ABSTRACT
The Debye scattering equation (DSE) [Debye (1915). Ann. Phys. 351, 809-823] is widely used for analyzing total scattering data of nanocrystalline materials in reciprocal space. In its modified form (MDSE) [Cervellino et al. (2010). J. Appl. Cryst. 43, 1543-1547], it includes contributions from uncorrelated thermal agitation terms and, for defective crystalline nanoparticles (NPs), average site-occupancy factors (s.o.f.'s). The s.o.f.'s were introduced heuristically and no theoretical demonstration was provided. This paper presents in detail such a demonstration, corrects a glitch present in the original MDSE, and discusses the s.o.f.'s physical significance. Three new MDSE expressions are given that refer to distinct defective NP ensembles characterized by: (i) vacant sites with uncorrelated constant site-occupancy probability; (ii) vacant sites with a fixed number of randomly distributed atoms; (iii) self-excluding (disordered) positional sites. For all these cases, beneficial aspects and shortcomings of introducing s.o.f.'s as free refinable parameters are demonstrated. The theoretical analysis is supported by numerical simulations performed by comparing the corrected MDSE profiles and the ones based on atomistic modeling of a large number of NPs, satisfying the structural conditions described in (i)-(iii).
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We propose a novel method alternative to the classical Dynamic Light Scattering (DLS) technique for performing particle sizing on diluted dispersions of nanosized particles. Differently from DLS, which works by determining the correlation function of the intensity scattered by the sample, our method does not require the use of a correlator because it exploits the behavior of the variance (VAR) of the scattered signal as a function of the sampling time Δt. By using a wide range of sampling times Δtmin ⪠τc ⪠Δtmax, it is possible to recover the correlation time τc of the scattered field and, in turn (by using the Stokes-Einstein relation), the hydrodynamic diameter of the particles. The new method is endowed with an analytical expression for the error bars associated with to the VAR data. Extensive computer simulations carried out on monodisperse and narrow polydisperse samples show that VAR and DLS techniques provide fairly similar performances. The same results were obtained on calibrated polystyrene spheres and fluorescent perovskite nanoparticles tested with different setups and detection schemes.
ABSTRACT
Light scattering and turbidimetry techniques are classical tools for characterizing the dynamics and structure of single nanoparticles or nanostructured networks. They work by analyzing, as a function of time (Dynamic Light Scattering, DLS) or angles (Static Light Scattering, SLS), the light scattered by a sample, or measuring, as a function of the wavelength, the intensity scattered over the entire solid angle when the sample is illuminated with white light (Multi Wavelength Turbidimetry, MWT). Light scattering methods probe different length scales, in the ranges of ~5−500 nm (DLS), or ~0.1−5 µm (Wide Angle SLS), or ~1−100 µm (Low Angle SLS), and some of them can be operated in a time-resolved mode, with the possibility of characterizing not only stationary, but also aggregating, polymerizing, or self-assembling samples. Thus, the combined use of these techniques represents a powerful approach for studying systems characterized by very different length scales. In this work, we will review some typical applications of these methods, ranging from the field of colloidal fractal aggregation to the polymerization of biologic networks made of randomly entangled nanosized fibers. We will also discuss the opportunity of combining together different scattering techniques, emphasizing the advantages of a global analysis with respect to single-methods data processing.
ABSTRACT
Background: In psoriasis, several studies have indicated sex differences in clinical characteristics, type of treatment, and outcomes. A higher impact of psoriasis on quality of life (QoL) and a lower treatment satisfaction have been reported in women by different authors. Objectives: This article reports the results of a post hoc gender analysis of CANOVA study, aimed at assessing 16/24/52-week effectiveness of biologics in patients with moderate-severe plaque psoriasis. Materials and Methods: CANOVA was a real-world, multicenter, noninterventional, retro-prospective study conducted in 17 Italian hospital dermatology clinics. Results: Of the 669 eligible patients, 63.8% were men. Demographic and baseline characteristics and duration of disease were rather homogeneous between sexes. Slightly more women had been treated with biologics (50.4% vs. 46.5%) and had received ≥2 biologic treatment lines (17.2% vs. 12.4%) before study treatment. The most frequently used biologics were secukinumab, ustekinumab, adalimumab, and ixekizumab in both sexes. At 6 months, Psoriasis Area Severity Index (PASI) 75/90/100 responders were 90.8%/72.3%/45.3% of men and 89.2%/76.6%/48.2% of women. Sustained PASI responders were 79.5% of men and 75.9% of women. Treatment satisfaction was significantly lower in women at enrolment for all subscales, and was still lower at 6 months, no longer significantly. Gender distribution in Dermatology Life Quality Index total score classes showed a significantly greater effect of psoriasis on QoL in women, both at enrolment and at the 6-month follow-up. Conclusions: In conclusion, this gender analysis confirms in both genders the efficacy of biologics in psoriasis. However, women reported a greater impact of the disease on QoL and lower treatment satisfaction.
ABSTRACT
Over the recent years, a typical implementation of diffuse correlation spectroscopy (DCS) instrumentation has been adapted widely. However, there are no detailed and accepted recipes for designing such instrumentation to meet pre-defined signal-to-noise ratio (SNR) and precision targets. These require specific attention due to the subtleties of the DCS signals. Here, DCS experiments have been performed using liquid tissue simulating phantoms to study the effect of the detected photon count-rate, the number of parallel detection channels and the measurement duration on the precision and SNR to suggest scaling relations to be utilized for device design.
ABSTRACT
BACKGROUND: Disease awareness is a challenge in the management of chronic obstructive pulmonary disease (COPD). OBJECTIVES: The aim of this analysis was to explore the association between COPD optimal and suboptimal awareness, clinical parameters, and the following patient-reported outcomes: modified Medical Research Council (mMRC), Treatment Satisfaction Questionnaire (TSQM-9), COPD Assessment Test (CAT), Morisky Medication-Taking Adherence Scale (MMAS-4), and Brief Illness Perception Questionnaire (B-IPQ). METHODS: This post hoc analysis of the SAT study included all enrolled patients for whom awareness (Disease Awareness in COPD Questionnaire - DACQ) was assessed at baseline and 12 months. DACQ scores ≥80 were considered an indicator of an optimal awareness. RESULTS: 367 patients (25.8% women, median age 72 years) were included in the analysis. At enrollment, 74 patients (20.2%) had a DACQ score ≥80. Patients with suboptimal awareness, compared to those in which awareness was optimal, had higher median scores for CAT (p = 0.0001) and mMRC (p = 0.0031), a lower median TSQM-9 global score (p < 0.0001), and higher median B-IPQ score (p < 0.0001). The proportion of patients who had exacerbations during the previous year was higher in patients with suboptimal COPD awareness than in those with DACQ score ≥80 (42.8 vs. 21.4%, p = 0.0009). During the 12-month observation period, illness perception, adherence, and treatment satisfaction were found to be independent factors significantly associated with level of disease awareness. CONCLUSION: The results of our post hoc analysis suggest that patients' awareness of their COPD disease is related to both clinical outcomes and how they perceive and manage their condition.
Subject(s)
Diagnostic Self Evaluation , Health Behavior , Pulmonary Disease, Chronic Obstructive , Self-Management , Treatment Adherence and Compliance , Aged , Female , Health Knowledge, Attitudes, Practice , Humans , Italy/epidemiology , Male , Patient Reported Outcome Measures , Patient Satisfaction , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/psychology , Self-Management/methods , Self-Management/psychology , Severity of Illness Index , Surveys and Questionnaires , Symptom Flare Up , Treatment Adherence and Compliance/psychology , Treatment Adherence and Compliance/statistics & numerical dataABSTRACT
The occurrence of an amorphous calcium phosphate layer covering the crystalline apatite core has been suggested to be an intrinsic feature of both bone mineral and synthetic biomimetic analogs. However, an exahustive quantitative picture of the amorphous-crystalline relationship in these materials is still missing. Here, we present a multiple scale modelling that combines small-angle X-ray scattering (SAXS) and synchrotron wide-angle X-ray total scattering (WAXTS) analyses to investigate the amorphous-crystalline spatial interplay in bone sample and biomimetic carbonated nano-apatites. SAXS analysis indicates the presence of a single morphology consisting of tiny nanoplates (NPLs) and provides a measure of their thickness (falling in the 3-5 nm range). WAXTS analysis was performed by developing atomistic models of apatite NPLs incorporating lattice strain, mostly attributed to the carbonate content, and calculating the X-ray patterns using the Debye Scattering Equation. Upon model optimization, the size and strain parameters of the crystalline platelets were derived and the amorphous component, co-existing with the crystalline one, separated and quantified (in the 23-33 wt% range). Notably, the thickness of the apatite core was found to exhibit nearly null (bone) or minor (< 0.5 nm, biomimetic samples) deviations from that of the entire NPLs, suggesting that the amorphous material remains predominantly distributed along the lateral sides of the NPLs, in a core-crown-like arrangement. The lattice strain analysis indicates a significant stiffness along the c axis, which is comparable in bone and synthetic samples, and larger deformations in the other directions. STATEMENT OF SIGNIFICANCE: Current models of bone mineral and biomimetic nanoapatites suggest the occurrence of an amorphous layer covering the apatitic crystalline nanoplates in a core-shell arrangement. By combining X-ray scattering techniques in the small and wide angle regions, we propose a joint atomic-to-nanometre scale modelling to investigate the amorphous-crystalline interplay within the nanoplates. Estimates are extracted for the thickness of the entire nanoplates and the crystalline core, together with the quantification of the amorphous fraction and apatite lattice strain. Based on the thickness matching, the location of the amorphous material mostly along the edges of the nanoplates is inferred, with a vanishing or very thin layer in the thickness direction, suggesting a core-crown-like arrangement, with possible implications on the mineral surface reactivity.
Subject(s)
Apatites , Biomimetics , Scattering, Small Angle , X-Ray Diffraction , X-RaysABSTRACT
An increasingly important issue in nanoscience and nanotechnology is the accurate determination of nanoparticle sizing. Wide angle X-ray total scattering (WAXTS) data are frequently used to retrieve the Particle Size Distributions (PSDs) of nanocrystals of highly technological relevance; however, the PSD shape typically relies on an a-priori assumption. Here, we propose a modified version of the classical iterative Lucy-Richardson (LR) algorithm, which is simple, fast and highly reliable against noise, and demonstrate that the inversion of WAXTS data can be profitably used for recovering accurate PSD regardless of its shape. Computer simulations based on the use of the Debye Scattering Equation (DSE) modelling WAXTS data show that the algorithm is capable of recovering accurate PSDs even when the sample is made of a mixture of different polymorphs and/or exhibits microstrain effects. When applied to the inversion of WAXTS data taken on real samples, the method requires accurate modelling of the nanoparticle crystal structure, which includes structural defects, microstrain and surface induced distortions. Provided that this information is correctly fed to the program, the inversion algorithm reconstructs the WAXTS data with high accuracy and recovers highly robust (against noise) PSDs. Two examples reporting the characterization of Magnetite-Maghemite and commercial P25-Titania nanopowders, are discussed. We demonstrate that pre-assumption of wrong PSD shape leads to inaccurate number-based average sizes in highly polydisperse samples.
ABSTRACT
Characterization of functional nanocrystalline materials in terms of quantitative determination of size, size dispersion, type, and extension of exposed facets still remains a challenging task. This is particularly the case of anisotropically shaped nanocrystals (NCs) like the TiO2 photocatalysts. Here, commercially available P25 and P90 titania nanopowders have been characterized by wide-angle X-ray total scattering techniques. Synchrotron data were modelled by the reciprocal space-based Debye scattering equation (DSE) method using atomistic models of NC populations (simultaneously carrying atomic and nanoscale structural features) for both anatase and rutile phases. Statistically robust descriptors are provided of size, morphology, and {101} vs. {001} facet area of truncated tetragonal bipyramids for anatase, jointly to polymorph quantification. The effects of using the proper NC shape on the X-ray diffraction pattern are analyzed in depth through DSE simulations by considering variable bipyramid aspect ratios (resulting in different {101} vs. {001} surface) and relative dispersion in a bivariate manner. We demonstrate that using prismatic NCs having equal volume and aspect ratio as bipyramids provides reasonably accurate sizes and {101} and {001} surface areas of the parent morphology.
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BACKGROUND: Gender differences in asthma perception and control have been reported. The PROXIMA observational study assessed these outcomes in a cohort of Italian severe allergic asthma (SAA) patients. This post hoc analysis of the PROXIMA results was aimed at assessing gender differences in SAA in a real-world setting, focusing on disease perception and impact on quality of life (QoL). METHODS: The PROXIMA study was an observational, multicenter study, consisting of a cross-sectional and a prospective longitudinal phase, including adult outpatients diagnosed with SAA at step 4 requiring a therapeutic step-up. Patients on omalizumab treatment at baseline were included in the 12-month longitudinal phase. Disease control was assessed by the Asthma Control Questionnaire (ACQ) score, patients' disease perception by the Brief Illness Perception Questionnaire (BIPQ), and QoL by the EuroQoL five-dimensional three-level questionnaire (EQ-5D-3 L) at baseline and after 6 and 12 months. Two regression models were used to evaluate the association between gender and BIPQ total score and EQ-5D-3L score, respectively. RESULTS: 357 patients (65% females) were analyzed for the cross-sectional phase and 99 (62.6% females) for the longitudinal phase. The prevalence of perennial and seasonal aeroallergens was similar between genders. ACQ score decreased similarly during omalizumab treatment at 6 and 12 months in both genders; no gender differences were observed in control rates. Asthma perception was worse among females at all study visits reaching statistical significance at 12 months (mean (SD) B-IPQ total score 41.8 (9.4) vs 35.6 (12.0); T test p-value (males vs females) < 0.05). Statistically significant gender differences were observed for some specific items, with males reporting less symptom experience, concern about the disease, and emotional impact at 12-months. The results of the multivariate regression model for repeated measures showed that overall treatment with omalizumab improved disease perception overtime regardless from gender. Males reported a significantly better QoL compared to females at both 6 and 12 months. CONCLUSIONS: In this real-world setting, females confirmed to have a worse perception of asthma, feel it as more symptomatic and suffer a greater impact on their QoL, even though having similar baseline severity and obtaining similar level of control.
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BACKGROUND: Patient awareness of COPD refers to knowledge and acceptance of the disease and its treatment. Although it is relevant to management and outcomes, the disease awareness of patients is poorly investigated, and no validated questionnaires are currently available. We aimed to develop the novel Disease Awareness in COPD Questionnaire (DACQ), which was validated in relation to demographic and clinical features, in patients participating in the SATisfaction and Adherence to COPD Treatment (SAT) study. METHODS: DACQ was developed according to a list of items regarding the patient's knowledge, acceptance, and perception of COPD as well as of treatment needs. The questionnaire was validated by assessing internal structure and consistency, correlations with other patient-reported outcomes, and stability over time. Furthermore, the extent of disease awareness of patients enrolled in the SAT study was assessed by using DACQ, and correlations with demographic and clinical features were evaluated. RESULTS: DACQ was composed of four domains. Overall reliability and stability over time were adequate; correlations between DACQ and other tools measuring different constructs (ie, treatment satisfaction, illness perception, impact of COPD symptoms on daily life, and dyspnea severity) were, as expected, more limited. In the enrolled patient sample, a suboptimal level of disease awareness (<70%) was detected, especially in terms of disease acceptance and perception. Disease knowledge was positively associated with COPD severity, while the impact of symptoms on daily life was negatively associated with disease acceptance, awareness of treatment needs, and overall awareness. CONCLUSION: DACQ proved to be a reliable tool to assess awareness in COPD patients. Awareness of COPD patients need to be improved. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID# NCT02689492.
Subject(s)
Awareness , Dyspnea/psychology , Health Knowledge, Attitudes, Practice , Lung/physiopathology , Patient Acceptance of Health Care , Pulmonary Disease, Chronic Obstructive/psychology , Activities of Daily Living , Aged , Aged, 80 and over , Cost of Illness , Dyspnea/diagnosis , Dyspnea/physiopathology , Dyspnea/therapy , Female , Humans , Illness Behavior , Italy , Male , Middle Aged , Patient Compliance , Patient Satisfaction , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Disease, Chronic Obstructive/therapy , Reproducibility of Results , Severity of Illness Index , Surveys and Questionnaires , Time FactorsABSTRACT
We revisited the classical Schätzel formulas (K. Schätzel, Quantum Optics2, 2871990) of the variance and covariance matrix associated to the normalized auto-correlation function in a Dynamic Light Scattering experiment when the sample is characterized by a single exponential decay function. Although thoroughly discussed by Schätzel who also outlined a correcting procedure, such formulas do not include explicitly the effects of triangular averaging that arise when the sampling time Δt is comparable or larger than the correlation time τc. If these effects are not taken into account, such formulas might be highly inaccurate. In this work we have solved this problem and worked out two exact analytical expressions that generalize the Schätzel formulas for any value of the ratio Δt/τc. By the use of extensive computer simulations we tested the correctness of the new formulas and showed that the variance formula can be exploited also in the case of fairly broad bell-shaped polydisperse samples (polydispersities up to â¼ 50 - 100%) and in connection with single exponential decay cross-correlation functions, provided that the average count rate is computed as the geometrical mean of the average count rates of the two channels. Finally, when tested on calibrated polystyrene particles, the new variance formula is able to reproduce quite accurately the error bars obtained by averaging the experimental data.
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In this work, mixed alkali metaphosphate glasses based on K-Na, Rb-Na, Rb-Li, Cs-Na and Cs-Li combinations were studied by differential scanning calorimetry (DSC), complex impedance spectroscopy, and Raman spectroscopy. DSC analyses show that both the glass transition (Tg) and melting temperatures (Tm) exhibit a clear mixed-ion effect. The ionic conductivity shows a strong mixed-ion effect and decreases by more than six orders of magnitude at room temperature for Rb-Na or Cs-Li alkali pairs. This study confirms that the mixed-ion effect may be explained as a natural consequence of random ion mixing because ion transport is favoured between well-matched energy sites and is impeded due to the structural mismatch between neighbouring sites for dissimilar ions.
ABSTRACT
A 10 ns time resolution, multi-tau software correlator, capable of computing simultaneous autocorrelation (A-A, B-B) and cross (A-B) correlation functions at count rates up to â¼10 MHz, with no data loss, has been developed in LabVIEW and C++ by using the National Instrument timer/counterboard (NI PCIe-6612) and a fast Personal Computer (PC) (Intel Core i7-4790 Processor 3.60 GHz ). The correlator works by using two algorithms: for large lag times (τ â³ 1 µs), a classical time-mode scheme, based on the measure of the number of pulses per time interval, is used; differently, for τ â² 1 µs a photon-mode (PM) scheme is adopted and the correlation function is retrieved from the sequence of the photon arrival times. Single auto- and cross-correlation functions can be processed online in full real time up to count rates of â¼1.8 MHz and â¼1.2 MHz, respectively. Two autocorrelation (A-A, B-B) and a cross correlation (A-B) functions can be simultaneously processed in full real time only up to count rates of â¼750 kHz. At higher count rates, the online processing takes place in a delayed modality, but with no data loss. When tested with simulated correlation data and latex spheres solutions, the overall performances of the correlator appear to be comparable with those of commercial hardware correlators, but with several nontrivial advantages related to its flexibility, low cost, and easy adaptability to future developments of PC and data acquisition technology.
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BACKGROUND: Mass spectrometry (MS) is producing high volumes of data supporting oncological sciences, especially for translational research. Most of related elaborations can be carried out by combining existing tools at different levels, but little is currently available for the automation of the fundamental steps. For the analysis of MALDI/TOF spectra, a number of pre-processing steps are required, including joining of isotopic abundances for a given molecular species, normalization of signals against an internal standard, background noise removal, averaging multiple spectra from the same sample, and aligning spectra from different samples. In this paper, we present Geena 2, a public software tool for the automated execution of these pre-processing steps for MALDI/TOF spectra. RESULTS: Geena 2 has been developed in a Linux-Apache-MySQL-PHP web development environment, with scripts in PHP and Perl. Input and output are managed as simple formats that can be consumed by any database system and spreadsheet software. Input data may also be stored in a MySQL database. Processing methods are based on original heuristic algorithms which are introduced in the paper. Three simple and intuitive web interfaces are available: the Standard Search Interface, which allows a complete control over all parameters, the Bright Search Interface, which leaves to the user the possibility to tune parameters for alignment of spectra, and the Quick Search Interface, which limits the number of parameters to a minimum by using default values for the majority of parameters. Geena 2 has been utilized, in conjunction with a statistical analysis tool, in three published experimental works: a proteomic study on the effects of long-term cryopreservation on the low molecular weight fraction of serum proteome, and two retrospective serum proteomic studies, one on the risk of developing breat cancer in patients affected by gross cystic disease of the breast (GCDB) and the other for the identification of a predictor of breast cancer mortality following breast cancer surgery, whose results were validated by ELISA, a completely alternative method. CONCLUSIONS: Geena 2 is a public tool for the automated pre-processing of MS data originated by MALDI/TOF instruments, with a simple and intuitive web interface. It is now under active development for the inclusion of further filtering options and for the adoption of standard formats for MS spectra.
Subject(s)
Blood Proteins/analysis , Breast Neoplasms/metabolism , Proteome/analysis , Proteomics/methods , Software , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Algorithms , Automation , Databases, Factual , Female , Humans , Retrospective StudiesABSTRACT
We present a new hardware simulator (HS) for characterization, testing and benchmarking of digital correlators used in various optical correlation spectroscopy experiments where the photon statistics is Gaussian and the corresponding time correlation function can have any arbitrary shape. Starting from the HS developed in [Rev. Sci. Instrum. 74, 4273 (2003)], and using the same I/O board (PCI-6534 National Instrument) mounted on a modern PC (Intel Core i7-CPU, 3.07GHz, 12GB RAM), we have realized an instrument capable of delivering continuous streams of TTL pulses over two channels, with a time resolution of Δt = 50ns, up to a maximum count rate of ãIã â¼ 5MHz. Pulse streams, typically detected in dynamic light scattering and diffuse correlation spectroscopy experiments were generated and measured with a commercial hardware correlator obtaining measured correlation functions that match accurately the expected ones.
Subject(s)
Algorithms , Biometry/methods , Photons , Spectrum Analysis/instrumentation , Spectrometry, Fluorescence/instrumentationABSTRACT
The formation of a fibrin network following fibrinogen enzymatic activation is the central event in blood coagulation and has important biomedical and biotechnological implications. A non-covalent polymerization reaction between macromolecular monomers, it consists basically of two complementary processes: elongation/branching generates an interconnected 3D scaffold of relatively thin fibrils, and cooperative lateral aggregation thickens them more than 10-fold. We have studied the early stages up to the gel point by fast fibrinogen:enzyme mixing experiments using simultaneous small-angle X-ray scattering and wide-angle, multi-angle light scattering detection. The coupled evolutions of the average molecular weight, size, and cross section of the solutes during the fibrils growth phase were thus recovered. They reveal that extended structures, thinner than those predicted by the classic half-staggered, double-stranded mechanism, must quickly form. Following extensive modeling, an initial phase is proposed in which single-bonded "Y-ladder" polymers rapidly elongate before undergoing a delayed transition to the double-stranded fibrils. Consistent with the data, this alternative mechanism can intrinsically generate frequent, random branching points in each growing fibril. The model predicts that, as a consequence, some branches in these expanding "lumps" eventually interconnect, forming the pervasive 3D network. While still growing, other branches will then undergo a Ca(2+)/length-dependent cooperative collapse on the resulting network scaffolding filaments, explaining their sudden thickening, low final density, and basic mechanical properties.
Subject(s)
Fibrin/chemistry , Light , Fibrin/chemical synthesis , Kinetics , Models, Molecular , Polymerization , Scattering, Small Angle , Time Factors , X-Ray DiffractionABSTRACT
Gross cystic disease (GCDB) is a breast benign condition predisposing to breast cancer. Cryopreserved sera from GCDB patients, some of whom later developed a cancer (cases), were studied to identify potential risk markers. A MALDI-TOF mass spectrometry analysis found several complement C3f fragments having a significant increased abundance in cases compared to controls. After multivariate analysis, the full-length form of C3f maintained a predictive value of breast cancer risk. Higher levels of C3f in the serum of women affected by a benign condition like GCDB thus appears to be correlated to the development of breast cancer even 20 years later. BIOLOGICAL SIGNIFICANCE: Increased complement system activation has been found in the sera of women affected by GCDB who developed a breast cancer, even twenty or more years later. C3f may predict an increased breast cancer risk in the healthy population and in women affected by predisposing conditions.