Effectiveness of Nifurtimox in the Treatment of Chagas Disease: a Long-Term Retrospective Cohort Study in Children and Adults.

Chagas disease (ChD), caused by Trypanosoma cruzi, has a global prevalence due to patient migration. However, despite its worldwide distribution, long-term follow-up efficacy studies with nifurtimox (NF) are scarce and have been conducted with only small numbers of patients. A retrospective study of a large cohort of ChD treated children and adults with NF. Treatment response was evaluated by clinical, parasitological, and serological after-treatment evaluation. A total of 289 patients were enrolled, of which 199 were children and 90 adults. At diagnosis, 89.6% of patients were asymptomatic. Overall, all symptomatic patients showed clinical improvement. At baseline, parasitemia was positive in 130 of 260 (50%) patients. All but one adult patient had cleared their parasitemia by the end of treatment. That patient was considered a treatment failure. Median follow-up time for children was 37.7 months, with an interquartile range of (IQR25-75 12.2 to 85.3), and for adults was 14.2 months (IQR25-75, 1.9 to 33.8). After treatment, a decrease of T. cruzi antibodies and seroconversion were observed in 34.6% of patients. The seroconversion profile showed that, the younger the patient, the higher the rate of seroconversion (log rank test; P value, <0.01). At least 20% seroreduction at 1 year follow-up was observed in 33.2% of patients. Nifurtimox was highly effective for ChD treatment. Patients had excellent treatment responses with fully resolved symptoms related to acute T. cruzi infection. Clearance of parasitemia and a decrease in T. cruzi antibodies were observed as markers of treatment response. This study reinforces the importance of treating patients during childhood since the treatment response was more marked in younger subjects. (This protocol was registered at ClinicalTrials.gov under registration number NCT04274101).

Adverse Events Associated with Nifurtimox Treatment for Chagas Disease in Children and Adults.

Nifurtimox (NF) is one of the only two drugs currently available for Chagas disease (ChD) treatment. However, data on NF safety are scarce, and many physicians defer or refuse NF treatment because of concerns about drug tolerance. In a retrospective study of adverse drug reactions (ADRs) associated with NF treatment of ChD, children received NF doses of 10 to 15 mg/kg/day for 60 to 90 days, and adults received 8 to 10 mg/kg/day for 30 days. A total of 215 children (median age, 2.6 years; range, 0 to 17 years) and 105 adults (median age, 34 years; range, 18 to 57 years) were enrolled. Overall, 127/320 (39.7%) patients developed ADRs, with an incidence of 64/105 adults and 63/215 children (odds ratio [OR] = 3.7; 95% confidence interval [CI], 2.2 to 6.3). We observed 215 ADRs, 131 in adults (median, 2 events/patient; interquartile range for the 25th to 75th percentiles [IQR25-75], 1 to 3) and 84 in children (median, 1 event/patient; IQR25-75 = 1 to 1.5) (Padjusted < 0.001). ADRs were mainly mild and moderate. Severe ADRs were infrequent (1.2% in children and 0.9% in adults). Nutritional, central nervous, and digestive systems were the most frequently affected, without differences between groups. Treatment was discontinued in 31/320 (9.7%) patients without differences between groups. However, ADR-related discontinuations occurred more frequently in adults than in children (OR = 5.5, 95% CI = 1.5 to 24). Our study supports the safety of NF for ChD treatment. Delaying NF treatment due to safety concerns does not seem to be supported by the evidence. (This study has been registered in ClinicalTrials.gov under identifier NCT04274101.).

Imaginary time density-density correlations for two-dimensional electron gases at high density.

We evaluate imaginary time density-density correlation functions for two-dimensional homogeneous electron gases of up to 42 particles in the continuum using the phaseless auxiliary field quantum Monte Carlo method. We use periodic boundary conditions and up to 300 plane waves as basis set elements. We show that such methodology, once equipped with suitable numerical stabilization techniques necessary to deal with exponentials, products, and inversions of large matrices, gives access to the calculation of imaginary time correlation functions for medium-sized systems. We discuss the numerical stabilization techniques and the computational complexity of the methodology and we present the limitations related to the size of the systems on a quantitative basis. We perform the inverse Laplace transform of the obtained density-density correlation functions, assessing the ability of the phaseless auxiliary field quantum Monte Carlo method to evaluate dynamical properties of medium-sized homogeneous fermion systems.

Imaginary time correlations and the phaseless auxiliary field quantum Monte Carlo.

The phaseless Auxiliary Field Quantum Monte Carlo (AFQMC) method provides a well established approximation scheme for accurate calculations of ground state energies of many-fermions systems. Here we address the possibility of calculating imaginary time correlation functions with the phaseless AFQMC. We give a detailed description of the technique and test the quality of the results for static properties and imaginary time correlation functions against exact values for small systems.

Accurate Quantum Monte Carlo Forces for Machine-Learned Force Fields: Ethanol as a Benchmark.

Quantum Monte Carlo (QMC) is a powerful method to calculate accurate energies and forces for molecular systems. In this work, we demonstrate how we can obtain accurate QMC forces for the fluxional ethanol molecule at room temperature by using either multideterminant Jastrow-Slater wave functions in variational Monte Carlo or just a single determinant in diffusion Monte Carlo. The excellent performance of our protocols is assessed against high-level coupled cluster calculations on a diverse set of representative configurations of the system. Finally, we train machine-learning force fields on the QMC forces and compare them to models trained on coupled cluster reference data, showing that a force field based on the diffusion Monte Carlo forces with a single determinant can faithfully reproduce coupled cluster power spectra in molecular dynamics simulations.

Minimum energy pathways via quantum Monte Carlo.

We perform quantum Monte Carlo (QMC) calculations to determine minimum energy pathways of simple chemical reactions, and compare the computed geometries and reaction barriers with those obtained with density functional theory (DFT) and quantum chemistry methods. We find that QMC performs in general significantly better than DFT, being also able to treat cases in which DFT is inaccurate or even unable to locate the transition state. Since the wave function form employed here is particularly simple and can be transferred to larger systems, we suggest that a QMC approach is both viable and useful for reactions difficult to address by DFT and system sizes too large for high level quantum chemistry methods.

Excitation spectrum of a supersolid.

Conclusive experimental evidence of a supersolid phase in any known condensed matter system is presently lacking. On the other hand, a supersolid phase has been recently predicted for a system of spinless bosons in continuous space, interacting via a broad class of soft-core, repulsive potentials. Such an interaction can be engineered in assemblies of ultracold atoms, providing a well-defined pathway to the unambiguous observation of this fascinating phase of matter. In this Letter, we study by first principles computer simulations the elementary excitation spectrum of the supersolid, and show that it features two distinct modes, namely, a solidlike phonon and a softer collective excitation, related to broken translation and gauge symmetry, respectively.

Optimizing the Energy with Quantum Monte Carlo: A Lower Numerical Scaling for Jastrow-Slater Expansions.

We present an improved formalism for quantum Monte Carlo calculations of energy derivatives and properties (e.g., the interatomic forces), with a multideterminant Jastrow-Slater function. As a function of the number Ne of Slater determinants, the numerical scaling of O(Ne) per derivative we have recently reported is here lowered to O(Ne) for the entire set of derivatives. As a function of the number of electrons N, the scaling to optimize the wave function and the geometry of a molecular system is lowered to O(N3) + O(NNe), the same as computing the energy alone in the sampling process. The scaling is demonstrated on linear polyenes up to C60H62 and the efficiency of the method is illustrated with the structural optimization of butadiene and octatetraene with Jastrow-Slater wave functions comprising as many as 200 000 determinants and 60 000 parameters.

Age, menopausal status and homocysteine levels in women around menopause.

OBJECTIVE: To obtain data on the relation between age, menopause and homocysteine levels in women around menopause, we collected data for a sample of about 500 women attending a menopause clinic in Milan, Italy. STUDY DESIGN: Eligible for the study were all women aged 45-75 years, never HRT users consecutively observed for the first time at the Menopause Center of the 1st Obstetric Gynecological Clinic of the University of Milan. Fasting blood samples for total homocysteine plasma levels were collected during the visit. Of the 490 study subjects, 107 were pre-menopausal and 383 post-menopausal. RESULTS: In the total series, the mean homocysteine level was 8.3 micromol/L (S.D. 3.7, range 3.2-48.8). The values increased from 7.8 micromol/L in women aged <47 years to 9.0 micromol/L in those aged >59. Among pre-menopausal women the mean homocysteine level was 7.7 micromol/L compared to 8.3 micromol/L in post-menopausal women: this difference disappeared on the adjusted values. In post-menopausal women only, no clear relationship emerged between years since menopause and homocysteine levels. CONCLUSION: In our population, age, and not menopausal status, was the main determinant of homocysteine levels in women around menopause.

Pelvic inflammatory disease and risk of ovarian cancer.

We analyzed the association between history of pelvic inflammatory disease (PID) and the risk of subsequent epithelial ovarian cancer, using data from a large case-control study conducted between 1983-1991 in Italy. Data were collected from a network of hospitals, including the main teaching and general hospitals in the greater Milan area, Northern Italy. The cases studied were 971 women below the age of 75 years (median age, 54 years) with histologically confirmed epithelial ovarian cancer, diagnosed within 1 year before the interview. Control subjects were 2758 women admitted to the same hospitals where cases were identified for acute, nonmalignant, nonhormone-related conditions, who had not undergone bilateral oophorectomy. The median age of the control group was 52 years (range, 23-74). A total of 14 (1.4%) cases and 72 (2.6%) controls reported a history of PID/ salpingitis, the corresponding multivariate relative risk being 0.7 (95% confidence interval, 0.4-1.3). A separate analysis of the association between history of PID/salpingitis and risk of ovarian cancer in strata of parity and education confirmed the results based on the whole series. In conclusion, although based on limited numbers of cases and controls with PID, this studies was able to exclude, at the conventional 95% confidence limit, an increased risk of ovarian cancer of over 30% in women with previous PID in this population.

Ovarian cancer risk and history of selected medical conditions linked with female hormones.

To investigate the role of selected medical conditions on the risk of ovarian cancer, we analysed data from a case-control study. Cases were 971 women below the age of 75 years with histologically confirmed epithelial ovarian cancer, admitted to a network of hospitals including the major teaching and general hospitals in the greater Milan area. Controls were 2758 women admitted to the same network of hospitals for acute, non-gynaecological, non-hormone related, non-neoplastic conditions. Obesity/severe overweight were inversely associated with the risk of ovarian cancer (multivariate relative risk, RR, 0.66, 95% confidence interval, CI, 0.52-0.85). Hyperlipidaemia was also inversely related to ovarian cancer risk, (RR 0.64, 95% CI 0.45-0.89). No relationship emerged between ovarian cancer risk and diabetes (RR 0.80, 95% CI 0.54-1.19), hypertension (RR 0.85, 95% CI 0.68-1.06), thyroid diseases (RR 0.89, 95% CI 0.63-1.13) and cholelithiasis (RR 0.86, 95% CI 0.66-1.12). A decreased frequency of ovarian cancer was seen in women with a history of uterine leiomyomas (RR 0.66, 95% CI 0.47-0.92) and benign ovarian cysts (RR 0.69, 95% CI 0.41-1.13).

Equation of state of solid 3He

We present results of diffusion Monte Carlo calculations for the bcc and hcp phases of solid 3He, using a recent ab initio interatomic potential, including two- and three-body terms. This potential is found to yield an equation of state for condensed 4He in excellent agreement with experiment, in a wide density range. For 3He, we find a systematic discrepancy, worth 0.7 K, between our computed equation of state and a commonly accepted experimental one. We attribute such a discrepancy to an improper choice of reference energy in the determination of the experimental equation of state.

Condensation of helium in nanotube bundles

Helium atoms are strongly attracted to the interstitial channels within a bundle of carbon nanotubes. The strong corrugation of the axial potential within a channel can produce a lattice gas system wherein the weak mutual attraction between atoms in neighboring channels induces a transition to an anisotropic condensed phase. At low temperatures, the specific heat of the adsorbate phase (with fewer than 2% of the atoms) greatly exceeds that of the host.

Identification of AFLP and microsatellite markers linked with an aluminium tolerance gene in barley ( Hordeum vulgare L.).

Barley is the most sensitive among the cereals to aluminium (Al) stress and breeding for more tolerant cultivars is a priority. To enhance selection efficiency for Al tolerance in barley, PCR-based AFLP and microsatellite markers linked to a locus conferring tolerance to aluminium were identified. The study used F(2) progeny derived from a single cross between Yambla (moderately tolerant of Al) and WB229 (tolerant of Al) and developed hydroponic pulse-recovery screening methods to assess tolerance of phenotypes based on root growth. The segregation ratios of tolerant and sensitive genotypes and F(3) progeny testing suggest that a single major gene controlled Al tolerance ( Alt). In order to determine the chromosomal location of the Alt gene, we used the AFLP technique coupled with bulk segregant analysis. We evaluated tolerant and sensitive bulks using 30 combinations of EcoRI/ MseI primers, and 12 of these permitted differentiation of the sensitive and tolerant bulks. More than 1,000 amplified fragments were obtained, and 98 polymorphic bands were scored. AFLP analysis of wheat-barley chromosome addition lines indicated that the Alt gene was located on barley chromosome 4H. Four chromosome 4H-specific microsatellite markers (Bmac310, Bmag353, HVM68 and HVMCABG) were tightly linked to Alt. The large allelic variation detected with microsatellite marker Bmag353 allowed us to implement this marker for routine marker-assisted selection for Al tolerance, and 396 plants could be screened on a single gel.

Enhanced survival and differentiation in vitro of different neuronal populations by some interleukins.

Data from the literature demonstrate the existence of a growing family of neuropoietic cytokines; members of this group have structural motifs in common with other members and with neurotrophic factors. In this research we studied the responses elicited in vitro by some of these molecules in two different neuronal populations: murine neuroblastoma N18TG2 and neurons from chicken dorsal root ganglia. Both IL-2 and IL-6 improve the survival of murine neuroblastoma cells in clonal density plating experiments; in addition IL-2 significantly inhibits thymidine incorporation by single cell suspension. The survival of sensory neurons, on the other hand, non-responsive to IL-2 and IL-6, was significantly supported by IL-3, which also stimulates their morphological differentiation, inducing the formation of a well-developed neural net. In conclusion, results reported here confirm the neurotrophic activity of some ILs and provide additional neuronal models for future investigations.

Risk factors for seromucinous benign ovarian cysts in northern Italy.

STUDY OBJECTIVE: To analyse risk factors for seromucinous benign ovarian cysts. DESIGN: Between 1984 and 1994 a case-control study was carried out. Cases were 225 women aged less than 65 year with a histologically confirmed diagnosis of benign seromucinous ovarian cysts admitted to a network of obstetrics and gynaecology departments in Milan. Controls were a random sample of 450 women admitted for acute conditions that were not gynaecological, hormonal or neoplastic. They were interviewed within the framework of a case-control study of female genital neoplasms. SETTING: Network of hospitals in the greater Milan area, Italy. MAIN RESULTS: The risk of seromucinous benign ovarian cysts was higher in more educated women than in women with fewer than seven years of schooling. The odds ratios (OR) for seromucinous ovarian cysts were 1.3 and 1.4 respectively in women reporting 7-11 and > or = 12 years of schooling, and the trend in risk was statistically significant (chi(2)1 trend 5.20, p < 0.05). There was no clear relationship between the risk of seromucinous ovarian cysts and marital status, age at first marriage, oral contraceptive use, smoking or body mass index. In comparison with women reporting menstrual cycles lasting < 28 days, the risks of seromucinous cysts were 1.6, 2.6, and 2.5 respectively in women reporting cycles lasting 28-30, > or = 31 days, or with totally irregular ones. Among ever married women, nine cases and two controls reported difficulty in conception, and the corresponding OR for seromucinous cysts was 17.7 (95% confidence interval 4.2, 83.8). CONCLUSIONS: The risk of seromucinous benign ovarian tumours is greater in more educated women and in women with a history of infertility and with long or irregular menstrual cycles.

Estroprogestin vs. gonadotrophin agonists plus estroprogestin in the treatment of endometriosis-related pelvic pain: a randomized trial. Gruppo Italiano per lo Studio dell'Endometriosi.

OBJECTIVE: This is a randomized clinical trial comparing estroprogestin (E/P) pill given for 12 months vs. gonadotrophin releasing hormone agonist (GNRHa) given for 4 months followed by E/P pill treatment for 8 months in the relief of endometriosis-related pelvic pain. METHODS: Eligible for the study were women with laparoscopically confirmed endometriosis and pelvic pain lasting 3-12 months after diagnosis. Eligible women were randomly assigned to treatment with E/P pill (gestroden 0.75 mg and ethynlestradiol 0.03 mg) for 12 months (47 patients) vs. tryptorelin 3.75 mg slow release every 28 days for 4 months followed by E/P pill for 8 months (55 patients). RESULTS: At baseline, dysmenorrhea was reported in 46 women allocated to E/P pill only (97.9%), and in all the 55 women allocated to GNRHa+E/P pill. The corresponding value at the 12 months follow-up visit was 14 subjects (35.9%) and 16 subjects (34.8%). The baseline median values of the multidimensional and analog scale were for dysmenorrhea 4 and 6 in the EP only and 3 and 6 in the GNRHa+E/P group. The corresponding value at the 12 months follow-up visit were 2 and 6 and 0 and 5. Non-menstrual pain was reported, respectively, at baseline and 12 month visit by 46 (97.9%) and 15 (38.5%) subjects in the E/P pill group and 49 (89.1%) and 17 (37.0%) of the GNRHa+E/P pill one. The baseline median values of the multidimensional and analog scale were for non-menstrual pain 3 and 5 in the E/P only and 2 and 6 in the GNRHa+E/P group. The corresponding values at the 12 month follow-up visit were 0 and 4 and 0 and 4. These differences between the two groups were not statistically significant. CONCLUSIONS: 1 year after randomization, the two treatment schedules show similar relief of pelvic pain in women with endometriosis.

The effects of a rehabilitation program with mnemotechniques on the institutionalized elderly subject.

After having screened the cognitive functions in 103 institutionalized elderly subjects in Terni, a sample affected by mnemic deficit was obtained so as to verify the use of mnemotechniques on the same. Generally the findings show an improvement in cognitive performance in those treated which leads to suppose that our patients were affected by apparent cognitive deficits rather than real ones, supporting in any case the use of neuropsychological rehabilitative treatment in institutionalized subjects.

Case-control study of oestrogen replacement therapy and risk of cervical cancer.

OBJECTIVE: To examine the relation between use of oestrogen replacement therapy and risk of cervical cancer. DESIGN: Case-control study. SETTING: Northern Italy. SUBJECTS: 645 women aged 40-75 years with cervical cancer admitted between 1981 and 1993 to university and general hospitals. The control group consisted of 749 women aged 40-75 years admitted to the same hospitals with acute conditions judged to be unrelated to any of the known or suspected risk factors for cervical cancer. MAIN OUTCOME MEASURES: Use of oestrogen replacement therapy and risk of cervical cancer. RESULTS: 40 cases versus 86 controls had ever used oestrogens, and the corresponding multivariate odds ratio was 0.5 (95% confidence interval 0.3 to 0.8). The odds ratios of cervical cancer decreased with duration of use, being 0.6 (0.4 to 1.1) for less than 12 months' use and 0.5 (0.2 to 1.0) for use for 12 months or more compared with never users. The protection tended to be somewhat stronger for women reporting first oestrogen use before age 50. The odds ratio was 0.9 (0.5 to 1.7) for women who had taken oestrogens within the past 10 years and 0.4 (0.2 to 0.7) for those who had taken them 10 or more years ago. CONCLUSION: These findings suggest that exogenous oestrogens do not increase the risk of cervical cancer and may decrease the risk.

Practical Schemes for Accurate Forces in Quantum Monte Carlo.

While the computation of interatomic forces has become a well-established practice within variational Monte Carlo (VMC), the use of the more accurate Fixed-Node Diffusion Monte Carlo (DMC) method is still largely limited to the computation of total energies on structures obtained at a lower level of theory. Algorithms to compute exact DMC forces have been proposed in the past, and one such scheme is also put forward in this work, but remain rather impractical due to their high computational cost. As a practical route to DMC forces, we therefore revisit here an approximate method, originally developed in the context of correlated sampling and named here the Variational Drift-Diffusion (VD) approach. We thoroughly investigate its accuracy by checking the consistency between the approximate VD force and the derivative of the DMC potential energy surface for the SiH and C2 molecules and employ a wide range of wave functions optimized in VMC to assess its robustness against the choice of trial function. We find that, for all but the poorest wave function, the discrepancy between force and energy is very small over all interatomic distances, affecting the equilibrium bond length obtained with the VD forces by less than 0.004 au. Furthermore, when the VMC forces are approximate due to the use of a partially optimized wave function, the DMC forces have smaller errors and always lead to an equilibrium distance in better agreement with the experimental value. We also show that the cost of computing the VD forces is only slightly larger than the cost of calculating the DMC energy. Therefore, the VD approximation represents a robust and efficient approach to compute accurate DMC forces, superior to the VMC counterparts.