Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND) : a randomised, controlled, open-label, phase 3b/4 trial

Background Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin. Methods In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1: 1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1-5, then once daily on alternate days on days 7-25) or vancomycin (125 mg oral capsules, four times daily on days 1-10), stratified by baseline C difficile infection severity, cancer presence, age (>= 75 years vs Findings Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1.0-20.7], p=0.030; odds ratio 1.62 [95% CI 1.04-2.54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug. Interpretation Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection.Peer reviewe

Credit and information in universal banking : a clinical study

We studied information and interaction processes in six lending relationships between a universal bank and medium sized firms. The study is based on the credit files of the respective firms. If no problems occur in these lending relationships, bank monitoring is based mainly on cheap, retrospective and internal data. In case of distress, more expensive, prospective and external information is used. The level of monitoring and the willingness to renegotiate the lending relationship depends on what the lending officers can learn about the future prospects of the firm from the behaviour of the debtors. We identify both signalling and bonding activities. Such learning from past behaviour seems to allow monitoring at low cost, whereas the direct observation of the firm's investment outlook seems to be very costly. Also, too much knowledge about the firm's investments might leave the bank in a very strong bargaining position and distort investment incentives. Therefore, the traditional view of credit assessment as observation of the quality of a borrower's investment programme needs to be reconsidered

Bacillary angiomatosis in HIV-infected patients - An epidemiological and clinical study

Background: No data were available on the epidemiological and clinical characteristics of bacillary angiomatosis (BA) in Germany. Objective:To determine epidemiological and clinical data on HIV-associated BA. Methods: A chart review of all BA cases between 1990 and 1998 was performed in 23 German AIDS treatment units. Results: A total of 21 cases of BA was diagnosed. During th is period, the participating HIV centers treated about 17,000 HIV-infected patients. As a result, a BA prevalence of 1.2 cases/1,000 patients can be assumed. 19 BA were localized in the skin; in 5 cases bones and in 4 cases the liver were involved. Out of 20 patients who received antibiotic therapy, 13 had complete remission. The median time of duration up to complete remission was 32 days (9-82), During the follow-up of the 20 patients, 7 relapses were observed, Conclusion: BA is a rare HIV-associated disease with a prevalence of 1,2 cases/1,000 patients in the presented study. Copyright (C) 2000 S. Karger AG, Basel

Butorphanol for Post-Operative Analgesia - A Comparative Clinical Study with Ketorolac

Introduction: Butorphanol, an opioid derivative has been shown to have, in addition to its analgesic properties, several other advantageous effects like antistressor, sedative and anti-shivering action. The efficacy and safety profile of ketorolac, yet another widely used post-operative analgesic is well documented. This study aims to compare the two analgesics. Aims and objectives: This study was conducted to compare the analgesic efficacy and other effects of butorphanol and ketorolac, administered intramuscularly, in post-operative patients who have undergone lower abdominal and pelvic surgeries. Materials and methods: 50 patients undergoing lower abdominal and pelvic surgeries under general or spinal anaesthesia were randomly divided into two Groups (25 each). At a particular level of post-operative pain, the patients Groups I and II were administered intramuscular ketorolac 30mg and butorphanol 2mg respectively. The analgesic effect was studied using Visual Analogue Scale (VAS) and the verbal category scale. Patients were monitored for the sedative action, respiratory status and other vital parameters for 300 minutes and for other adverse reactions over the next twelve hours. Observations: Butorphanol provided better analgesia within the first two hours of administration, while ketorolac was more effective at 4-5 hours. Better sedative action without any significant respiratory depressant effect was demonstrated with butorphanol. There were no clinically significant hemodynamic fluctuations or adverse reactions with butorphanol or ketorolac. Conclusions: Butorphanol provides better early analgesia as compared to ketorolac with a desirable and safe sedative effect in post-operative patients who have undergone lower abdominal and pelvic surgeries

Modeling long-term longitudinal HIV dynamics with application to an AIDS clinical study

A virologic marker, the number of HIV RNA copies or viral load, is currently used to evaluate antiretroviral (ARV) therapies in AIDS clinical trials. This marker can be used to assess the ARV potency of therapies, but is easily affected by drug exposures, drug resistance and other factors during the long-term treatment evaluation process. HIV dynamic studies have significantly contributed to the understanding of HIV pathogenesis and ARV treatment strategies. However, the models of these studies are used to quantify short-term HIV dynamics ($<$ 1 month), and are not applicable to describe long-term virological response to ARV treatment due to the difficulty of establishing a relationship of antiviral response with multiple treatment factors such as drug exposure and drug susceptibility during long-term treatment. Long-term therapy with ARV agents in HIV-infected patients often results in failure to suppress the viral load. Pharmacokinetics (PK), drug resistance and imperfect adherence to prescribed antiviral drugs are important factors explaining the resurgence of virus. To better understand the factors responsible for the virological failure, this paper develops the mechanism-based nonlinear differential equation models for characterizing long-term viral dynamics with ARV therapy. The models directly incorporate drug concentration, adherence and drug susceptibility into a function of treatment efficacy and, hence, fully integrate virologic, PK, drug adherence and resistance from an AIDS clinical trial into the analysis. A Bayesian nonlinear mixed-effects modeling approach in conjunction with the rescaled version of dynamic differential equations is investigated to estimate dynamic parameters and make inference. In addition, the correlations of baseline factors with estimated dynamic parameters are explored and some biologically meaningful correlation results are presented. Further, the estimated dynamic parameters in patients with virologic success were compared to those in patients with virologic failure and significantly important findings were summarized. These results suggest that viral dynamic parameters may play an important role in understanding HIV pathogenesis, designing new treatment strategies for long-term care of AIDS patients.Comment: Published in at http://dx.doi.org/10.1214/08-AOAS192 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

REGULATORY APPROVAL OF NEW MEDICAL DEVICES: A CROSS SECTIONAL STUDY

Objective To investigate the regulatory approval of new medical devices. Design Cross sectional study of new medical devices reported in the biomedical literature. Data sources PubMed was searched between 1 January 2000 and 31 December 2004 to identify clinical studies of new medical devices. The search was carried out during this period to allow time for regulatory approval. Eligibility criteria for study selection Articles were included if they reported a clinical study of a new medical device and there was no evidence of a previous clinical study in the literature. We defined a medical device according to the US Food and Drug Administration as an “instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article.” Main outcome measures Type of device, target specialty, and involvement of academia or of industry for each clinical study. The FDA medical databases were then searched for clearance or approval relevant to the device. Results 5574 titles and abstracts were screened, 493 full text articles assessed for eligibility, and 218 clinical studies of new medical devices included. In all, 99/218 (45%) of the devices described in clinical studies ultimately received regulatory clearance or approval. These included 510(k) clearance for devices determined to be “substantially equivalent” to another legally marketed device (78/99; 79%), premarket approval for high risk devices (17/99; 17%), and others (4/99; 4%). Of these, 43 devices (43/99; 43%) were actually cleared or approved before a clinical study was published. Conclusions We identified a multitude of new medical devices in clinical studies, almost half of which received regulatory clearance or approval. The 510(k) pathway was most commonly used, and clearance often preceded the first published clinical study

a clinical study

Deckblatt-Impressum persönlicher Dank Inhaltsverzeichnis Verzeichnis der verwendeten Abkürzungen Einleitung Literaturübersicht Material und Methoden Ergebnisse Diskussion Zusammenfassung Summary Literaturverzeichnis Anhang Danksagung SelbständigkeitserklärungDie Anämie aufgrund entzündlicher Erkrankungen (AID) ist die häufigste Anämieform bei Mensch und Tier, wurde aber bei der Katze nur in wenigen, hauptsächlich experimentellen Studien untersucht. Die Pathogenese der AID ist multifaktoriell und resultiert aus einer verminderten Eisenverfügbarkeit, einer verkürzten erythrozytären Überlebenszeit und einer reduzierten Regenerationsantwort auf die Anämie. Ziel dieser klinischen Studie war es, den Verlauf der AID, für Diagnostik und Pathogenese der AID relevante Laborparameter sowie die Therapie bei 26 Katzen mit entzündlichen Erkrankungen (Abszess [A] n=13, Pyothorax [Pt] n=7, Pyometra [Pyo] n=1, Mykobakterien- Infektion n=1, Fettgewebsnekrose [FN] n=4) zu beschreiben. Ausgeschlossen wurden Katzen mit einem positiven FeLV/FIV-Test, mit einer Neoplasie, Nephro- oder Hepatopathie sowie Tiere mit einer Blutungsanämie. Untersucht wurden hämatologische und blutchemische Parameter, die Serum-Konzentrationen von Erythropoetin (EPO), Eisen und Ferritin, die Eisenbindungskapazität (TIBC), die Akute-Phase-Proteine 1-AGP und Haptoglobin (Hp) sowie die mittlere osmotische Fragilität (MOF) der Erythrozyten, und es wurde ein direkter Coombs-Test durchgeführt. Der Hkt-Verlauf wurde über 3-51 Tage (MW: 15,5; M: 11) beobachtet. Elf der 26 Katzen waren bei Vorstellung anämisch, während 12 Katzen während des stationären Aufenthaltes eine Anämie entwickelten. Drei Katzen wurden nicht anämisch, wobei der Hkt bei 2 Katzen (Pt, FN) innerhalb des Referenzbereiches absank und bei einer Katze (A) anstieg. Die Anämie war überwiegend gering- bis mittelgradig (bei 47,9% bzw. 39,1% der Katzen), vereinzelt (13%) aber auch hochgradig. Der Hkt nahm - je nach Messzeitpunkt - ab dem 2.-7. Tag ab und sank über einen Zeitraum von 3-16 Tagen weiter ab. Eine Normalisierung des Hkt wurde bei 6 Katzen 2-18 Tage post OP (A), 18 Tage nach Therapiebeginn (Pt) bzw. 10-19 Tage post OP (FN) festgestellt. Demgegenüber blieben 17 Katzen über einen Zeitraum von bis zu 29 Tagen (A), bis zu 16 Tagen (Pt), bis zu 40 Tagen (Pyo) bzw. 51 Tagen (Mykobakterien- Infektion) und 15 Tagen (FN) anämisch. Die Anämie war bei 95,6% der Patienten überwiegend normozytär, während bei einer Katze (4,4%) eine dauerhaft mikrozytäre Anämie vorlag. Bei 3 Katzen (13%) trat zeitweilig eine geringgradige Makrozytose auf. Bei allen Patienten war die Anämie überwiegend normochrom und nur in Einzelmessungen hypo- oder hyperchrom (26,1% bzw. 21,7%). Eine nicht-regenerative Anämie bestand in 73,9% der Fälle, während bei 6 Katzen (26,1%) eine geringgradige Regeneration (43.200-84.450 aggregierte Retikulozyten/µl) festgestellt wurde. Eine Leukozytose (18,9-150,0109/l) wurde bei 22 von 26 und eine Kernlinksverschiebung bei 12 von 19 Patienten nachgewiesen, wobei auch Katzen ohne Leukozytose eine AID entwickelten. Das Akute-Phase-Protein 1-AGP war bei allen 19 untersuchten Patienten in einem Zeitraum von 7 Tagen prä bis 14 Tage post OP erhöht, während Hp bei 16 der 19 Katzen erhöht und bei 3 Tieren 5, 7 und 14 Tage nach Therapiebeginn normal war. Weder der Hkt-Wert noch die Anzahl aggr. Retikulozyten korrelierten invers mit der Leukozytenzahl, der 1-AGP- oder Hp-Konzentration. Auffällig waren ein vermindertes Albumin/Globulin-Verhältnis bei 92,3% der Patienten sowie eine Hypoalbuminämie (84,6%) und Hyperglobulinämie (76,9%); diese Befunde sind mit den Veränderungen während einer Akute-Phase-Reaktion vereinbar. Die Serum-Eisenkonzentration war entgegen den Beschreibungen von Mensch und Hund nur selten (13%) erniedrigt. Bei 47,8% der Katzen lag die Eisenkonzentration allerdings im unteren Drittel des Referenzbereiches. Da die TIBC häufig (39,1%) erniedrigt oder im unteren Drittel des Referenzbereiches lag (47,8%) und nie erhöht war und die Ferritinkonzentration überwiegend (60,9%) erhöht und nie erniedrigt war, scheinen diese Parameter für die Diagnose der AID und zur Abgrenzung von einer Eisenmangelanämie hilfreich zu sein. Der positive Coombs-Test bei 2 der 10 untersuchten Katzen (Pt: IgG positiv, Mykobakterien-Infektion: C3b positiv), eine geringgradige Hyperbilirubinämie bei 6 von 26 Katzen (23,1%), sowie eine erhöhte MOF der Erythrozyten bei 2 von 17 Tieren (11,8%) waren Hinweise für eine Verkürzung der erythrozytären Überlebenszeit. Trotz einer gering- bis mittelgradigen Anämie lagen die EPO-Konzentrationen bei 30,8% der Katzen im Referenzbereich und waren bei 61,5% der Tiere lediglich geringgradig erhöht. Es bestand keine inverse Korrelation zwischen den EPO-Konzentrationen und den Anämie-Parametern (Hkt, Hb-Konzentration, Erythrozytenzahl). Eine inadäquate EPO-Produktion ist demnach ein wichtiger Pathomechanismus der AID der Katze. Außerdem scheint das Knochenmark auch bei der AID der Katze unzureichend auf gebildetes EPO zu reagieren, da die Anämie bei 6 von 8 Katzen mit geringgradig erhöhten EPO- Konzentrationen nicht-regenerativ war. Lediglich ein Tier (7,7%) hatte hohe EPO-Konzentrationen und mußte aufgrund des schlechten Befindens euthanasiert werden. Möglicherweise geht ein hoher EPO-Spiegel, wie bei der AID des Menschen, mit einer schlechten Prognose einher. Eine spezifische Therapie der AID ist bei Mensch und Hund aufgrund der milden Form in der Regel nicht notwendig. In dieser Studie konnte die AID meist durch die Therapie der Grundkrankheit behoben werden. Drei Katzen benötigten jedoch 2-4 Bluttransfusionen aufgrund einer hochgradigen Anämie oder um einen narkosefähigen Zustand zu erreichen. In dieser Arbeit wurde gezeigt, dass die Anämie bei Katzen mit entzündlichen Erkrankungen überwiegend gering- bis mittelgradig, nicht-regenerativ, normozytär und normochrom ist. Die Entzündung kann bei der Katze aber auch zu einer hochgradigen, transfusionsbedürftigen Anämie führen, so dass bei felinen AID-Patienten häufige Hkt-Kontrollen indiziert sind. Die AID schien, wie die AID des Menschen, multifaktoriell bedingt zu sein, da Hinweise für eine verkürzte erythrozytäre Überlebenszeit, eine Eisensequestration sowie eine inadäquate EPO-Produktion nachgewiesen werden konnten. Ob eine Therapie mit EPO, das bei der AID des Menschen eingesetzt wird, auch bei der AID der Katze hilfreich ist, wurde bisher nicht untersucht.Anemia of inflammatory disease (AID) is the most common anemia in humans and animals but has been investigated in the cat only in a few, mainly experimentally studies. The pathogenesis in AID is multifactorial, resulting from decreased iron availability, a decline in erythrocyte survival time and a decreased response to anemia. The aim of this clinical study was to describe the course of AID, laboratory parameters important for the diagnosis and pathogenesis of AID and the therapy of 26 cats with inflammatory diseases (abscess [a] n=13, pyothorax [pt] n=7, pyometra [pyo] n=1, mycobacterial infection n=1, fat necrosis [fn] n=4). Cats with a positive FeLV/FIV test result, with a neoplasia, nephro- or hepatopathy as well as animals with blood loss anemia were excluded from the study. A complete blood cell count, clinical chemistry, serum concentrations of erythropoietin (EPO), iron and ferritin, the total iron binding capacity (TIBC), the acute-phase-proteins 1-AGP and haptoglobin, the osmotic fragility (OF) of erythrocytes as well as a direct Coombs test were performed. The hct was monitored over 3-51 days (mean 15.5, median 11). Eleven of 26 cats were anemic on presentation, whereas 12 cats developed anemia during hospitalization. Three other cats did not develop anemia; the hematocrit (Hct) of 2 cats decreased within the reference range (pt, fn) and an increase was noted in one cat (a). The anemia was predominantly mild (47.9%) to moderate (39.1%), but in some cases (13%) also severe. The Hct decreased depending on the timepoint of measurement from the 2nd to 7th day after hospitalization and decreased further throughout a period of 3-16 days. In 6 cats the Hct values were within the reference range 2-18 days after surgery (a), 18 days after start of the therapy (pt) and 10-19 days after surgery (fn). On the other hand 17 of the cats remained anemic over various timespans: up to 29 days (a), up to 16 days (pt), up to 40 days (pyo) or 51 days (mycobacterial infection) and 15 days (fn). In 95.6% of patients the anemia was mainly normocytic, whereas a constant microcytic anemia was present in one cat (4,4%). A temporary mild macrocytosis occured in 3 cats (13%). In all patients, anemia was predominantly normochromic with only a few measurements of hypo- or hyperchromic anemia (26.1% and 21.7%). In 73.9% of cases the anemia was non-regenerative, whereas in 6 cats (26.1%) a mild regeneration (43,200-84,450 aggregated reticulocytes/µl) was noticed. Leukocytosis (18.9-150.0109/l) was observed in 22 of 26 and a left shift in 12 of 19 patients, however the cats without leukocytosis also developed an AID. The acute-phase-protein 1-AGP was elevated in all examined 19 patients over a period of 7 days prior to 14 days after surgery. Haptoglobin however was elevated in 16 of 19 cats and within the reference range in 3 animals 5, 7 and 14 days after beginning of the therapy. Neither the Hct value nor the number of aggregated reticulocytes showed an inverse correlation with the number of leukocytes, the 1-AGP or haptoglobin concentration. Conspicuous results were a lowered albumin/globulin-ratio in 92.3% of the patients as well as hypoalbuminemia (84.6%) and hyperglobulinemia (76.9%). These results agree with abnormalities seen in the acute-phase-reaction. As opposed to documentations on serum iron levels for humans and dogs cats rarely (13%) had lowered serum iron levels. However 47.8% of the cats had levels within the lower third of the reference range. As TIBC was often (39.1%) lowered or within the lower third of the reference range (47.8%) and was never elevated and the ferritin concentration was predominantly (60.9%) elevated and never lowered, it seems that these parameters are helpful for the diagnosis of the AID and for the differentiation from an iron deficiency anemia. The positive Coombs test in 2 of 10 examined cats (pt: IgG positive, mycobacterial infection: C3b positive), a mild hyperbilirubinemia in 6 of 26 cats (23.1%) and an elevated OF of erythrocytes in 2 of 17 animals (11.8%) led to the assumption of a shortening of the erythrocyte survival time. In spite of a mild to moderate anemia, EPO concentrations of 30.8% of the cats were within the reference range and only slightly elevated in 61.5% of the animals. There was no inverse correlation between the EPO concentrations and the parameters of anemia (hct, hemoglobin concentration, number of erythrocytes). Therefore an inadequate EPO production is an important pathomechanism of AID in the cat. Furthermore the bone marrow regeneration response to produced EPO seems to be insufficient, because anemia was non-regenerative in 6 of 8 cats with slightly elevated EPO concentrations. Only one cat (7.7%) had high EPO concentrations and had to be euthanized because of its poor condition. A high EPO, as with AID in humans, may be associated with a negative prognosis. A specific therapy of the anemia is usually not necessary because AID in humans and dogs is normally mild. In most animals it was possible to resolve the anemia by treating the underlying disease. However, 3 cats needed 2-4 blood transfusions either because of the severity of anemia or for stabilisation before anesthesia. In this study it was shown that feline anemia of inflammatory disease is usually mild to moderate, non-regenerative and normocytic, normochromic. An inflammation, however, may also result in a severe, transfusion-dependent anemia, so that frequent Hct controls are indicated in feline patients with AID. As in humans the pathogenesis of AID seemed to be multifactorial, due to evidence of a shortened erythrocyte survival time, an iron sequestration and an inadequate production of EPO. To this point in time it has not been studied whether EPO, which is used to treat human AID, might be useful in cats with AID

Evaluation of the esthetic properties of developmental defects of enamel: a spectrophotometric clinical study

Objectives. Detailed clinical quantification of optical properties of developmental defect of enamel is possible with spectropho- tometric evaluation. Developmental defects of enamel (DDE) are daily encountered in clinical practice. DDE are an alteration in quality and quantity of the enamel, caused by disruption and/or damage to the enamel organ during amelogenesis. Methods. Several clinical indices have been developed to categorize enamel defects based on their nature, appearance, microscopic features, or cause. A sample of 39 permanent teeth presenting DDE on labial surface was examined using the DDE Modified Index and SpectroShade evaluation. The spectrophotometric approach quantifies L∗ (luminosity), a∗ (quantity of green-red), and b∗ (quantity of blue- yellow) of different DDE. Conclusions. SpectroShade evaluation of the optical properties of the enamel defect enhances clinical understanding of severity and extent of the defect and characterizes the enamel alteration in terms of color discrepancy and surface characterization

National Rugby League athletes and tendon tap reflex assessment: A matched cohort clinical study

BACKGROUND: Limited research suggests elite athletes may differ from non-athletes in clinical tendon tap reflex responses. METHODS: In this matched cohort study, 25 elite rugby league athletes were compared with 29 non-athletes to examine differences in tendon reflex responses. Relationships between reflex responses and lengths of players’ careers were also examined. Biceps, triceps, patellar and Achilles tendon reflexes were clinically assessed. RESULTS: Right and left reflexes were well correlated for each tendon (r(S) = 0.7–0.9). The elite rugby league athletes exhibited significantly weaker reflex responses than non-athletes in all four tendons (p < 0.005). Biceps reflexes demonstrated the largest difference and Achilles reflexes the smallest difference. Moderate negative correlations (r(S) = −0.3–0.6) were observed between reflex responses and lengths of players’ careers. CONCLUSIONS: Future research is required to further elucidate mechanisms resulting in the observed differences in tendon reflexes and to ensure clinical tendon tap examinations and findings can be interpreted appropriately in this athletic population