On the mass of atoms in molecules: Beyond the Born-Oppenheimer approximation

Describing the dynamics of nuclei in molecules requires a potential energy surface, which is traditionally provided by the Born-Oppenheimer or adiabatic approximation. However, we also need to assign masses to the nuclei. There, the Born-Oppenheimer picture does not account for the inertia of the electrons and only bare nuclear masses are considered. Nowadays, experimental accuracy challenges the theoretical predictions of rotational and vibrational spectra and requires to include the participation of electrons in the internal motion of the molecule. More than 80 years after the original work of Born and Oppenheimer, this issue still is not solved in general. Here, we present a theoretical and numerical framework to address this problem in a general and rigorous way. Starting from the exact factorization of the electron-nuclear wave function, we include electronic effects beyond the Born-Oppenheimer regime in a perturbative way via position-dependent corrections to the bare nuclear masses. This maintains an adiabatic-like point of view: the nuclear degrees of freedom feel the presence of the electrons via a single potential energy surface, whereas the inertia of electrons is accounted for and the total mass of the system is recovered. This constitutes a general framework for describing the mass acquired by slow degrees of freedom due to the inertia of light, bounded particles. We illustrate it with a model of proton transfer, where the light particle is the proton, and with corrections to the vibrational spectra of molecules. Inclusion of the light particle inertia allows to gain orders of magnitude in accuracy

Complementarity of neutron reflectometry and ellipsometry for the study of atmospheric reactions at the air–water interface

The combined application of neutron reflectometry (NR) and ellipsometry to determine the oxidation kinetics of organic monolayers at the air–water interface is described for the first time. This advance was possible thanks to a new miniaturised reaction chamber that is compatible with the two techniques and has controlled gas delivery. The rate coefficient for the oxidation of methyl oleate monolayers by gas-phase O3 determined using NR is (5.4 ± 0.6) × 10−10 cm2 per molecule per s, which is consistent with the value reported in the literature but is now better constrained. This highlights the potential for the investigation of faster atmospheric reactions in future studies. The rate coefficient determined using ellipsometry is (5.0 ± 0.9) × 10−10 cm2 per molecule per s, which indicates the potential of this more economical, laboratory-based technique to be employed in parallel with NR. In this case, temporal fluctuations in the optical signal are attributed to the mobility of islands of reaction products. We outline how such information may provide critical missing information in the identification of transient reaction products in a range of atmospheric surface reactions in the future

Cryoglobulinemic vasculitis and skin ulcers. Our therapeutic strategy and review of the literature

Objective: Cryoglobulinemic vasculitis (CV) involving small- and medium-sized vessels is very frequently associated with hepatitis C virus and may be responsible for multiple organ involvement and skin ulcers (SU). Skin ulcers are often non-healing cutaneous lesions, possibly complicated by local infection and gangrene; they may severely affect the patients[U+05F3] quality of life and the overall prognosis. Therefore, the treatment of cryoglobulinemic SU is particularly challenging in the clinical practice.The present work evaluated the prevalence and correlations of cryoglobulinemic SU with other clinico-epidemiological features of CV; moreover, our long-term experience with the management strategies of these cutaneous lesions was compared with the world literature on this topic. Methods: The study included 126 CV patients (24 male and 102 female, aged 69 ± 11.2 SD years, disease duration 7 ± 6.9 SD years), followed at our Rheumatology Unit during the past decade. All patients were carefully evaluated regarding the entire cryoglobulinemic syndrome with particular concern for clinical characteristics and treatment of SU. Results: Among 126 CV patients, 36 individuals (29%) experienced at least one episode of SU, more commonly localized at the lower limbs. Patients with complicating SU showed significantly higher percentage of purpuric manifestations (p < 0.01) and liver (p < 0.001), peripheral nerve (p < 0.02), and/or thyroid involvement (p = 0.019).Therapeutic approach to SU included both systemic (immunosuppressors, corticosteroids, and/or plasma exchange) and local treatments. Local treatments consisted of sharp or surgical debridement as well as interactive dressing according to the condition of wound bed, perilesional skin, and the possible presence of infection, detected in 29 of 36 (81%) individuals in our Rheumatology unit. All patients underwent analgesic treatment for SU-related background pain as well as procedural pain, which was critical for an effective local SU management.The large majority of patients with SU healed at a variable time interval according to the severity of the single lesion; only five patients with very severe, non-healing SU needed amputation.The updated review of the literature revealed the presence of SU in around a quarter of CV patients. Among systemic treatments, the anti-CD20 monoclonal antibody rituximab represents one of the most effective and frequently employed therapies; however, the available data focusing on local therapeutic approach are generally limited to anecdotal observations. Conclusions: Overall, the treatment of cryoglobulinemic SU should be tailored to the single patient[U+05F3]s conditions using combined systemic and local treatments; lesional sharp debridement and interactive dressing as well as procedural pain management were decisive, particularly for more severe, non-healing cutaneous lesions

Simultaneous neutron reflectometry and infrared reflection absorption spectroscopy (IRRAS) study of mixed monolayer reactions at the air–water interface

The simultaneous application of neutron reflectometry (NR) and infrared reflection absorption spectroscopy (IRRAS) to the study of the oxidation kinetics of organic monolayers at the air–water interface is described for the first time. This advance was possible thanks to the development of a new sample environment that includes a gas-delivery system and is compatible with in situ application of the two techniques within the constraints of short-term neutron beam-line access. We studied the oxidation of monolayers of the mono-molecular film palmitoleic acid and of a binary mixture of oleic (OA) and stearic (SA) acids by gas-phase ozone. We contrast the two highly complementary techniques and demonstrate that IRRAS provides key additional insight into the alignment of surfactant molecules at the air–water interface. We highlight the potential of the more economical and widely available IRRAS technique to complement NR studies. We also found an apparent increase of the NR signal upon oxidation of a mixed SA/OA monolayer, as well as evidence of slow intensity fluctuations of the SA- generated IRRAS signal. We demonstrate how simultaneous NR-IRRAS substantially enhances future studies of increasingly complex surfactant mixtures and their atmospheric surface reactions

Combining Weighted Total Variation and Deep Image Prior for natural and medical image restoration via ADMM

In the last decades, unsupervised deep learning based methods have caught researchers attention, since in many real applications, such as medical imaging, collecting a great amount of training examples is not always feasible. Moreover, the construction of a good training set is time consuming and hard because the selected data have to be enough representative for the task. In this paper, we focus on the Deep Image Prior (DIP) framework and we propose to combine it with a space-variant Total Variation regularizer with an automatic estimation of the local regularization parameters. Differently from other existing approaches, we solve the arising minimization problem via the flexible Alternating Direction Method of Multipliers (ADMM). Furthermore, we provide a specific implementation also for the standard isotropic Total Variation. The promising performances of the proposed approach, in terms of PSNR and SSIM values, are addressed through several experiments on simulated as well as real natural and medical corrupted images.Comment: conference pape

COST ANALYSIS RELATED TO SUBCUTANEOUS IMMUNOGLOBULINS IN PATIENTS WITH INFLAMMATORY MYOPATHIES AND IMMUNE-MEDIATED CHRONIC NEUROPATHIES. RESULTS OF AN OPEN LABEL STUDY

Background: Intravenous Immunoglobulins (IVIg) represent a relevant treatment option in various immune-mediated disorders such as idiopathic inflammatory muscle diseases (IIMD), immune-mediated chronic neuropathies (IMCN), hematologic autoimmune diseases, Still disease, Felty syndrome, systemic lupus erythematosus, vasculitis, some organ-specific autoimmune disease, and atopic diseases. The IVIg treatment is expensive and need of hospital-based assistance for administration; the recent avaibility of home-therapy with subcutaneous immunoglobulins (SCIg) may significantly reduce costs and improve the patient's quality of life. Objectives: The primary objective was to perform an analysis of costs of SCIg administration in patients affected by IIMD or IMCN compared to that of previous IVIg treatments. Methods: We prospectively evaluated 6 consecutive patients (3 males and 3 females, mean age 65,3 years, range 63 - 77), 2 affected by IIMD in the context of polymiositis and 4 by IMCN, 3 in the context of vasculitis and 1 in the context of undifferentiated connective tissue disease. All patients were previously treated with IVIg at the dosage of 2g/Kg monthly, (mean monthly dosage 143 g, range 98 – 160, average patient weight 71,5 kg, range 49 - 80), with good clinical and humoral response. After a mean therapy duration of 49.8 months (range 12 – 125) all patients were shifted to SCIg at the dosage of 10 g twice a week (80 g monthly). Each patient was followed-up by humoral and clinical evaluation, including Medical Research Council (MRC) score to quantify muscle strength and INCAT Sensory Score to evaluate sensory symptoms. The costs of the two therapeutic strategies were also compared, excluding indirect costs (absences from work and productivity losses, transport and parking, health care sector costs). Results: In 5/6 patients, we observed the maintenance of clinical and humoral status after a mean follow-up of 21 months (range 4 - 51), in particular we observed a stability in MRC score in patients presenting loss of strenght and INCAT score in patients presenting sensory symptoms. Furthermore, the treatment with SCIg was well-accepted and preferred to IVIg by all patients. In one patient SCIg were discontinued after 2 weeks, because of the appearance of a haemorrhagic lesions nearby the injection site (in the same patient IVIg have been stopped because of a hypertensive crisis during the infusion). Direct cost associated to IVIg amount to 252€ for 5 g of immunoglobulins (7,056€ monthly, considering a protocol of 2 g/kg/monthly and a patient-weight of 70kg), while direct costs associated to SCIg (20g weekly) amount to 6,400€/monthly, with a saving of 656€/monthly and 7,872€/yearly. In our case-series the annual saving was 9,686.40€/patient (from 86,486.40€ to 76,800€, for IVIg and SCIg, respectively). Conclusions: Our experience suggests that the shift to SCIg from IVIg in patients affected by IIMD and IMCN is feasible, cost-effective, safe and well-accepted by patients. Further studies are needed to evaluate the effectiveness of SCIg in first-line therapy of these diseases

Review of structural design guiding the development of lipid nanoparticles for nucleic acid delivery

Lipid nanoparticles (LNPs) are the most versatile and successful gene delivery systems, notably highlighted by their use in vaccines against COVID-19. LNPs have a well-defined core-shell structure, each region with its own distinctive compositions, suited for a wide range of in vivo delivery applications. Here, we discuss how a detailed knowledge of LNP structure can guide LNP formulation to improve the efficiency of delivery of their nucleic acid payload. Perspectives are detailed on how LNP structural design can guide more efficient nucleic acid transfection. Views on key physical characterization techniques needed for such developments are outlined including opinions on biophysical approaches both correlating structure with functionality in biological fluids and improving their ability to escape the endosome and deliver they payload

Acceptability and Adherence in a Chemoprevention Trial among Women at Increased Risk for Breast Cancer Attending the Modena Familial Breast and Ovarian Cancer Center (Italy)

Chemoprevention for women at risk for breast cancer has been shown to be effective, but in actual practice, women's uptake of chemoprevention has been poor. We explored factors that influence acceptability, adherence, and dropout in the International Breast (Prevention) Intervention Study during our first 3 years of activity at the Modena Familial Breast and Ovarian Cancer Center. We evaluated socio-demographic characteristics, health status, adherence, and side effect intensity. Semi-structured interviews analyzed reasons for accepting/refusing/stopping the trial. A total of 471 postmenopausal women were invited to participate, of which 319 declined to participate (68%), 137 accepted to participate (29%), and 15 participants did not make a final decision (3%). Breast cancer-related worries and trust in our preventive and surveillance programs were the most frequent reasons for accepting. Side effect-related worry was the most frequent reason for refusing. General practitioners' and family members' opinions played an important role in the decision-making process. Adherence significantly decreased after a 12-month follow-up, but it remained unchanged after 24- and 36-month follow-ups. Mild/moderate side effects reported by women did not change after 12 months of treatment. Forty percent of women withdrew from the study due to complaints of side effects. We concluded that chemoprevention trials are difficult medical experiments and that the process of deciding about whether or not to participate is based mainly on beliefs and values. This study has important clinical implications. During counselling with prospective participants, it is important to emphasize the potential benefits and to promote an informed choice. How participants make decisions, their belief systems, and their perception of risk are all factors that should be investigated in future research

Degradation rate of 5-fluorouracil in metastatic colorectal cancer. A new predictive outcome biomarker?

BACKGROUND: 5-FU based chemotherapy is the most common first line regimen used for metastatic colorectal cancer (mCRC). Identification of predictive markers of response to chemotherapy is a challenging approach for drug selection. The present study analyzes the predictive role of 5-FU degradation rate (5-FUDR) and genetic polymorphisms (MTHFR, TSER, DPYD) on survival. MATERIALS AND METHODS: Genetic polymorphisms of MTHFR, TSER and DPYD, and the 5-FUDR of homogenous patients with mCRC were retrospectively studied. Genetic markers and the 5-FUDR were correlated with clinical outcome. RESULTS: 133 patients affected by mCRC, treated with fluoropyrimidine-based chemotherapy from 2009 to 2014, were evaluated. Patients were classified into three metabolic classes, according to normal distribution of 5-FUDR in more than 1000 patients, as previously published: poor-metabolizer (PM) with 5-FU-DR ≤ 0,85 ng/ml/106 cells/min (8 pts); normal metabolizer with 0,85 < 5-FU-DR < 2,2 ng/ml/106 cells/min (119 pts); ultra-rapid metabolizer (UM) with 5-FU-DR ≥ 2,2 ng/ml/106 cells/min (6 pts). PM and UM groups showed a longer PFS respect to normal metabolizer group (14.5 and 11 months respectively vs 8 months; p = 0.029). A higher G3-4 toxicity rate was observed in PM and UM, respect to normal metabolizer (50% in both PM and UM vs 18%; p = 0.019). No significant associations between genes polymorphisms and outcomes or toxicities were observed. CONCLUSION: 5-FUDR seems to be significantly involved in predicting survival of patients who underwent 5-FU based CHT for mCRC. Although our findings require confirmation in large prospective studies, they reinforce the concept that individual genetic variation may allow personalized selection of chemotherapy to optimize clinical outcomes