight subjects received rectal THC-HS (Phase 2, completed by seven patients). In Phase 3, six patients were treated with oral THC and seven with placebo. Major outcome parameters were the spasticity sum score (SSS) using the Modified Ashworth Scale (MAS) and self-ratings of spasticity. RESULTS: Mean daily doses were 31 mg with THC and 43 mg with THC-HS. Mean SSS for THC decreased significantly from 16.72 (+/-7.60) at baseline to 8.92 (+/-7.14) on day 43. Similar improvement was seen with THC-HS. We observed a significant improvement of SSS with active drug (P=0.001) in the seven subjects who received oral THC in Phase 1 and placebo in Phase 3. Major reasons for drop out were increase of pain and psychological side effects. CONCLUSION: THC is an effective and safe drug in the treatment of spasticity. At least 15-20 mg per day were needed to achieve a therapeutic effect.

"An on-going individual adjustment" : a qualitative study of midwives' experiences counselling pregnant women on physical activity in Sweden

Background: In Sweden, midwives play prominent supportive role in antenatal care by counselling and promoting healthy lifestyles. This study aimed to explore how Swedish midwives experience the counselling of pregnant women on physical activity, specifically focusing on facilitators and barriers during pregnancy. Also, addressing whether the midwives perceive that their own lifestyle and body shape may influence the content of the counselling they provide. Methods: Eight focus group discussions (FGD) were conducted with 41 midwives working in antenatal care clinics in different parts of Sweden between September 2013 and January 2014. Purposive sampling was applied to ensure a variation in age, work experience, and geographical location. The FGD were digitally recorded, transcribed verbatim, and analyzed using manifest and latent content analysis. Results: The main theme- "An on-going individual adjustment" was built on three categories: "Counselling as a challenge"; "Counselling as walking the thin ice" and "Counselling as an opportunity" reflecting the midwives on-going need to adjust their counselling depending on each woman's specific situation. Furthermore, counselling pregnant women on physical activity was experienced as complex and ambiguous, presenting challenges as well as opportunities. When midwives challenged barriers to physical activity, they risked being rejected by the pregnant women. Despite risking rejection, the midwives tried to promote increased physical activity based on their assessment of individual needs of the pregnant woman. Some participants felt that their own lifestyle and body shape might negatively influence the counselling; however, the majority of participants did not agree with this perspective. Conclusions: Counselling on physical activity during pregnancy may be a challenging task for midwives, characterized by on-going adjustments based on a pregnant woman's individual needs. Midwives strive to find individual solutions to encourage physical activity. However, to improve their counselling, midwives may benefit from further training, also organizational and financial barriers need to be addressed. Such efforts might result in improved opportunities to further support pregnant women's motivation for performance of physical activity.

Ajuste del balance de pagos, política crediticia y control del endeudamiento externo = Balance-of-payments adjustment, credit policy and control of the external debt

Incluye Bibliografía

Internal debt and financial adjustment in Peru

Includes bibliography

Políticas de ajuste y renegociación de la deuda externa = Adjustment policies and renegotiation of the external debt

Incluye Bibliografía