Chemical resistance of the gram-negative bacteria to different sanitizers in a water purification system

Abstract Background Purified water for pharmaceutical purposes must be free of microbial contamination and pyrogens. Even with the additional sanitary and disinfecting treatments applied to the system (sequential operational stages), Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas alcaligenes, Pseudomonas picketti, Flavobacterium aureum, Acinetobacter lowffi and Pseudomonas diminuta were isolated and identified from a thirteen-stage purification system. To evaluate the efficacy of the chemical agents used in the disinfecting process along with those used to adjust chemical characteristics of the system, over the identified bacteria, the kinetic parameter of killing time (D-value) necessary to inactivate 90% of the initial bioburden (decimal reduction time) was experimentally determined. Methods Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas alcaligenes, Pseudomonas picketti, Flavobacterium aureum, Acinetobacter lowffi and Pseudomonas diminuta were called in house (wild) bacteria. Pseudomonas diminuta ATCC 11568, Pseudomonas alcaligenes INCQS , Pseudomonas aeruginosa ATCC 15442, Pseudomonas fluorescens ATCC 3178, Pseudomonas picketti ATCC 5031, Bacillus subtilis ATCC 937 and Escherichia coli ATCC 25922 were used as 'standard' bacteria to evaluate resistance at 25°C against either 0.5% citric acid, 0.5% hydrochloric acid, 70% ethanol, 0.5% sodium bisulfite, 0.4% sodium hydroxide, 0.5% sodium hypochlorite, or a mixture of 2.2% hydrogen peroxide (H2O2) and 0.45% peracetic acid. Results The efficacy of the sanitizers varied with concentration and contact time to reduce decimal logarithmic (log10) population (n cycles). To kill 90% of the initial population (or one log10 cycle), the necessary time (D-value) was for P. aeruginosa into: (i) 0.5% citric acid, D = 3.8 min; (ii) 0.5% hydrochloric acid, D = 6.9 min; (iii) 70% ethanol, D = 9.7 min; (iv) 0.5% sodium bisulfite, D = 5.3 min; (v) 0.4% sodium hydroxide, D = 14.2 min; (vi) 0.5% sodium hypochlorite, D = 7.9 min; (vii) mixture of hydrogen peroxide (2.2%) plus peracetic acid (0.45%), D = 5.5 min. Conclusion The contact time of 180 min of the system with the mixture of H2O2+ peracetic acid, a total theoretical reduction of 6 log10 cycles was attained in the water purified storage tank and distribution loop. The contact time between the water purification system (WPS) and the sanitary agents should be reviewed to reach sufficient bioburden reduction (over 6 log10).

Nutritional strategies to control mycotoxin damages in swine

Mycotoxins are contaminants of agricultural products both in the field and during storage and can enter the food chain through contaminated cereals and foods (milk, meat, and eggs) obtained from animals fed mycotoxin contaminated feeds. Mycotoxins are genotoxic carcinogens that cause health and economic problems. Ochratoxin A and fumonisin B1 have been classified by the International Agency for Research on Cancer in 1993, as “possibly carcinogenic to humans” (class 2B). To control mycotoxins induced damages, different strategies have been developed to reduce the growth of mycotoxigenic fungi as well as to decontaminate and/or detoxify mycotoxin contaminated foods and animal feeds. Critical points, target for these strategies, are: prevention of mycotoxin contamination, detoxification of mycotoxins already present in food and feed, inhibition of mycotoxin absorption in the gastrointestinal tract, reduce mycotoxin induced damages when absorption occurs. Decontamination processes, as indicate by FAO, needs the following requisites to reduce toxic and economic impact of mycotoxins: it must destroy, inactivate, or remove mycotoxins; it must not produce or leave toxic and/or carcinogenic/mutagenic residues in the final products or in food products obtained from animals fed decontaminated feed; it must be capable of destroying fungal spores and mycelium in order to avoiding mycotoxin formation under favorable conditions; it should not adversely affect desirable physical and sensory properties of the feedstuff; it has to be technically and economically feasible. One important approach to the prevention of mycotoxicosis in livestock is the addition in the diets of the non-nutritionally adsorbents that bind mycotoxins preventing the absorption in the gastrointestinal tract. Activated carbons, hydrated sodium calcium aluminosilicate (HSCAS), zeolites, bentonites, and certain clays, are the most studied adsorbent and they possess a high affinity for mycotoxins. In recent years, there has been increasing interest on the hypothesis that the absorption in consumed food can be inhibited by microorganisms in the gastrointestinal tract. Numerous investigators showed that some dairy strains of LAB and bifidobacteria were able to bind aflatoxins effectively. There is a strong need for prevention of the mycotoxin-induced damages once the toxin is ingested. Nutritional approaches, such as supplementation of nutrients, food components, or additives with protective effects against mycotoxin toxicity are assuming increasing interest. Since mycotoxins have been known to produce damages by increasing oxidative stress, the protective properties of antioxidant substances have been extensively investigated. Purpose of the present study was to investigate in vitro and in vivo, strategies to counteract mycotoxin threat particularly in swine husbandry. The Ussing chambers technique was applied in the present study that for the first time to investigate in vitro the permeability of OTA and FB1 through rat intestinal mucosa. Results showed that OTA and FB1 were not absorbed from rat small intestine mucosa. Since in vivo absorption of both mycotoxins normally occurs, it is evident that in these experimental conditions Ussing diffusion chambers were not able to assess the intestinal permeability of OTA and FB1. A large number of LAB strains isolated from feces and different gastrointestinal tract regions of pigs and poultry were screened for their ability to remove OTA, FB1, and DON from bacterial medium. Results of this in vitro study showed low efficacy of isolated LAB strains to reduce OTA, FB1, and DON from bacterial medium. An in vivo trial in rats was performed to evaluate the effects of in-feed supplementation of a LAB strain, Pediococcus pentosaceus FBB61, to counteract the toxic effects induced by exposure to OTA contaminated diets. The study allows to conclude that feed supplementation with P. pentosaceus FBB61 ameliorates the oxidative status in liver, and lowers OTA induced oxidative damage in liver and kidney if diet was contaminated by OTA. This P. pentosaceus FBB61 feature joined to its bactericidal activity against Gram positive bacteria and its ability to modulate gut microflora balance in pigs, encourage additional in vivo experiments in order to better understand the potential role of P. pentosaceus FBB61 as probiotic for farm animals and humans. In the present study, in vivo trial on weaned piglets fed FB1 allow to conclude that feeding of 7.32 ppm of FB1 for 6 weeks did not impair growth performance. Deoxynivalenol contamination of feeds was evaluated in an in vivo trial on weaned piglets. The comparison between growth parameters of piglets fed DON contaminated diet and contaminated diet supplemented with the commercial product did not reach the significance level but piglet growth performances were numerically improved when the commercial product was added to DON contaminated diet. Further studies are needed to improve knowledge on mycotoxins intestinal absorption, mechanism for their detoxification in feeds and foods, and nutritional strategies to reduce mycotoxins induced damages in animals and humans. The multifactorial approach acting on each of the various steps could be a promising strategy to counteract mycotoxins damages.

Thermochronologic and geodynamic evolution of the Pontides: Sakarya terrane (Karakaya Complex) and Istanbul terrane, Turkey.

An integrated array of analytical methods -including clay mineralogy, vitrinite reflectance, Raman spectroscopy on carbonaceous material, and apatite fission-track analysis- was employed to constrain the thermal and thermochronological evolution of selected portions of the Pontides of northern Turkey. (1) A multimethod investigation was applied for the first time to characterise the thermal history of the Karakaya Complex, a Permo-Triassic subduction-accretion complex cropping out throughout the Sakarya Zone. The results indicate two different thermal regimes: the Lower Karakaya Complex (Nilüfer Unit) -mostly made of metabasite and marble- suffered peak temperatures of 300-500°C (greenschist facies); the Upper Karakaya Complex (Hodul and the Orhanlar Units) –mostly made of greywacke and arkose- yielded heterogeneous peak temperatures (125-376°C), possibly the result of different degree of involvement of the units in the complex dynamic processes of the accretionary wedge. Contrary to common belief, the results of this study indicate that the entire Karakaya Complex suffered metamorphic conditions. Moreover, a good degree of correlation among the results of these methods demonstrate that Raman spectroscopy on carbonaceous material can be applied successfully to temperature ranges of 200-330°C, thus extending the application of this method from higher grade metamorphic contexts to lower grade metamorphic conditions. (2) Apatite fission-track analysis was applied to the Sakarya and the İstanbul Zones in order to constrain the exhumation history and timing of amalgamation of these two exotic terranes. AFT ages from the İstanbul and Sakarya terranes recorded three distinct episodes of exhumation related to the complex tectonic evolution of the Pontides. (i) Paleocene - early Eocene ages (62.3-50.3 Ma) reflect the closure of the İzmir-Ankara ocean and the ensuing collision between the Sakarya terrane and the Anatolide-Tauride Block. (ii) Late Eocene - earliest Oligocene (43.5-32.3 Ma) ages reflect renewed tectonic activity along the İzmir-Ankara. (iii) Late Oligocene- Early Miocene ages reflect the onset and development of the northern Aegean extension. The consistency of AFT ages, both north and south of the tectonic contact between the İstanbul and Sakarya terranes, suggest that such terranes were amalgamated in pre-Cenozoic times. (3) Fission-track analysis was also applied to rock samples from the Marmara region, in an attempt to constrain the inception and development of the North Anatolian Fault system in the region. The results agree with those from the central Pontides. The youngest AFT ages (Late Oligocene - early Miocene) were recorded in the western portion of the Marmara Sea region and reflect the onset and development of northern Aegean extension. Fission-track data from the eastern Marmara Sea region indicate rapid Early Eocene exhumation induced by the development of the İzmir-Ankara orogenic wedge. Thermochronological data along the trace of the Ganos Fault –a segment of the North Anatolian Fault system- indicate the presence of a tectonic discontinuity active by Late Oligocene time, i.e. well before the arrival of the North Anatolian Fault system in the area. The integration of thermochronologic data with preexisting structural data point to the existence of a system of major E-W-trending structural discontinuities active at least from the Late Oligocene. In the Early Pliocene, inception of the present-day North Anatolian Fault system in the Marmara region occurred by reactivation of these older tectonic structures. 


Analysis and developments of uncertainty processors for real time flood forecasting

The hydrologic risk (and the hydro-geologic one, closely related to it) is, and has always been, a very relevant issue, due to the severe consequences that may be provoked by a flooding or by waters in general in terms of human and economic losses. Floods are natural phenomena, often catastrophic, and cannot be avoided, but their damages can be reduced if they are predicted sufficiently in advance. For this reason, the flood forecasting plays an essential role in the hydro-geological and hydrological risk prevention. Thanks to the development of sophisticated meteorological, hydrologic and hydraulic models, in recent decades the flood forecasting has made a significant progress, nonetheless, models are imperfect, which means that we are still left with a residual uncertainty on what will actually happen. In this thesis, this type of uncertainty is what will be discussed and analyzed. In operational problems, it is possible to affirm that the ultimate aim of forecasting systems is not to reproduce the river behavior, but this is only a means through which reducing the uncertainty associated to what will happen as a consequence of a precipitation event. In other words, the main objective is to assess whether or not preventive interventions should be adopted and which operational strategy may represent the best option. The main problem for a decision maker is to interpret model results and translate them into an effective intervention strategy. To make this possible, it is necessary to clearly define what is meant by uncertainty, since in the literature confusion is often made on this issue. Therefore, the first objective of this thesis is to clarify this concept, starting with a key question: should be the choice of the intervention strategy to adopt based on the evaluation of the model prediction based on its ability to represent the reality or on the evaluation of what actually will happen on the basis of the information given by the model forecast? Once the previous idea is made unambiguous, the other main concern of this work is to develope a tool that can provide an effective decision support, making possible doing objective and realistic risk evaluations. In particular, such tool should be able to provide an uncertainty assessment as accurate as possible. This means primarily three things: it must be able to correctly combine all the available deterministic forecasts, it must assess the probability distribution of the predicted quantity and it must quantify the flooding probability. Furthermore, given that the time to implement prevention strategies is often limited, the flooding probability will have to be linked to the time of occurrence. For this reason, it is necessary to quantify the flooding probability within a horizon time related to that required to implement the intervention strategy and it is also necessary to assess the probability of the flooding time.

Towards a new test of time dilation: Laser spectroscopy on lithium ions stored at a velocity of 33.8 % of the speed of light

The subject of the presented thesis is the accurate measurement of time dilation, aiming at a quantitative test of special relativity. By means of laser spectroscopy, the relativistic Doppler shifts of a clock transition in the metastable triplet spectrum of ^7Li^+ are simultaneously measured with and against the direction of motion of the ions. By employing saturation or optical double resonance spectroscopy, the Doppler broadening as caused by the ions' velocity distribution is eliminated. From these shifts both time dilation as well as the ion velocity can be extracted with high accuracy allowing for a test of the predictions of special relativity. A diode laser and a frequency-doubled titanium sapphire laser were set up for antiparallel and parallel excitation of the ions, respectively. To achieve a robust control of the laser frequencies required for the beam times, a redundant system of frequency standards consisting of a rubidium spectrometer, an iodine spectrometer, and a frequency comb was developed. At the experimental section of the ESR, an automated laser beam guiding system for exact control of polarisation, beam profile, and overlap with the ion beam, as well as a fluorescence detection system were built up. During the first experiments, the production, acceleration and lifetime of the metastable ions at the GSI heavy ion facility were investigated for the first time. The characterisation of the ion beam allowed for the first time to measure its velocity directly via the Doppler effect, which resulted in a new improved calibration of the electron cooler. In the following step the first sub-Doppler spectroscopy signals from an ion beam at 33.8 %c could be recorded. The unprecedented accuracy in such experiments allowed to derive a new upper bound for possible higher-order deviations from special relativity. Moreover future measurements with the experimental setup developed in this thesis have the potential to improve the sensitivity to low-order deviations by at least one order of magnitude compared to previous experiments; and will thus lead to a further contribution to the test of the standard model.

Mechanisms Contributing to Tyrosin Kinase Inhibitor Resistance in GISTs: Toward a Personalized Therapy

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. This work considers the pharmacological response in GIST patients treated with imatinib by two different angles: the genetic and somatic point of view. We analyzed polymorphisms influence on treatment outcome, keeping in consideration SNPs in genes involved in drug transport and folate pathway. Naturally, all these intriguing results cannot be considered as the only main mechanism in imatinib response. GIST mainly depends by oncogenic gain of function mutations in tyrosin kinase receptor genes, KIT or PDGFRA, and the mutational status of these two genes or acquisition of secondary mutation is considered the main player in GIST development and progression. To this purpose we analyzed the secondary mutations to better understand how these are involved in imatinib resistance. In our analysis we considered both imatinib and the second line treatment, sunitinib, in a subset of progressive patients. KIT/PDGFRA mutation analysis is an important tool for physicians, as specific mutations may guide therapeutic choices. Currently, the only adaptations in treatment strategy include imatinib starting dose of 800 mg/daily in KIT exon-9-mutated GISTs. In the attempt to individualize treatment, genetic polymorphisms represent a novelty in the definition of biomarkers of imatinib response in addition to the use of tumor genotype. Accumulating data indicate a contributing role of pharmacokinetics in imatinib efficacy, as well as initial response, time to progression and acquired resistance. At the same time it is becoming evident that genetic host factors may contribute to the observed pharmacokinetic inter-patient variability. Genetic polymorphisms in transporters and metabolism may affect the activity or stability of the encoded enzymes. Thus, integrating pharmacogenetic data of imatinib transporters and metabolizing genes, whose interplay has yet to be fully unraveled, has the potential to provide further insight into imatinib response/resistance mechanisms.

When Beauty Goes to Sleep: an analysis of the symbolism behind the sleeping beauty tale

Approaching the world of the fairy tale as an adult, one soon realizes that things are not what they once seemed during story time in bed. Something that once appeared so innocent and simple can become rather complex when digging into its origin. A kiss, for example, can mean something else entirely. I can clearly remember my sister, who is ten years older than I am, telling me that the fairy tales I was told had a mysterious hidden meaning I could not understand. I was probably 9 or 10 when she told me that the story of Sleeping Beauty, which I used to love so much in Disney’s rendering, was nothing more than the story of an adolescent girl, with all the necessary steps needed to become a woman, the bleeding of menstruation and the sexual awakening - even though she did not really put it in these terms. This shocking news troubled me for a while, so much so that I haven’t watched that movie since. But in reality it was not fear that my sister had implanted in me: it was curiosity, the feeling that I was missing something terribly important behind the words and images. But it was not until last year during my semester abroad in Germany, where I had the chance to take a very interesting English literature seminar, that I fully understood what I had been looking for all these years. Thanks to what I learned from the work of Bruno Bettelheim, Jack Zipes, Vladimir Propp, and many other authors that wrote extensively about the subject, I feel I finally have the right tools to really get to know this fairy tale. But what I also know now is that the message behind fairy tales is not to be searched for behind only one version: on the contrary, since they come from oral traditions and their form was slowly shaped by centuries of recountals and retellings, the more one digs, the more complete the understanding of the tale will be. I will therefore look for Sleeping Beauty’s hidden meaning by looking for the reason why it did stick so consistently throughout time. To achieve this goal, I have organized my analysis in three chapters: in the first chapter, I will analyze the first known literary version of the tale, the French Perceforest, and then compare it with the following Italian version, Basile’s Sun, Moon, and Talia; in the second chapter, I will focus on the most famous and by now classical literary versions of Sleeping Beauty, La Belle Au Bois Dormant, written by the Frenchman, Perrault, and the German Dornröschen, recorded by the Brothers Grimm’s; finally, in the last chapter, I will analyze Almodovar’s film Talk to Her as a modern rewriting of this tale, which after a closer look, appears closely related to the earliest version of the story, Perceforest.

Vertical bias in neglect: A question of time?

Neglect is defined as the failure to attend and to orient to the contralesional side of space. A horizontal bias towards the right visual field is a classical finding in patients who suffered from a right-hemispheric stroke. The vertical dimension of spatial attention orienting has only sparsely been investigated so far. The aim of this study was to investigate the specificity of this vertical bias by means of a search task, which taps a more pronounced top-down attentional component. Eye movements and behavioural search performance were measured in thirteen patients with left-sided neglect after right hemispheric stroke and in thirteen age-matched controls. Concerning behavioural performance, patients found significantly less targets than healthy controls in both the upper and lower left quadrant. However, when targets were located in the lower left quadrant, patients needed more visual fixations (and therefore longer search time) to find them, suggesting a time-dependent vertical bias.

Atorvastatin added to interferon beta for relapsing multiple sclerosis: a randomized controlled trial

Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects. The present study evaluated the effect of atorvastatin added to interferon beta-1b in multiple sclerosis (MS) in a multicenter, randomized, parallel-group, rater-blinded study performed in eight Swiss hospitals. Seventy-seven patients with relapsing-remitting MS started interferon beta-1b every other day. After 3 months, they were randomized 1:1 to receive atorvastatin 40 mg/day or not in addition to interferon beta-1b until month 15. The primary endpoint was the proportion of patients with new lesions on T2-weighted images at month 15 compared to baseline at month three. At study end, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.14; 95 % CI 0.36-3.56; p = 0.81). All predefined secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of new Gd-enhancing lesions on T1-weighted images, total brain volume, volume of grey matter, volume of white matter, EDSS, MSFC, relapse rate, time to first relapse, number of relapse-free patients and neutralizing antibodies did not show any significant differences (all p values >0.1). Transient elevations of liver enzymes were more frequent with atorvastatin (p = 0.02). In conclusion, atorvastatin 40 mg/day in addition to interferon beta-1b did not have a beneficial effect on relapsing-remitting MS compared to interferon beta-1b monotherapy over a 12-month period.

SPIRIT Women, evaluation of the safety and efficacy of the XIENCE V everolimus-eluting stent system in female patients: referral time for coronary intervention and 2-year clinical outcomes

SPIRIT Women is the first interventional trial dedicated exclusively to women, focusing on symptoms at presentation, referral time to coronary intervention and the safety and performance of the XIENCE V stent.

A new double-tracer gas single-breath washout to assess early cystic fibrosis lung disease

In cystic fibrosis (CF), tests for ventilation inhomogeneity are sensitive but not established for clinical routine. We assessed feasibility of a new double-tracer gas single-breath washout (SBW) in school-aged children with CF and control subjects, and compared SBW between groups and with multiple-breath nitrogen washout (MBNW). Three SBW and MBNW were performed in 118 children (66 with CF) using a side-stream ultrasonic flowmeter setup. The double-tracer gas containing 5% sulfur hexafluoride and 26.3% helium was applied during one tidal breath. Outcomes were SBW phase III slope (SIII(DTG)), MBNW-derived lung clearance index (LCI), and indices of acinar (S(acin)) and conductive (S(cond)) ventilation inhomogeneity. SBW took significantly less time to perform than MBNW. SBW and MBNW were feasible in 109 (92.4%) and 98 (83.0%) children, respectively. SIII(DTG) differed between children with CF and controls, mean±sd was -456.7±492.8 and -88.4±129.1 mg·mol·L(-1), respectively. Abnormal SIII(DTG) was present in 36 (59%) children with CF. SIII(DTG) was associated with LCI (r= -0.58) and S(acin) (r= -0.58), but not with S(cond). In CF, steeply sloping SIII(DTG) potentially reflects ventilation inhomogeneity near the acinus entrance. This tidal SBW is a promising test to assess ventilation inhomogeneity in an easy and fast way.

Duration of methicillin-resistant Staphylococcus aureus carriage, according to risk factors for acquisition

OBJECTIVE: To examine the duration of methicillin-resistant Staphylococcus aureus (MRSA) carriage and its determinants and the influence of eradication regimens. DESIGN: Retrospective cohort study. SETTING: A 1,033-bed tertiary care university hospital in Bern, Switzerland, in which the prevalence of methicillin resistance among S. aureus isolates is less than 5%. PATIENTS: A total of 116 patients with first-time MRSA detection identified at University Hospital Bern between January 1, 2000, and December 31, 2003, were followed up for a mean duration of 16.2 months. RESULTS: Sixty-eight patients (58.6%) cleared colonization, with a median time to clearance of 7.4 months. Independent determinants for shorter carriage duration were the absence of any modifiable risk factor (receipt of antibiotics, use of an indwelling device, or presence of a skin lesion) (hazard ratio [HR], 0.20 [95% confidence interval {CI}, 0.09-0.42]), absence of immunosuppressive therapy (HR, 0.49 [95% CI, 0.23-1.02]), and hemodialysis (HR, 0.08 [95% CI, 0.01-0.66]) at the time MRSA was first MRSA detected and the administration of decolonization regimen in the absence of a modifiable risk factor (HR, 2.22 [95% CI, 1.36-3.64]). Failure of decolonization treatment was associated with the presence of risk factors at the time of treatment (P=.01). Intermittent screenings that were negative for MRSA were frequent (26% of patients), occurred early after first detection of MRSA (median, 31.5 days), and were associated with a lower probability of clearing colonization (HR, 0.34 [95% CI, 0.17-0.67]) and an increased risk of MRSA infection during follow-up. CONCLUSIONS: Risk factors for MRSA acquisition should be carefully assessed in all MRSA carriers and should be included in infection control policies, such as the timing of decolonization treatment, the definition of MRSA clearance, and the decision of when to suspend isolation measures.

Immunologic response to antiretroviral therapy in hepatitis C virus-coinfected adults in a population-based HIV/AIDS treatment program

BACKGROUND: We sought to characterize the impact that hepatitis C virus (HCV) infection has on CD4 cells during the first 48 weeks of antiretroviral therapy (ART) in previously ART-naive human immunodeficiency virus (HIV)-infected patients. METHODS: The HIV/AIDS Drug Treatment Programme at the British Columbia Centre for Excellence in HIV/AIDS distributes all ART in this Canadian province. Eligible individuals were those whose first-ever ART included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor and who had a documented positive result for HCV antibody testing. Outcomes were binary events (time to an increase of > or = 75 CD4 cells/mm3 or an increase of > or = 10% in the percentage of CD4 cells in the total T cell population [CD4 cell fraction]) and continuous repeated measures. Statistical analyses used parametric and nonparametric methods, including multivariate mixed-effects linear regression analysis and Cox proportional hazards analysis. RESULTS: Of 1186 eligible patients, 606 (51%) were positive and 580 (49%) were negative for HCV antibodies. HCV antibody-positive patients were slower to have an absolute (P<.001) and a fraction (P = .02) CD4 cell event. In adjusted Cox proportional hazards analysis (controlling for age, sex, baseline absolute CD4 cell count, baseline pVL, type of ART initiated, AIDS diagnosis at baseline, adherence to ART regimen, and number of CD4 cell measurements), HCV antibody-positive patients were less likely to have an absolute CD4 cell event (adjusted hazard ratio [AHR], 0.84 [95% confidence interval [CI], 0.72-0.98]) and somewhat less likely to have a CD4 cell fraction event (AHR, 0.89 [95% CI, 0.70-1.14]) than HCV antibody-negative patients. In multivariate mixed-effects linear regression analysis, HCV antibody-negative patients had increases of an average of 75 cells in the absolute CD4 cell count and 4.4% in the CD4 cell fraction, compared with 20 cells and 1.1% in HCV antibody-positive patients, during the first 48 weeks of ART, after adjustment for time-updated pVL, number of CD4 cell measurements, and other factors. CONCLUSION: HCV antibody-positive HIV-infected patients may have an altered immunologic response to ART.

Markers Models in Survival Analysis and Applications to Issues Associated with AIDS

Jewell and Kalbfleisch (1992) consider the use of marker processes for applications related to estimation of the survival distribution of time to failure. Marker processes were assumed to be stochastic processes that, at a given point in time, provide information about the current hazard and consequently on the remaining time to failure. Particular attention was paid to calculations based on a simple additive model for the relationship between the hazard function at time t and the history of the marker process up until time t. Specific applications to the analysis of AIDS data included the use of markers as surrogate responses for onset of AIDS with censored data and as predictors of the time elapsed since infection in prevalent individuals. Here we review recent work on the use of marker data to tackle these kinds of problems with AIDS data. The Poisson marker process with an additive model, introduced in Jewell and Kalbfleisch (1992) may be a useful "test" example for comparison of various procedures.

Smooth Hazard Function Estimation for Interval Censored Data with Time Varying Covariates

In this paper we propose methods for smooth hazard estimation of a time variable where that variable is interval censored. These methods allow one to model the transformed hazard in terms of either smooth (smoothing splines) or linear functions of time and other relevant time varying predictor variables. We illustrate the use of this method on a dataset of hemophiliacs where the outcome, time to seroconversion for HIV, is interval censored and left-truncated.