Impact of Smoking, Body Weight, Diabetes, Hypertension and Kidney Dysfunction on Survival in Pancreatic Cancer Patients-A Single Center Analysis of 2323 Patients within the Last Decade.

In addition to being risk factors for pancreatic cancer, parameters such as smoking, diabetes, or obesity might also act as potential prognostic factors for the survival of patients initially diagnosed with pancreatic cancer. By implementing one of the largest retrospective study cohorts of 2323 pancreatic adenocarcinoma (PDAC) patients treated at a single high-volume center, potential prognostic factors for survival were evaluated on the basis of 863 cases. Since parameters such as smoking, obesity, diabetes, and hypertension can cause severe chronic kidney dysfunction, the glomerular filtration rate was also considered. In the univariate analyses, albumin (p < 0.001), active smoking (p = 0.024), BMI (p = 0.018), and GFR (p = 0.002) were identified as metabolic prognostic markers for overall survival. In multivariate analyses, albumin (p < 0.001) and chronic kidney disease stage 2 (GFR < 90 mL/min/1.37 m2; p = 0.042) were identified as independent metabolic prognostic markers for survival. Smoking presented a nearly statistically significant independent prognostic factor for survival with a p-value of 0.052. In summary, low BMI, status of active smoking, and reduced kidney function at the time of diagnosis were associated with lower overall survival. No prognostic association could be observed for presence of diabetes or hypertension.

Inflammation-Based Prognostic Scores in Pancreatic Cancer Patients-A Single-Center Analysis of 1294 Patients within the Last Decade.

Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer between 2009 and 2021 at our cancer center, inflammatory markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) were evaluated. We identified a new combined score, termed the inflammatory benchmark index (IBI). We performed univariate and multivariate overall survival analyses and identified optimal prognostic cut-off values for each parameter. In univariate analyses, advanced age (p < 0.001), gender (p < 0.001), tumor stage (p < 0.001), CA19-9 (p = 0.001), NLR (p = 0.001), LMR (p = 0.004), PLR (p = 0.004), CAR (p = 0.001) and IBI (p = 0.001) were identified as prognostic markers. In multivariate analyses advanced age (p < 0.001), gender (p = 0.001), tumor stage (p < 0.001), CA19-9 (p < 0.001), NLR (p = 0.001), LMR (p = 0.038), CAR (p < 0.001) and IBI (p < 0.001) were independent prognostic markers. These findings emphasize the impact of inflammation in pancreatic cancer, provide easily accessible prognostic values for the clinician, and may be useful as stratification parameters for trials aimed at patient inflammation or immune response.

Biodiversity policy beyond economic growth.

Increasing evidence-synthesized in this paper-shows that economic growth contributes to biodiversity loss via greater resource consumption and higher emissions. Nonetheless, a review of international biodiversity and sustainability policies shows that the majority advocate economic growth. Since improvements in resource use efficiency have so far not allowed for absolute global reductions in resource use and pollution, we question the support for economic growth in these policies, where inadequate attention is paid to the question of how growth can be decoupled from biodiversity loss. Drawing on the literature about alternatives to economic growth, we explore this contradiction and suggest ways forward to halt global biodiversity decline. These include policy proposals to move beyond the growth paradigm while enhancing overall prosperity, which can be implemented by combining top-down and bottom-up governance across scales. Finally, we call the attention of researchers and policy makers to two immediate steps: acknowledge the conflict between economic growth and biodiversity conservation in future policies; and explore socioeconomic trajectories beyond economic growth in the next generation of biodiversity scenarios.

Phylogenetic analysis of human parvovirus b19 sequences from eleven different countries confirms the predominance of genotype 1 and suggests the spread of genotype 3b.

Phylogenetic analysis of 166 human parvovirus B19 sequences from 11 different countries attributed 91.57% to genotype 1, 5.42% to genotype 3b, and 3.01% to genotype 3a. Very similar viruses of genotype 1 circulated widely in Europe and Israel. Genotype 3b seems to show an increasing spread outside of Africa.

Multilocus sequence typing, pulsed-field gel electrophoresis, and fla short variable region typing of clonal complexes of Campylobacter jejuni strains of human, bovine, and poultry origins in Luxembourg.

Campylobacter jejuni is the most common cause of bacterial gastroenteritis in Luxembourg, with a marked seasonal peak during summer. The majority of these infections are thought to be sporadic, and the relative contribution of potential sources and reservoirs is still poorly understood. We monitored human cases from June to September 2006 (n = 124) by molecular characterization of isolates with the aim of rapidly detecting temporally related cases. In addition, isolates from poultry meat (n = 36) and cattle cecal contents (n = 48) were genotyped for comparison and identification of common clusters between veterinary and human C. jejuni populations. A total of 208 isolates were typed by sequencing the fla short variable region, macrorestriction analysis resolved by pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST). We observed a high diversity of human strains during a given summer season. Poultry and human isolates had a higher diversity of sequence types than isolates of bovine origin, for which clonal complexes CC21 (41.6%) and CC61 (18.7%) were predominant. CC21 was also the most common complex found among human isolates (21.8%). The substantial concordance between PFGE and MLST results for this last group of strains suggests that they are clonally related. Our study indicates that while poultry remains an important source, cattle could be an underestimated reservoir of human C. jejuni cases. Transmission mechanisms of cattle-specific strains warrant further investigation.

Antimicrobial drug resistance in human nontyphoidal Salmonella isolates in Europe 2000-2004: a report from the Enter-net International Surveillance Network.

A 5-year survey, from 2000 to 2004, of results of antimicrobial susceptibility testing for 11 antimicrobials for 134,310 isolates of nontyphoidal salmonellas from cases of human infection in 10 European countries has demonstrated an overall increase in the occurrence of resistance, from 57% to 66% over the period of study. In contrast, multiple resistance (to four or more antimicrobial drugs) has declined from 18% to 15%. The most significant increase in resistance has been to nalidixic acid (14% to 20%), particularly in Salmonella enterica serovar Enteritidis (10% to 26%), the most common serovar. For England and Wales this increase has for the most part been attributed to infections linked to contaminated eggs originating outside the United Kingdom. For Salmonella Typhimurium, the second most prevalent serovar, there has been an overall decline in the occurrence of resistance to ampicillin, chloramphenicol, and tetracyclines, attributed to a decline in the occurrence of multiresistant Salmonella Typhimurium DT 104. For Salmonella Virchow, a serotype with a predilection for invasive disease, there has been a substantive increase in resistance to most antimicrobials, attributed to the spread of drug-resistant strains associated with poultry. Because of the widespread importation of foods, it is important that controls to reduce the emergence and spread of drug-resistant strains of Salmonella are internationally implemented.

Re-exposure to wild-type virus stabilizes measles-specific antibody levels in late convalescent patients.

BACKGROUND: Infection with wild-type (wt) measles virus strains induces high antibody levels believed to provide life-long protection against disease. OBJECTIVES: Humoral immunity was followed up in convalescent measles patients to assess the persistence of specific antibodies after measles disease in individuals without and with documented re-exposure to wt virus. STUDY DESIGN: Paired sera were collected from 43 late convalescents (LC) before re-exposure and 3.7-4.8 years after re-exposure to at least one measles patient (LC+ group). Antibody persistence in this group was compared to paired sera from 43 age- and sex-matched controls without documented exposure to wt virus (LC- group). Paired sera were also obtained from 26 measles patients 1.3-1.7 and 3.8-4.1 years after they had recovered from measles to observe the waning of antibodies in early convalescents (EC group). RESULTS: Antibody levels decreased by 12.1% (CI: 3.2-20.3%, p=0.01) within 6.3 years in the LC- group of late convalescent measles patients. In contrast, in the LC+ group GMT of first and second sera were virtually identical, indicating that exposure to wt virus stabilizes antibody levels even in absence of a detectable secondary immune response. In a subset of late convalescents of group LC+ with a secondary immune response, antibody waning after re-exposure was as high as 15.6%/year (CI: 13.0-17.7%/year), corresponding to a half-life of 4.1 years (CI: 3.5-5.0 years), but antibodies were still higher than before re-exposure. In the EC group GMT decreased by 6.5% (95% CI: -13.3% to +0.1%) during 2.5 years but significance was low (p=0.08). CONCLUSION: The maintenance of antibody levels in convalescent measles patients is at least partially dependant on recurrent exposure to circulating wt virus.

European seroepidemiology network 2: Standardisation of assays for seroepidemiology of varicella zoster virus.

BACKGROUND: The aim of the European Sero-Epidemiology Network (ESEN2) is to harmonise the serological surveillance of vaccine-preventable diseases in Europe. OBJECTIVE: To allow comparison of antibody prevalence in different countries by standardising results into common units. STUDY DESIGN: For varicella zoster virus (VZV), a reference laboratory established a panel of 148 samples, characterised by indirect enzyme-immunoassay (ELISA), indirect immunofluorescence, and complement fixation test. Fifty-seven samples were also studied by the fluorescence antibody to membrane antigen test. The geometric mean of the antibody activity (GMAA) obtained from four ELISA determinations was used to characterise each sample of the panel as positive (GMAA: >100 mIU/ml), equivocal (GMAA: 50-100 mIU/ml) or negative (GMAA: <50 mIU/ml) for antibody to VZV (anti-VZV). Thirteen laboratories, using five different ELISA tests, tested the panel. RESULTS: Agreement with the reference laboratory was above 85% in all cases, and the R(2) values obtained from regression analysis of the quantitative results were always higher than 0.87. Finally, the regression equations could be used to convert national values into a common unitage. CONCLUSION: This study confirmed that results for anti-VZV obtained by different ELISA methods can be converted into common units, enabling the comparison of the seroprevalence profiles obtained in the participant countries.

A new recombinant virus system for the study of HIV-1 entry and inhibition.

The construction is described of a HIV-1 proviral, eGFP-tagged plasmid that allows for the recombination of any selected env gene without the use of restriction enzymes and for the quantitation of the infection by the recombinant virus using flow cytometry. The system was tested showing that an isoleucine to valine substitution at residue position 37 of the HIV-1 gp41 impairs the fitness of the virus but does not lead by itself to T-20 resistance.

Rare and new V3 loop variants in HIV-1-positive long-term non-progressors from Rwanda.

We identified uncommon amino acid substitutions in the V3 loop regions of HIV-1 strains infecting patients from Rwanda. Their frequency was greater in long-term non-progressors (LTNP) compared with late-stage patients (P = 0.006), particularly in a sequence region that has crucial interactions with the cell surface, and is highly relevant for the host's immune response. These variants might reflect a viral response to a strong immune pressure, or represent attenuated HIV-1 strains infecting LTNP in Rwanda.

HIV-1 subtypes in Luxembourg, 1983-2000.

OBJECTIVES: To study the prevalence of HIV-1 subtypes in Luxembourg between 1983 and 2000. To compare the drug susceptibility of non-B and B clade viruses and the prevalence of resistance-associated mutations and polymorphisms before antiretroviral treatment. DESIGN: A retrospective study on plasma samples of HIV-infected patients registered at the National Service of Infectious Diseases, Luxembourg, between 1983 and 2000. METHODS: Genotyping was performed by sequencing of the reverse transcriptase (RT) and protease coding region of the pol gene. Drug susceptibility was assessed in a recombinant virus assay. RESULTS: A total of 20.1% of the HIV-positive patients were infected with non-B subtypes, and since 1990 the proportion of non-B viruses has increased ninefold. Eleven out of 14 F1 subtypes occurred in patients native to Luxembourg. Major resistance mutations related to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) occurred in less than 3% of treatment-naive viruses; however, 87% of the viruses had at least one PI-associated mutation. Natural polymorphism of the protease and RT coding region was observed more frequently among non-B than B viruses. Significantly more B viruses displayed resistance to the tested PI, NRTI and NNRTI (P = 0.044). CONCLUSION: The proportion of non-B viruses has increased dramatically since 1990. Non-B subtypes showed no decreased susceptibility to antiretroviral drugs, but displayed minor mutations and polymorphisms at higher frequency in their protease and RT coding region. In contrast, a significantly higher proportion of B viruses showed resistance to a range of antiretroviral drugs.

HIV type 1 pol gene diversity and archived nevirapine resistance mutation in pregnant women in Rwanda.

This study aimed to find out whether genetic polymorphisms were present in positions potentially affecting susceptibility to antiretrovirals in non-B subtypes from HIV-1-infected patients in Rwanda. Viral pol gene diversity was investigated by direct sequencing in 43 treatment-naive women. In addition, 10 DNA sequences from uncultured peripheral blood mononuclear cells were analyzed 6 weeks after a single dose of nevirapine (prevention of mother-to-child transmission program). Phylogenetic analyses have shown 34 subtype A1, 6 subtype C, and 2 subtype D strains. In addition, an A/C recombinant between the protease (PR) (subtype A1) and the reverse transcriptase (RT) (subtype C) was identified. In the PR coding region, high numbers of polymorphisms were found, including substitutions in secondary PR resistance sites. PR 35D, 36I, and 37N were always present within subtype A as were PR 93L in subtype C strains. PR 10I/V, 20R, 33F, and 77V were found in subtype A whereas PR 36I was highly prevalent in subtype C strains. The A/C recombinant displayed substitutions related to resistance (PR 10, 33, 36 and RT 118). One nevirapine resistance mutation (RT 181Y/C) was found in proviral DNA after 6 weeks. In conclusion, subtypes A and C are predominant in this cohort in Rwanda. Substitutions similar to secondary protease inhibitor resistance mutations are common before treatment whereas major resistance mutation may be archived after a single dose of nevirapine. Accordingly, the hypothesis of a genetic background effect in non-B strains has to be further addressed in programs of introduction of antivirals in Africa.

Resistance testing in children changing human immunodeficiency virus type 1 protease inhibitor.

OBJECTIVE: To assess genotypic and phenotypic resistance testing in HIV-1-infected children failing a first protease inhibitor (PI) therapy. METHODS: In a multicenter observational study 21 children, ages 3 to 16 years, were given two reverse transcriptase inhibitors and one PI (mainly ritonavir, n = 18). They were subsequently treated with single or dual PI-based therapy (predominantly nelfinavir, n = 10, or ritonavir-saquinavir, n = 7). Resistance testing was performed at the time of therapy switch via direct sequencing and a recombinant virus susceptibility assay. RESULTS: A total of 21 genotypic and 15 phenotypic resistance profiles were obtained. Most viruses displayed several reverse transcriptase mutations; however, 7 isolates maintained a wild-type protease. Ritonavir targeted the well-known pathway containing 82, 54, 46 and other secondary (nonactive site) mutations including T74A. No in vitro cross-resistance, i.e. > or = 8-fold resistance to saquinavir or amprenavir, was encountered. Secondary mutations enhanced the prediction of ritonavir resistance (i.e. L10I) and in vitro nelfinavir cross-resistance (i.e. K20R/I) conferred by primary (active site) resistance mutations. Either the 82, 54, 46 mutational genotype or the phenotype showing > or = 8-fold nelfinavir cross-resistance predicted a poorer virologic response to nelfinavir salvage therapy. CONCLUSION: In a small cohort of heavily pretreated pediatric patients, resistance testing appears to predict the response to nelfinavir as salvage for a ritonavir-based therapy. This is further supported by the correlation between ritonavir-selected mutations and in vitro nelfinavir cross-resistance. Prospective studies should assess clinical outcome in children undergoing regimen changes based on resistance testing.

Prevalence of HIV co-receptor polymorphisms in HIV-infected patients and uninfected volunteers in Luxembourg.

PURPOSE: To describe the prevalence of nine HIV-1 co-receptor polymorphisms in Luxembourg (CCR5-Delta 32, CCR5-58755-A/G, CCR5m303, CCR5-59029-A/G, CCR2-64I, CCR5-59653-C/T, CX(3) CR1-V249I, CX(3) CR1-T280M, and SDF1-3'A) in 288 HIV-1-infected patients and in 158 uninfected, healthy volunteers. METHOD: The presence of mutations was detected using PCR-restriction fragment length polymorphism (RFLP)-based methods. RESULTS: We did not find any significant differences in genotype distributions and allele frequencies between infected and uninfected participants in Luxembourg. The distribution of genotypes agreed in all groups with Hardy-Weinberg predicted proportions. CCR5-Delta 32 was significantly associated with HIV-1-infected slow progressor patients. CONCLUSION: Overall, allele frequencies were comparable to frequencies reported in previous studies in Caucasian populations.

[Recombinant virus assay: a rapid assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates].

OBJECTIVE: To establish a rapid assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates (Recombinant virus assay). METHODS: This procedure allows the generation of viable virus with SI phenotype by homologous recombination of a RT-PCR-derived pool of reverse transcriptase (RT) coding sequences into an RT-deleted, noninfectious proviral clone, pHIV delta RTBstE II. Then the drug susceptibility of recombinant virus to RT inhibitors can be assessed in the Hela CD4+ plaque reduction assays. RESULTS: Analysis of 7 HIV strains with SI or NSI phenotype showed that recombinant viruses accurately exhibited the same genotype as that of the original HIV1 isolates. The results of drug susceptibilities of HIV1 isolate got by recombinant virus assay were the same as that by standardized peripheral blood mononuclear cell culture assay. CONCLUSION: Recombinant virus assay is a rapid and accurate method to assess the drug sensitivity of HIV1 isolates with SI or NSI phenotype.

Emergence of oseltamivir-resistant influenza A H1N1 virus during the 2007-2008 winter season in Luxembourg: clinical characteristics and epidemiology.

Human cases of oseltamivir-resistant influenza A H1N1 virus emerging in 2007-2008 in Luxembourg were not associated with treatment, prophylaxis or stockpiling of oseltamivir. Following initial local seeding, oseltamivir-resistant strains spread synchronously to sensitive strains causing a similar epidemiology and clinical symptoms.

European Sero-Epidemiology Network 2: standardisation of immunoassay results for pertussis requires homogeneity in the antigenic preparations.

A standardisation process, already developed during the earlier European Sero-Epidemiology Network (ESEN) project, was employed with a more robust algorithm to harmonise results of pertussis serological assays performed in 12 European and non-European countries. Initially, results from each country's own assay were compared with those obtained at the reference laboratory by means of an in-house pertussis toxin (PT)-based ELISA: seven countries used in-house or commercial PT-ELISAs; the other countries used assays based on Bordetella pertussis whole cell extracts (WCE) (three countries) or on combined PT-FHA (filamentous haemagglutinin) antigenic preparations (two countries). The WCE assays, although admitted for diagnostic purposes, confirmed their low correlation with the PT-ELISAs and their results could not be used for standardisation; the PT-FHA ELISAs gave results that were suitable for standardisation in one country but unsatisfactory in the other; the use of purified PT in serological assays confirmed its better reliability than other preparations and all PT-ELISAs results could be calibrated against those of the reference centre. In the standardisation process two high-titre cut-offs indicative of likelihood of recent infection (from within 4 weeks of disease onset up to 1 year after) were included for evaluations as they are suggested to be more useful, for the sero-epidemiological assays of immunity to pertussis, than the cut-off of protection, commonly employed, but still not defined for pertussis. Providing PT-ELISAs are used, standardisation of pertussis assay results is always possible and, when standardisation is performed, evaluation and comparison of the impact of different interventions can be also allowed, by measuring at the distribution of high antibody titres in the populations.

Waning antibodies in measles and rubella vaccinees--a longitudinal study.

The evolution of measles- and rubella-specific serum IgG was followed in a longitudinal study in 224 young adolescent vaccinees, with or without boost vaccination before or during the 6.8-year observation period. Antibody titres were monitored by enzyme immuno assay (Enzygnost, Dade-Behring). After revaccination (second dose) rubella seropositivity rate increased from 92.1 to 100%, whereas measles seroprevalence (about 90%) did not significantly change between the paired sera. Significantly higher IgG (> three-fold) in the second serum of 5.2% (measles) and 7.8% (rubella) of participants with low antibodies (measles: < 1500 mIU; rubella < 40 IU) in first serum, suggest a secondary immune response (SIR) during the study period, only partially explained by revaccination. Excluding individuals with SIR, minimal annual antibody decay rates of -2.9% (confidence interval, CI: -0.7 to -4.8%) for rubella and -1.6% (CI: -0.1 to -3%) for measles were determined in participants with single dose vaccination. Thus, two-dose vaccination was adequate to protect women from rubella infection at least during childbearing age. Similarly only few individuals may become seronegative for measles again after successful vaccination due to minimal waning of low antibody levels (< 1500 mIU). However, as a result of a more rapid decay of high-titre (> 1500 mIU) antibodies (-2.4%/year), many vaccinees may eventually become susceptible to vaccine-modified measles (VMM) and consequently complicate measles control strategies.

The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes.

BACKGROUND: The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe. METHODS: The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype. RESULTS: Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes. CONCLUSIONS: Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.