Analysis of prognostic factors in patients with newly diagnosed diffuse large B-cell lymphoma and skeletal involvement

Background: Skeletal involvement (SI) is observed at low prevalence in patients with diffuse large B-cell lymphoma (DLBCL). Due to the rareness of this particular condition, prospective trials for these patients are scarce. Methods: We analyzed clinical characteristics and outcome of 75 patients with DLBCL and SI in order to identify factors with prognostic impact towards progression-free survival (PFS) and overall survival (OS). Results: Limited stage disease (Ann Arbor stage IE-IIE) was present in 34 patients (45%), 41 patients (55%) had advanced stage disease (Ann Arbor stage IIIE-IVE). Outcome was generally favorable for patients with DLBCL and SI with 3-year OS of 83%. The international prognostic index (IPI) was able to distinguish between different risk groups within this specific entity. Additionally, hypercalcemia showed to be a factor significantly associated with inferior survival. In regard to first-line treatment modalities, consolidative radiotherapy was positively associated with prolonged PFS and OS while intensification of chemotherapy had no significant impact. Conclusions: In our cohort of patients with DLBCL and SI, high-risk IPI as well as presence of hypercalcemia were associated with inferior outcome. Consolidative radiotherapy had a positive impact on survival

Constraints on Primordial Non-Gaussianity from a Needlet Analysis of the WMAP-5 Data

We look for a non-Gaussian signal in the WMAP 5-year temperature anisotropy maps by performing a needlet-based data analysis. We use the foreground-reduced maps obtained by the WMAP team through the optimal combination of the W, V and Q channels, and perform realistic non-Gaussian simulations in order to constrain the non-linear coupling parameter \fnl. We apply a third-order estimator of the needlet coefficients skewness and compute the $\chi^2$ statistics of its distribution. We obtain -80<\fnl<120 at 95% confidence level, which is consistent with a Gaussian distribution and comparable to previous constraints on the non-linear coupling. We then develop an estimator of \fnl based on the same simulations and we find consistent constraints on primordial non-Gaussianity. We finally compute the three point correlation function in needlet space: the constraints on \fnl improve to -50<\fnl<110 at 95% confidence level.Comment: 9 pages, 6 figures. MNRAS in press, updated to accepted versio

Pregnancy as a risk factor for severe influenza infection: an individual participant data meta-analysis

Background: WHO identifies pregnant women to be at increased risk for severe outcomes from influenza virus infections and recommends that they be prioritized for influenza vaccination. The evidence supporting this, however, is inconsistent. Ecologic studies in particular suggest more severe outcomes from influenza infection during pregnancy than studies based on individual patient data. Individual studies however may be underpowered and, as reported in a previous systematic review, confounding factors could not be adjusted for. We therefore conducted an individual participant data meta-analysis to assess the risk for severe outcomes of influenza infection in pregnant women while adjusting for other prognostic factors. Methods: We contacted authors of studies included in a recently published systematic review. We pooled the individual participant data of women of reproductive age and laboratory confirmation of influenza virus infection. We used a generalized linear mixed model and reported odds ratios (OR) and 95% confidence intervals (CI). Results: A total of 33 datasets with data on 186,656 individuals were available, including 36,498 eligible women of reproductive age and known pregnancy status. In the multivariable model, pregnancy was associated with a 7 times higher risk of hospital admission (OR 6.80, 95%CI 6.02–7.68), among patients receiving medical care as in- or outpatients, pregnancy was associated with a lower risk of admission to intensive care units (ICU; OR 0.57, 95%CI 0.48–0.69), and was not significantly associated with death (OR 1.00, 95%CI 0.75–1.34). Conclusions: Our study found a higher risk of influenza associated hospitalization among pregnant women as compared to non-pregnant women. We did not find a higher mortality rate or higher likelihood of ICU admission among pregnant women who sought medical care. However, this study did not address whether a true community based cohort of pregnant women is at higher risk of influenza associated complications.Fil: Mertz, Dominik. Mc Master University; CanadáFil: Lo, Calvin Ka Fung. Mc Master University; CanadáFil: Lytvyn, Lyubov. Mc Master University; CanadáFil: Ortiz, Justin R.. Organizacion Mundial de la Salud; ArgentinaFil: Loeb, Mark. Mc Master University; CanadáFil: Ang, Li Wei. Ministry of Health; SingapurFil: Anlikumar, Mehta Asmita. Amrita Vishwa Vidyapeetham; IndiaFil: Bonmarin, Isabelle. Santé publique; FranciaFil: Borja Aburto, Victor Hugo. Instituto Mexicano del Seguro Social; MéxicoFil: Burgmann, Heinz. Medical University Vienna; AustriaFil: Carratalà, Jordi. Universidad de Barcelona; España. Instituto de Investigación Biomédica de Bellvitge; España. Spanish Network for Research in Infectious Diseases; EspañaFil: Chowell, Gerardo. Georgia State University; Estados Unidos. National Institutes of Health; Estados UnidosFil: Cilloniz, Catia. Universidad de Barcelona; España. Instituto de Investigaciones Biomédicas August Pi i Sunyer; EspañaFil: Cohen, Jessica. Centers for Disease Control and Prevention; Estados UnidosFil: Cutter, Jeffery. Ministry of Health; SingapurFil: Filleul, Laurent. Santé publique; Francia. French National Public Health Agency; FranciaFil: Garg, Shikha. Centers for Disease Control and Prevention; Estados UnidosFil: Geis, Steffen. London School of Hygiene and Tropical Medicine; Reino UnidoFil: Helferty, Melissa. Public Health Agency; CanadáFil: Huang, Wan Ting. Taiwan Centers for Disease Control; ChinaFil: Jain, Seema. Centers for Disease Control and Prevention; Estados UnidosFil: Sevic, Biljana Joves. Institute for Pulmonary Diseases of Vojvodina; SerbiaFil: Kelly, Paul. Australian Capital Territory Health Directorate; Australia. Australian National University Medical School; AustraliaFil: Kusznierz, Gabriela. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Instituto de Salud "Dr. C. G. Malbran". Instituto Nacional de Enfermedades Respiratorias; ArgentinaFil: Lehners, Nicola. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Lenzi, Luana. Universidade Federal do Paraná; BrasilFil: Ling, Ivan T.. Sir Charles Gairdner Hospital; AustraliaFil: Mitchell, Robyn. Public Health Agency; CanadáFil: Mulrennan, Siobhain A.. Sir Charles Gairdner Hospital; Canadá. University of Western Australia; AustraliaFil: Nishioka, Sergio A.. Ministerio de Salud de Brasil; BrasilFil: Norton, Robert. Townsville Hospital; AustraliaFil: Oh, Won Sup. Kangwon National University School of Medicine; Corea del SurFil: Orellano, Pablo Wenceslao. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

A thirteen-year analysis of Plasmodium falciparum populations reveals high conservation of the mutant pfcrt haplotype despite the withdrawal of chloroquine from national treatment guidelines in Gabon

<p>Abstract</p> <p>Background</p> <p>Chloroquine resistance (CR) decreased after the removal of chloroquine from national treatment guidelines in Malawi, Kenia and Tanzania. In this investigation the prevalence of the chloroquine resistance (CQR) conferring mutant <it>pfcrt </it>allele and its associated chromosomal haplotype were determined before and after the change in Gabonese national treatment guidelines from chloroquine (CQ) to artesunate plus amodiaquine (AQ) in 2003.</p> <p>Methods</p> <p>The prevalence of the wild type <it>pfcrt </it>allele was assessed in 144 isolates from the years 2005 - 07 by PCR fragment restriction digest and direct sequencing. For haplotype analysis of the chromosomal regions flanking the <it>pfcrt </it>locus, microsatellite analysis was done on a total of 145 isolates obtained in 1995/96 (43 isolates), 2002 (47 isolates) and 2005 - 07 (55 isolates).</p> <p>Results</p> <p>The prevalence of the mutant <it>pfcrt </it>allele decreased from 100% in the years 1995/96 and 2002 to 97% in 2005 - 07. Haplotype analysis showed that in 1995/96 79% of the isolates carried the same microsatellite alleles in a chromosomal fragment spanning 39 kb surrounding the <it>pfcrt </it>locus. In 2002 and 2005 - 07 the prevalence of this haplotype was 62% and 58%, respectively. <it>Pfcrt </it>haplotype analysis showed that all wild type alleles were CVMNK.</p> <p>Conclusion</p> <p>Four years after the withdrawal of CQ from national treatment guidelines the prevalence of the mutant <it>pfcrt </it>allele remains at 97%. The data suggest that the combination of artesunate plus AQ may result in continued selection for the mutant <it>pfcrt </it>haplotype even after discontinuance of CQ usage.</p

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Genetic analysis of the return of chloroquine sensitive parasites to Lambaréné, Gabun

Die weltweite Ausbreitung Chloroquin-resistenter Plasmodium falciparum Stämme stellt ein großes Problem bei der Behandlung der Malaria tropica dar. Vor Kurzem wurde aus Malawi jedoch eine umfangreiche Rückkehr sensitiver Stämme berichtet, nachdem dort der Einsatz von Chloroquin vor Jahren erfolgreich unterbunden worden war. Diese Beobachtung wirft zwei grundlegende Fragen auf: erstens, ob es sich hierbei um ein weltweit reproduzierbares Phänomen handelt, und zweitens, welcher genetische Mechanismus dem zu Grunde liegt. In dieser Arbeit wurde versucht, diesen Fragen an Hand der ehemals zu 100% resistenten Region von Lambaréné, Gabun, nachzugehen, wo Chloroquin im Jahre 2003 aus den nationalen Therapieleitlinien entfernt worden war. Wir untersuchten parasitäre DNA aus 145 Proben der Jahre 2005 – 07 auf das vorliegende Allel des Plasmodium falciparum chloroquine resistance transporter (pfcrt), dem für Chlorquin-Resistenz verantwortlichen Gen. Mit insgesamt vier sensitiven Isolaten (3%) konnten wir einen signifikanten Anstieg der Sensitivität feststellen (p = 0,026). Auf Grund eines selective sweeps sind in resistenten Parasiten neben dem pfcrt-Allel auch die benachbarten chromosomalen Regionen weitgehend konserviert. Mittels Analyse der Haplotypen – bestimmt durch Sequenzierung von Mikrosatellitenmarkern – konnte daher der jeweilige genetische Hintergrund von resistenten sowie sensitiven Stämmen charakterisiert werden. Eine Untersuchung von 132 resistenten Proben aus den Jahren 1995 – 2007 zeigte das Vorliegen eines lokal dominanten resistenten Haplotypen. Der Konservierungsgrad dieses Haplotypen war zu allen Zeitpunkten hoch, nahm im Laufe der Jahre jedoch ab. Im Gegensatz hierzu zeigten die sensitiven Isolate zwei verschiedene Varianten von Haplotypen – einen ohne jegliche Ähnlichkeiten zur lokalen resistenten Population und einen, der auf einer Länge von mindestens 27 kb identisch zum lokal dominanten resistenten Haploytpen war. Diese Daten legen nahe, dass eine Abnahme des vormals durch Chloroquin ausgeübten Selektionsdruckes eine Rückkehr sensitiver Stämme nach Lambaréné ermöglichte – wenn auch nur in begrenztem Ausmaß. Durch Einkreuzen konnte sich das sensitive Allel in der lokalen resistenten Population etablieren.The spread of chloroquine resistance has severely handicapped treatment of Plasmodium falciparum malaria in the past. Recently an extensive return of sensitive parasites was reported from Malawi after chloroquine use had been successfully discontinued for years. Now two aspects deserve closer attention: whether this phenomenon is reproducible worldwide and which is the causing genetic mechanism. Here we attempt to address these questions in the setting of the formerly 100% resistant area of Lambaréné, Gabon, where chloroquine was removed from the national treatment guidelines in 2003. We screened parasite DNA from 145 samples obtained in the years 2005 – 07 for the mutant allele of the P. falciparum chloroquine resistance transporter (pfcrt), the gene responsible for chloroquine resistance and found four sensitive isolates (3%) constituting a significant rise in sensitivity (p = 0.026). As the chromosomal regions flanking pfcrt are largely conserved in resistant parasites due to a selective sweep, haplotype analysis of local resistant and sensitive parasites via sequencing of microsatellites could be applied to characterize their specific genetic background. Analysis of 132 resistant samples obtained 1995 – 2007 revealed the presence of a dominant local resistant haplotype. Conservation of this haplotype was high, but decreased slowly over the years. In comparison, the sensitive isolates showed two different variants of haplotypes: one without similarities to the resistant population, one sharing a piece of at least 27 kb with the dominant local resistant haplotype. The data suggest that reduced drug pressure allowed sensitive parasites to return to Lambaréné, however on a small scale, and that incrossing let to reintroduction of the sensitive allele into the local parasite population

Changes in Severity of Influenza A(H1N1)pdm09 Infection from Pandemic to First Postpandemic Season, Germany

We studied risk factors for a severe clinical outcome in hospitalized patients with laboratory-confirmed influenza A(H1N1)pdm09 infection at the University Hospital Heidelberg in the pandemic and first postpandemic seasons. We identified 102 patients in 2009–10 and 76 in 2010–11. The proportion of severely diseased patients dramatically increased from 14% in 2009–10 to 46% in 2010–11 as did the mortality rate (5%–12%). Patients in the first postpandemic season were significantly older (38 vs. 18 years) and more frequently had underlying medical conditions (75% vs. 51%). Overall, 50 patients (28%) had a severe clinical outcome, resulting in 14 deaths. Multivariate analysis showed that older male patients with chronic lung disease were at increased risk for a severe clinical outcome. In summary, the proportion of patients with severe disease and fatal cases increased in the postpandemic season. Therefore, patients with suspected infections should be promptly identified and receive early treatment

Long-Term Shedding of Influenza Virus, Parainfluenza Virus, Respiratory Syncytial Virus and Nosocomial Epidemiology in Patients with Hematological Disorders

Respiratory viruses are a cause of upper respiratory tract infections (URTI), but can be associated with severe lower respiratory tract infections (LRTI) in immunocompromised patients. The objective of this study was to investigate the genetic variability of influenza virus, parainfluenza virus and respiratory syncytial virus (RSV) and the duration of viral shedding in hematological patients. Nasopharyngeal swabs from hematological patients were screened for influenza, parainfluenza and RSV on admission as well as on development of respiratory symptoms. Consecutive swabs were collected until viral clearance. Out of 672 tested patients, a total of 111 patients (17%) were infected with one of the investigated viral agents: 40 with influenza, 13 with parainfluenza and 64 with RSV; six patients had influenza/RSV or parainfluenza/RSV co-infections. The majority of infected patients (n = 75/111) underwent stem cell transplantation (42 autologous, 48 allogeneic, 15 autologous and allogeneic). LRTI was observed in 48 patients, of whom 15 patients developed severe LRTI, and 13 patients with respiratory tract infection died. Phylogenetic analysis revealed a variety of influenza A(H1N1)pdm09, A(H3N2), influenza B, parainfluenza 3 and RSV A, B viruses. RSV A was detected in 54 patients, RSV B in ten patients. The newly emerging RSV A genotype ON1 predominated in the study cohort and was found in 48 (75%) of 64 RSV-infected patients. Furthermore, two distinct clusters were detected for RSV A genotype ON1, identical RSV G gene sequences in these patients are consistent with nosocomial transmission. Long-term viral shedding for more than 30 days was significantly associated with prior allogeneic transplantation (p = 0.01) and was most pronounced in patients with RSV infection (n = 16) with a median duration of viral shedding for 80 days (range 35–334 days). Long-term shedding of respiratory viruses might be a catalyzer of nosocomial transmission and must be considered for efficient infection control in immunocompromised patients