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Dispositionalism is the theory of modality that grounds all modal truths in powers: all metaphysically possible and necessary truths are to be explained by pointing to some actual power, or absence thereof. One of the main reasons to endorse dispositionalism is that it promises to deliver an especially desirable epistemology of modality. However, so far this issue has not be fully investigated with the care it is due. The aim of this paper is to fill this gap. We will cast some doubts on whether the dispositionalist really is in a better position to explain our modal knowledge. In fact, we argue that there is a tension between some core tenets of a powers metaphysics and the very features that make dispositionalism the ideal backdrop for a desirable epistemology of modality. We conclude that this leaves dispositionalists who want to deliver the promised epistemology with a hard, currently unfulfilled, task.

In this paper I argue that even the most radical metaphysics of powers (such as that adopted by Mumford and Anjum, Cartwright, or Groff) are compatible with eternalism. I first offer a taxonomy of powers ontologies, and attempt to characterise the difference between moderate and radical powers ontologies—the latter are characterised by an emphasis on production and dynamicity. I consider an argument by C. Friebe to the effect that the productive character of powers is inconsistent with Eternalism and find it wanting. I then elucidate the notion of dynamicity that radical powers theorists employ by making apparent their link with an ontology of irreducible processes. Finally, I respond to an argument by Donatella Donati to the effect that eternalism entails a reductive account of change which is inconsistent with process ontologies, and show that the the two are compatible. I conclude that we have no reason to think that radical powers metaphysics (and, a fortiori, every powers ontology) are not compatible with eternalism.

Establishing Dispositionalism as a viable theory of modality requires the successful fulfilment of two tasks: (i) showing that all modal truths can be derived from truths about actual powers, and (ii) offering a suitable metaphysics of powers. These two tasks are intertwined: difficulties in one can affect the chances of success in the other. In this paper, I generalise an objection to Dispositionalism by Jessica Leech and argue that the theory in its present form is ill-suited to account for de re truths about merely possible entities. I argue that such difficulty is rooted in a problem in the metaphysics of powers. In particular, I contend that the well-known tension between two key principle of powers ontology, namely Directedness (all powers are “for” their manifestation) and Independence (some powers might fail to bring about their manifestation) has received an unsatisfactory solution so far, and that it is this unsatisfactory solution concerning the status of “unmanifested manifestations” that makes it hard for Dispositionalism to account for mere possibilia. I develop a novel account of the status of unmanifested manifestations and an overall metaphysics of powers which allows to better respond to Leech's objection and handle mere possibilia. The central idea of the proposal is that unmanifested manifestations are akin to mere logical existents, and are best characterised as non-essentially non-located entities.

In many forensic cases, the medical records of the deceased are not available at the time of the autopsy; therefore, no information about the deceased's state of health, including any infectious diseases contracted during life, is accessible. The detection of some of the principal viral infections, such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus type 1 (HIV-1), could contribute to determining causes of death and interesting applications could be found in medico-legal practice, such as occupational risk assessment. To date, accurate and sensitive serological and molecular assays capable of detecting these viruses have been validated on biological samples taken from living beings, while their efficiency on forensic post-mortem biological samples has yet to be thoroughly assessed. To further this aim, this study evaluated whether the nucleic acid amplification techniques (NAATs) for the detection of viral genomes that are applied in clinical settings can be used, with the same success rate, for these latter samples.Manual viral nucleic acid extraction processes and fully-automated amplification-based detection techniques developed in-house were evaluated on blood samples taken during the routine autopsies of 21 cadavers performed 2 to 9 days after death. Information on HBV, HCV, and HIV-1 seropositive status was previously known for only four of these cadavers.Using automated quantitative real-time PCR (qPCR) and qualitative PCR (end-point) analyses, it was possible to confirm the presence of viral genomes in the four post-mortem whole blood samples with previously reported specific serological positivity. In addition, the genomes of HCV and/or HIV-1 genomes were detected in three other blood samples with unknown serological status at the time of autopsy.Therefore, our findings suggest that molecular assays may detect the presence of viral genomes in forensic post-mortem blood samples up to five days after death. This provides an additional means of investigation that can contribute to the determination of the deceased's cause of death.

Monozygotic twins, also known as monovular twins, share an identical genetic heritage because they are two individuals who derive from the same zygote. For this reason, they have been considered indistinguishable. They represent a limit for the application of markers and analytical methods that are routinely used in forensic science because analyses of DNA fragments (short tandem repeats analysed by capillary electrophoresis) are unable to distinguish monozygotic twins. The recent introduction of ultra-deep next generation sequencing in forensic genetics, also known as massively parallel sequencing, has made it possible to identify a number of genetic variations through genome sequencing (such as copy number variations, single nucleotide polymorphisms and DNA methylation) that make it possible to distinguish monozygotic twins. Here, we present a case of ascertaining biological paternity, in which the alleged father had a monozygotic twin brother. This case led to the examination of international law in similar cases in which the only available biological evidence derives from classical forensic genetic analysis, performed with short tandem repeat (autosomal and/or gonosomal) capillary electrophoresis and the probative value, if recognised, of the next generation sequencing technology in the courtroom.

The morphology of carbonized materials resulting from an intumescence phenomenon was studied. The investigated material is a polyurethane matrix filled either by 30 wt.-% of ammonium polyphosphate or by a combination of 28 wt.-% of ammonium polyphosphate and 2 wt.-% of nano-magnesium oxide. These fillers were incorporated in the polyurethane directly during the synthesis step. The carbonized materials or char, are obtained in a specific fire scenario. Characterization of their morphology is carried out using X-ray computed tomography. The heat conductivity of the systems is additionally measured as a function of temperature in order to correlate structure and properties of the intumescent residues. The formation of different char structures with incorporation of magnesium oxide (in particular formation of bubbles of different size) is first evidenced. These observations are consistent with the heat conductivity data. Tomography images demonstrate that the intumescence process is a dynamic process since non degraded polymer is left at the beginning of the fire test, which is not the case for longer time. The dispersion of fillers has finally been investigated in the chars and it is evidenced different steps of intumescence's development in the material.

This work investigates the parameters influencing the mechanical resistance of intumescent chars. A polyurethane matrix containing 30 wt% of ammonium polyphosphate was used in this study as intumescent model system. Three heating devices (rheometer furnace, mass loss calorimeter, and tubular oven) were used as heat treatment scenarios to obtain a charred structure. This char is then analyzed by measuring its compression resistance using a protocol involving a plate–plate rheometer (estimation of the char strength). The study of the char strength reveals that the presence of a flame, the heating type (convective or radiative heating), and the quenching temperature do not modify the mechanical properties of the resulting intumescent char. On the contrary, it was found that the critical parameters involved in the formation of a resistant char are the heating temperature and the heating rate. The strongest charred structure is reached after a heat treatment at 10°C/min until 500°C. Additionally, the modification of the temperature at which the mechanical test is performed (linked to the experimental protocol) leads also to different mechanical resistance of the tested materials.

Fabrication of hierarchical porous thin films with controlled pore dimension and shape is a current challenge in materials science. In this work, bimodal hierarchical hybrid organic−inorganic thin films with pores in the meso and macro range have been fabricated. The first order of porosity is obtained through a self-assembly process using organic block copolymers as templates for mesopores; the mesophase in the films is well-ordered and has a tetragonal symmetry. We have introduced fluorinated organic nanoparticles of around 70 nm in the precursor solution to act as template of the second order of porosity. The introduction of the nanoparticles has not affected the organization of the mesophase and after the film deposition the nanoparticles become randomly dispersed within the mesostructured matrix. The organization of the mesophase has been studied in situ by small-angle X-ray scattering using synchrotron light; conventional and high-resolution transmission electron microscopy have been used for direct...

Objective The development of drugs that can be used as topical microbicides is currently recognized as a priority area of research. Design A preclinical evaluation of the potential effectiveness of TMC120, a non-nucleoside reverse transcriptase inhibitor (NNRTI), as a topical microbicide to prevent vaginal HIV-1 transmission in a humanized severe combined immunodeficient (hu-SCID) mouse model. Methods Reconstituted mice received an intravaginal application of a TMC120-containing gel 20 min prior to a non-invasive vaginal challenge with cell-associated HIV. The possible cytotoxic effect of TMC120-containing-gel on lymphocytes was assessed and their in vivo migration was followed using fluorescently labelled human lymphocytes. Systemic infection was monitored by p24 antigen detection in culture supernatant from cocultured intraperitoneal cells using antigen capture enzyme-linked immunosorbent assay test and by the presence of integrated proviral HIV-1 DNA in DNA extracted from spleen cells. In vivo migration of labelled lymphocytes was examined by analysis of cells isolated from regional lymph nodes. Results In this model, systemic infection was successfully inhibited by the presence of TMC120-containing gel at vaginal level. The in vivo migration of human lymphocytes from the vagina to regional lymph nodes, following the deposition of TMC120-containing gel, excluded the possibility that inhibition of systemic infection was a result of NNRTI toxicity. Conclusions Vaginal transmission of HIV was successfully prevented by the application of a gel formulation containing TMC120. This is the first evidence of the in vivo effectiveness of a microbicide preparation containing an NNRTI against cell-associated HIV.

Background AIDS defining events occur infrequently in the presence of CD4 counts above 200 cells/µL. It is, however, uncertain for most of the AIDS defining conditions whether this threshold can be considered equally safe in patients with a previously very low CD4 nadir. Methods We evaluated in detail all the AIDS defining events observed during a 48-week clinical trial in 1251 nucleoside reverse transcriptase inhibitor-experienced patients who started protease inhibitors (PIs) at CD4 counts below 50 cells/µL. The type of event, immunological status at the moment of event and time between start of PI treatment and event occurrence were analysed cumulatively and by event type; event rates were calculated. Results Concomitant data on CD4 counts were available for 338 AIDS defining events (81% of total events). Median time between start of treatment with PI and event was 94.5 days and median absolute CD4 value at the occurrence of event was 20 per µL. Only 14 events (in 12 patients) were observed above the threshold of 200 CD4 cells/µL. An analysis of the 67 deaths with concomitantly available CD4 counts (57%) showed a median CD4 count of 10 cells/µL, with only four deaths occurring in the presence of a CD4 count above 100 cells/µL. Conclusions Very few clinical AIDS defining conditions were observed in patients who start PIs at very low CD4 counts and with treatment restore absolute values in CD4 counts above 200 cells/µL. This threshold can therefore be considered a clinically effective goal of treatment with respect to occurrence of all AIDS defining conditions in patients starting PIs in very advanced HIV disease.

Objective: To develop an animal model of vaginal transmission of HIV-1 for the evaluation of vaginal microbicides. Design: Vaginal infection was performed in SCID mice reconstituted with 4 × 10 7 human peripheral blood lymphocytes (hu-PBL) by non-invasive vaginal administration. The hu-PBL were previously infected in vitro with a non-syncytium (NSI) strain of HIV-1 (SF162) (hu-PBL-SCID). Lymphocyte migration in vivo was examined using fluorescently labelled human lymphocytes. Methods: The percentage of CD4 T cells, plasma viral load and p24 antigen were evaluated using fluorescent activated cell sorting (FACS), the Amplicor HIV-1 monitor kit and enzyme-linked immunosorhent assay, respectively. Polymerase chain reaction (PCR) analysis was performed on DNA extracted from spleen and lymph nodes. For in vivo migration of labelled lymphocytes, the mice were sacrified after 4, 24 and 48 h; vaginae and local lymph nodes were removed, snap frozen with OCT, sectioned and examined by fluorescent microscopy and FACS. Results: HIV transmission was established using virus-infected cells inoculated vaginally, as shown by FACS, HIV viral load, p24 and PCR results. Labelled cells were easily located within the vaginal tissues after 4 h. However, few or no cells could be identified after 24 or 48 h at the vaginal level, whereas labelled cells could be detected at the level of regional lymph nodes. Conclusions: Because of its simplicity and practical features compared with other animal models, the vaginal HIV-infected hu-SCID mouse model may prove useful to test the activity of compounds against cell-associated HIV and, possibly, other sexually transmitted diseases.

Objectives: To evaluate the quality of life outcomes in antiretroviral-naive patients randomized to zidovudine plus didanosine versus zidovudine plus didanosine plus nevirapine for treatment of advanced HIV disease (the Istituto Superiore di Sanita 047 trial). Design: A 48-week randomized, double-blind trial. Methods: Sixty patients were enrolled and evaluated over 24 weeks. Quality of life was assessed using a modified version of the Medical Outcomes Study-HIV Health Survey. For analysis, we calculated two summary scores reflecting the physical (PHS) and the mental (MHS) components of health. Results: Although the three-drug combination was superior at inducing immunologic and virologic responses, the two-drug regimen was superior for both PHS and MHS, especially at week 8 where differences were both statistically and clinically significant (5.8 and 9.2 points, respectively, P < 0.02 for both). Quality of life changes paralleled trends in body weight and Karnofsky performance status score. Conclusion: Although a three-drug antiretroviral therapy regimen was superior in terms of short term virologic/immunologic response, the two-drug regimen was better in terms of quality of life. In general, triple therapy remains the most effective treatment option. However, quality of life assessments can yield results that may be discordant with and complementary to those obtained using conventional endpoints. Comparative trials should collect a comprehensive range of outcome measures, including patient-reported quality of life, in order to provide clinicians and patients with additional information that may influence treatment decisions.

To describe the cost of hospitalization and treatment in patients with very advanced disease who tart different regimens based on a protease inhibitor (PI).An observational retrospective analysis was performed on data from a 48-week randomized, multicenter study. Analysis was based on a subgroup of centers that were geographically defined. Costs of ordinary hospital admissions and of antiretroviral treatment were considered. Incidence of hospitalization and number of days free from hospitalization during the period of observation were calculated. Cost and hospitalization measures were compared among patients receiving three different therapeutic regimens: only PI, PI plus one nucleoside, or PI plus two nucleosides. A multivariate analysis was used to assess cost differences, controlling for variables potentially able to influence outcome.Overall, among 166 patients starting PI (PI plus two nucleosides, 71;PI plus one nucleoside, 65; only PI, 30), 162 ordinary hospital admissions were observed during about 1 year of follow-up. Monthly rates of admission per person and incidence of first hospitalization on 100 person-months showed a clear inverse relationship with the number of drugs comprising the baseline treatment regimen, with the lower rates for the triple therapy group (0.06 and 3.9, respectively), intermediate values for the dual therapy group (0.10 and 8.1, respectively), and higher rates for the PI monotherapy group (0.15 and 13.7, respectively). The average number of days free from hospitalization per month was 29.5 in the triple therapy group, 28.6 in the dual therapy group, and 27.9 in the monotherapy group. The results of cost analysis showed, despite higher cost of antiretroviral treatment, that global costs were progressively lower using regimens of increasing potency: Compared to PI monotherapy, global cost (costs of antiretroviral treatment and of hospitalizations combined) per month per patient was 31.9% lower for the triple therapy group and 19.3% lower for the dual therapy. Global cost for the triple therapy was 15.7% lower compared to global cost for dual therapy. After adjustment for CD4 count, AIDS status, and Karnofsky score, both hospitalization costs and global costs were significantly lower for triple therapy compared to monotherapy (p =.002 and.039, respectively).In advanced and nucleoside-experienced patients, PI-containing regimens have a differential impact according to the overall strength of the regimen, with the best effects on both hospitalizations and treatment costs obtained using PI within potent combination regimens.

Some studies on untreated patients have shown a general correlation between plasma HIV copy number and plasma infectivity in in vitro models. Recent observations also indicate that HIV-RNA level is an important predictor of perinatal transmission and may also have a role in heterosexual transmission. To further analyse the correlation between HIV viral load and plasma infectivity, we studied the relationship between HIV-1 plasma copy number and plasma infectivity prior to and during treatment with antiretroviral combination regimens in HIV-1 infected adults. Plasma infectivity was assessed in vitro by coculture of plasma from HIV-positive patients with PHA-stimulated fresh PBMC from uninfected donors. A positive plasma isolation, in almost all cases (43/45) and irrespective of treatment status, was associated with an HIV viral load higher than 100 000 copies per ml, with higher plasma HIV-1 RNA values in isolation-positive samples compared with isolation-negative samples (median values, 710 000 vs. 37 500 copies per ml, respectively). SI and NSI strains had similarly high viral load values (470 000 vs. 790 000 copies per ml), but CD4 counts were lower in the SI phenotype group. Our data indicate that low levels of viral load are only exceptionally associated with isolation from plasma in the in vitro model we used. This observation confirms indirectly the presence of an association between viral load and infectivity. The requisite of a high plasma viral load in order to obtain infectivity (i.e. positivity of HIV isolation from plasma) also seems maintained under antiretroviral treatment, adding confidence in the conclusion that reductions in viral load translate into reduction of plasma infectivity. Due to the extreme complexity of factors determining transmission, a very prudent interpretation of the results is essential when information from experimental studies has to be transferred to clinical situations requiring assessment of risks or clinical decisions.

During a randomized double-blind study to assess the antiviral activity of saquinavir (SQV) alone or in combination with zidovudine (ZDV), the emergence of phenotypic resistance was evaluated in 44 patients treated with SQV (13 subjects), ZDV (14 subjects), and SQV plus ZDV (17 subjects). A significant (P< 0.05) lower CD4 + cell count and higher HIV RNA copy number at entry were found in six patients who developed resistant viral strain (3 to ZDV and 3 to SQV) during the first 4 months of treatment. After 1 year, drug-resistant strains (12 to ZDV and 14 to SQV) were isolated in 26 out of 37 patients. A significant higher number of patients treated with ZDV alone (10/13) harbored ZDV-resistant strains compared to patients treated by combination therapy (2/13); whereas more than 50% of patients had SQV-resistant strains aside from treatment. Early SQV-resistant strains were isolated in a limited number of patients treated with SQV alone (3/13). The rates of emergence of resistant strains during ZDV or SQV monotherapies are comparable. Combination therapy may delay the emergence of phenotypic resistance to either drugs in the short term and to ZDV, but not to SQV, at least after 1 year.

The determination of 11 organic UV filters, worldwide authorised in sunscreen formulations, was performed by HPLC with UV spectrophotometric detection. The filters determined were: phenylbenzimidazole sulfonic acid, benzophenone-4, benzophenone-3, 4-methylbenzylidene camphor, ethylhexyl methoxycinnamate, octocrylene, methylene bis-benzotriazolyl tetramethylbutyl phenol, butyl methoxydibenzoylmethane, bis-ethylhexyloxyphenol methoxyphenyltriazine, ethylhexyl triazone, and diethylamino hydroxybenzoyl hexyl benzoate. Three analytical methods were developed which were based on an ultrasonic extraction of the sample in methanol/1% aqueous acetic acid (70:30, v/v) or dimethylacetamide/propan-2-ol (1:1, v/v) in dependence of the water or fat-solubility of the filter, followed by HPLC separation and quantitation. HPLC was carried out using three different columns and eluting conditions. Standard calibration curves were linear for all the analytes over the concentration range 0.5–100 μg mL−1. UV measurements were carried out at 280, 300, 310 or 360 nm with the aid of a diode array detector in dependence on the maximum absorption of each filter. Quantitative recoveries were obtained for all sunscreen compounds determined in homemade formulations. The proposed analytical procedure has been successfully applied for the analysis of commercial samples in order to check the presence of UV filters and to determine their concentration.

Objectives: The aim of the study was to investigate changes in virological characteristics of HIV strains isolated from 38 HIV-seropositive subjects during antiretroviral therapy. Design and methods: Patients with a CD4+ cell count ≤ 300 〈 10 6 /l were treated with zidovudine (12 individuals) and saquinavir (10 individuals) alone or in combination (16 individuals). CD4+ cell count, viral load, HIV biological phenotype and drug resistance were evaluated during the study period. Results: After 52 weeks, 28 subjects (74%) harboured drug-resistant strains. In patients with a syncytium-inducing (SI) strain, a decline of CD4+ cell count and an increase of viral load were observed aside from the emergence of drug resistance. Conversely, at the emergence of antiretroviral resistance, an immunological and virological deterioration was observed only in patients who had a non-syncytiuminducing (NSI) strain. During the study, a phenotype switching of HIV isolates was detected in eight (21%) patients and a temporal correspondence between the appearance of phenotype switching and the emergence of drug resistance was found in seven cases. Three patients harbouring saquinavir-resistant strains showed a switch from SI to NSI variants associated with a moderate increase in CD4+ cell count. Conclusions: The emergence of resistant strains during antiretroviral therapy may be associated with the selection of viral strains with less cytopathogenicity, while it could become a poor prognostic sign in patients with NSI isolates. AIDS 1997, 11:1211‐1217

Synopsis A simple and rapid analytical method was developed for the determination of vitamins Kand K 3 in facial anti-rash creams. The procedure is based on an ultrasonic extraction of the cosmetic sample with dimeth- ylacetamide, in the presence of an internal standard, followed by HPLC separation. HPLC was performed using a C18 column and spectrophotometric detection at 333 nm. A linear gradient elution was carried out starting with 50% acetonitrile-methanol (75:25 v/v) and water up to 100% acetonitrile-methanol for 5 min. Linearity was established over the concentration range from 0.2 to 1.0 mg/ml for vitamin Kand from 0.02 to 0.1 mg/rnl for vitamin K3, with LOD values of 100 ng and 20 ng injected, respectively. The accuracy was verified by spiking experiments on model cosmetic samples. The proposed method has been successfully applied for the analysis of commercial samples of creams.

Quantitative culture of human immunodeficiency virus (HIV) was performed on 202 plasma samples obtained from asymptomatic and early symptomatic HIV-1 infected patients (mean CD4+ count: 186/mm3) before antiretroviral therapy was started. HIV could be isolated from 84% of the plasma samples (titers ranging from 10(0) to 10(2.75) TCID50/ml). Immune complex dissociated p24 antigen (ICD-p24) was detected in 66% of the samples. Only 23 samples (11%) were negative for both ICD-p24 as well as HIV culture. Discordant results were obtained in 55 samples, and 45 samples negative for ICD-p24 were positive for HIV culture. A significant proportion (42%) of patients that were negative for ICD-p24 belonged to a very advanced group with very low CD4+ cell count. However, almost 90% of these ICD-p24 negative samples were positive for HIV plasma viremia, stressing the value of this virological marker in patients with low CD4+ cell count and without any detectable ICD-p24 antigenemia. HIV-1 RNA was detected in all ICD-p24 negative plasma samples tested by the branched DNA (bDNA) assay. A very good correlation was found between high RNA copy number and HIV plasma isolation in samples obtained from patients with low CD4+ cell count, suggesting that HIV-1 RNA quantitation may also reflect viral infectivity of plasma.

We evaluated the degree of correlation between the variation of different HIV-1 viral load measures in response to antiretroviral therapy. A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for plasma HIV-RNA, and HIV plasma infectivity titration, were performed on prospective samples obtained from 86 antiretroviral-naive patients with symptomatic infection and CD4+ < 300/mm3, enrolled in a randomized double-blind trial of the HIV protease inhibitor saquinavir (SQV) in combination with zidovudine (ZDV). Subjects were stratified according to plasma virus infectivity and examined for correlations between distinct response categories with respect to CD4 count and HIV RNA copy number changes. Infectious virus could be titrated in 72% of patients at baseline. A significant reduction (< 1 log10) in HIV plasma infectivity titer was observed during the study in 69% of these patients. The reduction in plasma infectivity was a good predictor of sustained CD4+ cell increases and of sustained decrease in HIV RNA plasma copies. A decrease of at least 0.5 log10 in HIV RNA copy number was observed in 82% of the treated patients. A good correlation was found between HIV plasma infectivity titer and plasma HIV RNA copy number variations (p < 0.001). However, 10 of 17 patients with unchanged plasma infectivity titer showed a significant reduction in HIV RNA copies. While a good correlation was found between plasma infectivity and RNA plasma copies variations, only a minor correlation was found between CD4+ cell count variation and plasma infectivity titer variation. However, reduction in plasma infectivity was a very good predictor of high CD4 changes.