Estimands for atopic dermatitis clinical trials: Expert opinion on the importance of intercurrent events.

Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.

Effect of secukinumab on the clinical activity and disease burden of nail psoriasis: 32-week results from the randomized placebo-controlled TRANSFIGURE trial.

BACKGROUND: Nail psoriasis is associated with functional impairment, pain and reduced quality of life. OBJECTIVES: To demonstrate the superiority of secukinumab over placebo in clearing nail psoriasis as assessed by the Nail Psoriasis Severity Index (NAPSI) at week 16 and over time up to week 132. Presented here is the week 32 interim analysis. Impact on quality of life was assessed by Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA) patient questionnaires. METHODS: TRANSFIGURE is a double-blind, randomized, placebo-controlled study in patients with moderate-to-severe plaque and nail psoriasis. RESULTS: The primary objective of this study was met: both doses of secukinumab were superior to placebo at week 16 (NAPSI improvements of -45·3%, -37·9% and -10·8% for secukinumab 300 mg and 150 mg and placebo, respectively, P < 0·001). Significant improvements were seen in patients' quality of life: the NAPPA-Quality of Life total score median decreases at week 16 were 60·9%, 49·9% and 15·8% for secukinumab 300 mg and 150 mg and placebo, respectively (P < 0·001). Improvement in nail psoriasis continued to week 32: NAPSI percentage change reached -63·2% and -52·6% for secukinumab 300 mg and 150 mg, respectively. Skin clearance measured by ≥ 90% improvement in Psoriasis Area and Severity Index was significant (rates of 72·5%, 54·0% and 1·7% for secukinumab 300 mg and 150 mg and placebo at week 16, respectively, P < 0·001) and was sustained to week 32. The most common adverse events were nasopharyngitis, headache and upper respiratory tract infections. CONCLUSIONS: Secukinumab demonstrated significant and clinically meaningful efficacy and quality-of-life improvements for patients with nail psoriasis up to week 32. What's already known about this topic? Nail psoriasis is understudied and there is a lack of effective treatment options. Nail psoriasis is correlated with more severe psoriatic disease and the development of psoriatic arthritis. What does this study add? TRANSFIGURE is one of the few prospective placebo-controlled trials specifically in nail psoriasis and includes nail-specific quality-of-life measures such as Nail Assessment in Psoriasis and Psoriatic Arthritis (NAPPA)-Quality of Life and NAPPA-Patient Benefit Index. In this trial, secukinumab demonstrates significant efficacy and quality-of-life improvements in this difficult-to-treat population.

Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients with moderate-to-severe psoriasis through 5 years of treatment (SCULPTURE Extension Study).

BACKGROUND: Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of moderate-to-severe psoriasis and psoriatic arthritis. OBJECTIVE: To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate-to-severe psoriasis. METHODS: In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double-blinded until the end of Year 3 and open-label from Year 4. Here, we focus on the 300 mg fixed-interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses. RESULTS: At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified. CONCLUSION: Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate-to-severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.

Seasonal and spatial occurrence of glycerol-3-phosphate dehydrogenase variability in Ixodes ricinus (Acari: Ixodidae) populations.

Previous results indicate that glycerol-3-phosphate dehydrogenase variability represents the adaptation of Ixodes ricinus L. (Acari: Ixodidae) to fluctuations of environmental conditions, particularly to temperature. Analysis of crucial polymorphisms in I. ricinus Gpdh gene was done by the restriction method, and three different haplotypes were obtained (GPDH441 1, GPDH441 2, and GPDH441 3), corresponding to GPDH alleles detected by allozyme electrophoresis. Differences in GPDH441 haplotype and genotype frequencies were found between samples from open and forest habitats. Significant seasonal variations of GPDH441 haplotype and genotype frequencies were detected in samples from the open habitats. No seasonal variations were observed at forest localities, probably because of the less pronounced amplitude of environmental factors. The possible role of host availability was discussed as an important factor that affects seasonal dynamics and genetic composition of tick populations.

Coexistence of emerging bacterial pathogens in Ixodes ricinus ticks in Serbia.

The list of tick-borne pathogens is long, varied and includes viruses, bacteria, protozoa and nematodes. As all of these agents can exist in ticks, their co-infections have been previously reported. We studied co-infections of emerging bacterial pathogens (Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum and Francisella tularensis) in Ixodes ricinus ticks in Serbia. Using PCR technique, we detected species-specific sequences, rrf-rrl rDNA intergenic spacer for B. burgdorferi s.l., p44/msp2 paralogs for A. phagocytophilum, and the 17 kDa lipoprotein gene, TUL4, for F. tularensis, respectively, in total DNA extracted from the ticks. Common infections with more than one pathogen were detected in 42 (28.8%) of 146 infected I. ricinus ticks. Co-infections with two pathogens were present in 39 (26.7%) of infected ticks. Simultaneous presence of A. phagocytophilum and different genospecies of B. burgdorferi s.l. complex was recorded in 16 ticks, co-infection with different B. burgdorferi s. l. genospecies was found in 15 ticks and eight ticks harbored mixed infections with F. tularensis and B. burgdorferi s.l. genospecies. Less common were triple pathogen species infections, detected in three ticks, one infected with A. phagocytophilum / B. burgdorferi s.s. / B. lusitaniae and two infected with F. tularensis / B. burgdorferi s.s. / B. lusitaniae. No mixed infections of A. phagocytophilum and F. tularensis were detected.

Exon variability of gene encoding glycerol-3-phosphate dehydrogenase of Ixodes ricinus ticks.

We have previously found apparent differences in Gpdh allele frequences between borrelia infected and uninfected Ixodes ricinus as revealed by native gel electrophoresis of allozyme polymorphisms. The present study deals with the genetic basis of the observed allozyme polymorphism. Multiple sequence alignment of 36 Gpdh open reading frames identified a total of 40 polymorphic nucleotide sites. Of the 40 polymorphic nucleotide sites, 34 were silent (did not result in amino acid residue change), while six were active causing a change in the amino acid chain. All polymorphic amino acid sites were situated within the N-terminal NAD-binding domain, whereas the C-terminal substrate-binding domain was highly conserved. Analysis of the obtained Gpdh sequences and GPDH allozyme polymorphisms for individual ticks pointed to amino acid changes at positions 61 (glycine-to-glutamic acid), 64 (serine-to-cysteine) and 102 (glycine-to-arginine) as a key for differential mobility of GPDH allozymes in an electric field. Our findings are discussed in the context of the molecular basis of I. ricinus host finding behavior.

Assessment of the risk of contracting Lyme disease in areas with significant human presence / Risco de contrair doença de Lyma em áreas com significativa presença humana

In order to describe seasonal changes in Lyme diseases risk rate at three localities in Serbia, during the period of 2003-2005, a total of 1542 Ixodes ricinus ticks (493 nymphs, 525 females and 524 males) were examined. The prevalence of Borrelia burgdorferi in Ixodes ricinus ticks at the Bovan Lake County were higher than the average for European localities (45.9 percent for adults and 18.8 percent for nymphs). In Mt. Avala and Kljajicevo counties adults and nymphs were, respectively, infected at the following percentages: 26.3, 10.7; 16.2 and 7.6 percent. The outcome indicates a relatively high risk of the contracting Lyme disease in all investigates areas.

Para estimar a variação sazonal das taxas de risco para doença de Lyme em três localidades da Sérvia foram examinados, no período de 2003-2005, 1542 espécimes do carrapato Ixodes ricinus (493 ninfas, 525 fêmeas e 524 machos). A prevalência de Borrelia burgdorferi em Ixodes ricinus no município de Bovan Lake foi mais alta que a registrada em outras localidades da Europa. Nos municípios de Mt. Avala e Kljajicevo as porcentagens de adultos e ninfas infectadas foram: 26,3 e 10,7; 16,2 e 7,6, respectivamente. Esses resultados indicam um relativo alto risco de se contrair doença de Lyme nas três localidades estudadas.

[Sensitivity of Streptococcus pneumoniae to antimicrobial drugs]. / Osetljivost sojeva streptokokus pneumonije na antimikrobne lekove.

INTRODUCTION: Streptococcus pneumoniae is the leading cause of community acquired pneumonia and a frequent cause of otitis media, sinusitis and meningitis. Although most pneumococci remain susceptible to penicillin, relatively less susceptible and resistant strains have been recognized with increasing frequency throughout the world (1). The aim of this study was to determine whether and to what degree pneumococci isolated in our laboratory were resistant to penicillin and other frequently used antimicrobial agents. MATERIAL AND METHODS: During the period from 1991 to 1995 1139 Streptococcus pneumoniae strains isolated from patients with different pneumococcal infections were tested for their susceptibility to antimicrobial agents at the Department of Bacteriology and Parasitology of the Institute of Public Health in Novi Sad. Antimicrobial agents tested included: penicillin, ampicillin, cephalexin, erythromycin, sulfamethoxazole-trimethoprim and clindamycin. Susceptibility test was performed by using Kirby-Bauer disc diffusion technique on Mueller-Hinton agar supplemented with 5% defibrinated bovine blood (5). RESULTS: Susceptibility of Streptococcus pneumoniae to seven antimicrobial agents used in the study is shown in Table 2. There was a resistance to all antimicrobial agents tested. It was the lowest to erythromycin (1.6%) and the highest to sulfamethoxazole+ trimethoprim (67.3%). The rate of resistance of penicillin was 3.3%. In Table 3 and 4 we can also see that the lowest resistance was to erythromycin, and the highest to sulfamethoxazole+trimethoprim, both for isolates from nose and other sources. Strains of Streptococcus pneumoniae isolated from nasal swabs were more susceptible to penicillin than those isolated from blood, sputum and cerebrospinal fluid. DISCUSSION: For many years penicillin has been the mainstay of therapy for pneumococcal diseases. Clinical resistance to penicillin was first reported in 1960's. Since this early reported, penicillin resistance has been encountered with increasing frequency in strains of Streptococcus pneumoniae from around the world. In our study resistance to penicillin was low (3.3%). This is in accordance with the authors from Italy, Great Britain, USA and Germany (7, 8, 9, 10). Much higher prevalence of resistant pneumococci we found in the reports from Spain, France and Hungary (13, 14, 15, 17). Many of these strains have been resistant to multiple drugs and have been isolated from patients with invasive infections (meningitis, pneumonia, bacteremia). Percentage of penicillin resistant pneumococci isolated from blood, sputum and cerebrospinal fluid in our study was relatively low (7.7%), but it was higher than the percentage of resistant isolates from nasal swabs (2.0%). These findings are in accordance with other reports (20, 21). CONCLUSION: The increasing number of Streptococcus pneumoniae isolates resistant to penicillin and other antimicrobial agents indicates the need to perform susceptibility testing for every isolated strain in order to avoid possible therapeutic failure.

Investigaçöes ecológicas sobre carrapatos (Acari, Ixodidae) na regiäo leste da Sérvia, com ênfase em Ixodes ricinus e Hyalomma savignyi / Ecological investigations on ticks (Acari, Ixodidae) of East Serbia, with emphasis on Ixodes ricinus and Hyalomma savignyi

Um estudo ecológico sobre carrapatos ixodídeos foi feito entre 1989 e 1995 na regiäo leste da Sérvia. Dentre as 14 espécies da família Ixodidae, nove foram identificadas: Dermacentor marginatus, Rhipicephalus bursa, Rhipicephalus sanguineus, Ixodes ricinus, Haemaphysalis punctata, Haemaphysalis sulcata, Haemaphysalis inermis, Hyalomma savignyi e Boophilus calcaratus. A composiçäo da fauna e da dinâmica populacional foram examinadas medindo-se e avaliando-se ao mesmo tempo o efeito de temperatura, umidade e precipitaçäo pluviométrica sobre a dinâmica da populaçäo dos carrapatos. A regiäo tem sido identificada como foco natural do vírus da febre hemorrágica Criméia-Congo (CCHF) e neste trabalho foi dada especial atençäo aos carrapatos Ixodes ricinus e Hyalomma savignyi vetores da CCHF e da doença de Lyme

[Distribution of Ixodes ricinus ticks in Yugoslavia]. / Rasirenost krpelja Ixodes ricinus na teriteoriji Jugoslavije.

In this paper the authors present distribution of tick Ixodes ricinus in both republics of Yugoslavia--Serbia and Montenegro. The ticks were collected from domestic animals and humans sporadically. The determination showed following species: Ixodes ricinus, I. persulcatus, I. hexagonus, Dermacentor marginatus, D. pictus, Rhipicephalus bursa, R. sanguineus, Haemaphysalis punctata, H. inermis, H. sulcata, H. leporis-palustriis, H. concinna, Boophilus (margaporus) calcaratus, Hyalomma savignyi, H. excavatum, H. detritum and H. rufipes. The species I. ricinus has been detacted in all parts of the country.

[Ticks in the region of Belgrade]. / Nasi nalazi krpelja na teritoriji Beograda.

The paper gives a brief introduction concerning the role of ticks in transmission of numerous diseases to both animals and humans. Methods of work, research goals and finally, results of tick findings on animals and people in Belgrade area are presented. Occasional findings of those arthropodes in various urban areas have also been described. The collected ticks belong to the species Ixodes ricinus and Rhipicephalus sanguineus. The authors conclude that ecologic research of ticks should be continued and expanded not only in Belgrade but in other areas of the country as well.

[Prophylaxis and therapy of infections in allogenic bone marrow transplantation in patients with hematologic diseases]. / Profilaksa i lecenje infekcije kod alogene transplantacije kosne srzi bolesnika sa hematoloskim oboljenjima.

Infection and acute graft versus host disease (GVHD) are the most common complications of allogeneic bone marrow transplantation, which compromise this therapeutical method for hematologic diseases. Beside the appreciation of customary preventive measures and the treatment of infections, it is necessary for every bone marrow transplantation center to analyze the development of bacterial, fungal and viral infections in the patients and to generate the most efficient and most rational program for their prevention and treatment. At the Hematology Department in Novi Sad seven allogenic bone marrow transplantations were performed in patients with malignant hematologic diseases and severe form of aplastic anemia. Prevention of the infection by isolation of the patient in a sterile unit, selective decontamination of the digestive tract with sterile food, skin and mucus hygiene and prophylactic drug administration proved rather beneficial and adequate for patients with the graft accepted, hematopoiesis recovered and immunity reconstructed. Risks of infections were increased by permanent vein catheter, acute GVHD and rejection of the bone marrow graft. Prompt isolation and identification of bacteria and fungi, especially in blood, the establishment of a minimal suppressing and bactericide antibiotic concentration, along with the assessment of their synergism, as well as early diagnosis of cytomegalovirus and administration of specific drugs, can significantly contribute to the more successful treatment of infections in transplanted patients.

Investigation of sandflies (Diptera, Phlebotomidae) in an endemic focus of visceral leishmaniasis in Yugoslavia.

The paper presents the results of faunistic, ecological and viral investigations concerning phlebotomine sandflies in an endemic focus of visceral leishmaniasis in Yugoslavia. These investigations were carried out in the period from 1969 to 1981.