Insights from the classical MD simulations

Salt bridges and ionic interactions play an important role in protein stability, protein-protein interactions, and protein folding. Here, we provide the classical MD simulations of the structure and IR signatures of the arginine (Arg)–glutamate (Glu) salt bridge. The Arg-Glu model is based on the infinite polyalanine antiparallel two-stranded β-sheet structure. The 1 μs NPT simulations show that it preferably exists as a salt bridge (a contact ion pair). Bidentate (the end-on and side-on structures) and monodentate (the backside structure) configurations are localized [Donald et al., Proteins 79, 898–915 (2011)]. These structures are stabilized by the short +N–H⋯O− bonds. Their relative stability depends on a force field used in the MD simulations. The side-on structure is the most stable in terms of the OPLS-AA force field. If AMBER ff99SB-ILDN is used, the backside structure is the most stable. Compared with experimental data, simulations using the OPLS all-atom (OPLS-AA) force field describe the stability of the salt bridge structures quite realistically. It decreases in the following order: side-on > end-on > backside. The most stable side-on structure lives several nanoseconds. The less stable backside structure exists a few tenth of a nanosecond. Several short-living species (solvent shared, completely separately solvated ionic groups ion pairs, etc.) are also localized. Their lifetime is a few tens of picoseconds or less. Conformational flexibility of amino acids forming the salt bridge is investigated. The spectral signature of the Arg-Glu salt bridge is the IR-intensive band around 2200 cm−1. It is caused by the asymmetric stretching vibrations of the +N–H⋯O− fragment. Result of the present paper suggests that infrared spectroscopy in the 2000–2800 frequency region may be a rapid and quantitative method for the study of salt bridges in peptides and ionic interactions between proteins. This region is usually not considered in spectroscopic studies of peptides and proteins

The Psychological Risks Associated With the Non-medical Switch From Biologics to Biosimilars

Biological products are therapeutic agents produced using a living system or organism. In many cases, access to these products is limited due to their expensive cost (Chow et al., 2011). A biosimilar is a biological product that is highly similar (not identic) to, and has no clinically meaningful differences from, an existing reference biological product on the market (Desai et al., 2020). “Non-medical” switching is the switching of a patient's medicine for reasons other than the patient's health and safety, like the reduction of costs (Dolinar et al., 2019)

First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis

Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk [RR], 4.28; 95% confidence interval [CI], 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities

A Protein Phosphorylation Threshold for Functional Stacking of Plant Photosynthetic Membranes

Phosphorylation of photosystem II (PSII) proteins affects macroscopic structure of thylakoid photosynthetic membranes in chloroplasts of the model plant Arabidopsis. In this study, light-scattering spectroscopy revealed that stacking of thylakoids isolated from wild type Arabidopsis and the mutant lacking STN7 protein kinase was highly influenced by cation (Mg++) concentrations. The stacking of thylakoids from the stn8 and stn7stn8 mutants, deficient in STN8 kinase and consequently in light-dependent phosphorylation of PSII, was increased even in the absence of Mg++. Additional PSII protein phosphorylation in wild type plants exposed to high light enhanced Mg++-dependence of thylakoid stacking. Protein phosphorylation in the plant leaves was analyzed during day, night and prolonged darkness using three independent techniques: immunoblotting with anti-phosphothreonine antibodies; Diamond ProQ phosphoprotein staining; and quantitative mass spectrometry of peptides released from the thylakoid membranes by trypsin. All assays revealed dark/night-induced increase in phosphorylation of the 43 kDa chlorophyll-binding protein CP43, which compensated for decrease in phosphorylation of the other PSII proteins in wild type and stn7, but not in the stn8 and stn7stn8 mutants. Quantitative mass spectrometry determined that every PSII in wild type and stn7 contained on average 2.5±0.1 or 1.4±0.1 phosphoryl groups during day or night, correspondingly, while less than every second PSII had a phosphoryl group in stn8 and stn7stn8. It is postulated that functional cation-dependent stacking of plant thylakoid membranes requires at least one phosphoryl group per PSII, and increased phosphorylation of PSII in plants exposed to high light enhances stacking dynamics of the photosynthetic membranes

Modelling birthweight as a function of gestational age at delivery in hypertensive disorder of pregnancy

Introduction Pre-eclampsia (PE) is a multifactorial syndrome with different clinical phenotypes. To address this heterogeneity, the syndrome has been subdivided, according to gestational age (GA), into early and late PE, but this classification is not completely satisfying [1]. The most-studied clinical phenotype is that caused by shallow trophoblastic invasion of the spiral arteries, with oxidative stress and release of placental factors, which lead to endothelial dysfunction and organ damage [2]. Doppler velocimetry of the uterine arteries (UtA-PI) and measurement of vascular growth factors can be used to screen for early vascular damage, associated with reduced placental growth and intrauterine growth restriction (IUGR) later in pregnancy [3]. This clinical phenotype is predominant in cases prior to 34 wks of GA, thus early PE can be regarded as a proxy for cases affected by this sequence of events. Anyhow, the disease does not end at 34 wks of GA, and less severe cases represent a large proportion of syndromic manifestations of PE in late gestation [1]. Cases affected by hypertensive disorders of pregnancy (HDP) including PE are frequently found to have normal neonates and placentas [4]. In these cases, endothelial dysfunction can be ascribed to the placental pro-inflammatory response, dyslipidemia or other pro-inflammatory conditions resulting in low-grade inflammation due to pre-existing maternal conditions, such as maternal metabolic syndrome and cardiovascular risk factors. These risk factors are not suppposed to operate only from 34 wks of GA onwards. The aim of this presentation is to verify whether a classification based only on fetal abdomen circumference (AC) and UtA-PI is suitable for defining two internally homogeneous subgroups of women affected by HDP, characterized by different effects on fetal growth, as can be inferred from the outcome, in terms of birthweight conditional on GA, and whether GA at the onset of HDP has a role in determining fetal growth. Data and methods This multicentre study includes all eligible cases of HDP consecutively admitted over a 12-month period (from December 2013) to seven Italian tertiary referral centres for maternal-fetal medicine. To be eligible for inclusion, the clinical records of each patient had to report two \u201ckey items\u201d: fetal assessment of abdomen circumference (AC) and mean UtA-PI. Women with multiple pregnancy and with chromosomal or structural fetal abnormalities were excluded. A total of 902 patients met these inclusion/exclusion criteria. Data concerning maternal characteristics, pregnancy complications and outcome were retrieved from the archived clinical records [5]. Pregnant women were grouped into two phenotypes, independently of GA at the onset of HDP. The first phenotype, which was named HDP-IUGR (n=124) [5], is characterized by maternal HDP associated with fetal AC at admission below the 5th centile of Todros et al reference [6], and an abnormal UtA-PI, defined as mean of right and left UtA-PI>95th centile of Gomez et al reference [7]. The second phenotype, which was named HDP-AGA, i.e. fetuses whose AC is appropriate-for-gestational age (n=205), is characterized by maternal HDP associated with fetal AC 655th centile and UtA-PI 6495th centile. The group was then subdivided in early and late-onset HDP, depending whether GA at the onset of disease was 95th centile, or AC at admission. Results Figure 1 shows birthweight as a function of GA at delivery in neonates classified by sex, maternal phenotype and GA at the onset of HDP. When the model includes only the term accounting for the effect of sex, birthweight of males is estimated to be higher than that of females by 4% (95%CL: 1%, 7%; p=0.0158). The introduction of the term expressing the effect of phenotype into the model consistently improves the goodness of fit: the coefficient of determination increased from 0.86 to 0.91 and the residual standard deviation decreased from 366 to 294 g. The children of women with phenotype HDP-IUGR show a birthweight lower by 23% (95%CL: 20%, 26%; p. Conclusions The use of the parametric nonlinear model presented in this study yielded a synthetic and faithful description of the relationship between birthweight and GA in over 3 hundred babies born to women suffering with hypertensive disorders of pregnancy, and delivered between the 25th and the 42nd week of GA. Furthermore the model provided estimates of the separate effects that sex, HDP phenotype, and GA at the onset of HDP exert on birthweight. Among babies born to HDP mothers, birthweight of males was found to be higher than that of by 4%: an identical difference was observed in the reference set used to trace INeS charts [10], this suggest that HDP impairs fetal growth independently of sex. The babies born to mothers with phenotype HDP-IUGR were found to have birthweight lower by about 25% than those born to mothers with phenotype HDP-AGA: this is not unexpected, fetal weight being partly determined by abdomen volume. Nonetheless, since delivery occurred, on the average, 3 weeks after the assessment of abdomen circumference, such a difference suggests the persistence of conditions unfavourable to fetal growth up to end of pregnancy. The third hypothesis that the model could test was whether GA at the onset of HDP affects the severity of fetal growth impairment. In this case we would expect that birthweight of babies born to mothers with early onset of HDP is considerably lower. Results showed that fetal growth follows the same pattern, independently of GA at the onset of HDP. References 1. Verlohren S, Melchiorre K, Khalil A, et al. Uterine artery Doppler, birth weight and timing of onset of pre-eclampsia: providing insights into the dual etiology of late-onset pre-eclampsia. Ultrasound Obstet Gynecol 2014; 44:293-298. 2. Cindrova-Davies T. Gabor Than Award Lecture 2008: pre-eclampsia \u2013 from placental oxidative stress to maternal endothelial dysfunction. Placenta 2009; 30:S55\u2013S65. 3. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of pre-eclampsia. N Engl J Med 2004; 350:672-683. 4. Conde-Agudelo A, Belizan JM. Risk factors for pre-eclampsia in a large cohort of Latin American and Caribbean women. BJOG 2000; 107:75-83. 5. Ferrazzi E, Zullino S, Stampalija T, et al. Bedside diagnosis of two major clinical phenotypes of hypertensive disorders of pregnancy. Ultrasound Obstet Gynecol 2016; 48:224-231 6. Todros T, Ferrazzi E, Nicolini U, et al. Fitting growth curves to head and abdomen measurements of the fetus: A multicentric study. J Clin Ultrasound 1987; 15:95-105. 7. Gomez O, Figueras F, Fernandez S, et al. Reference ranges for uterine artery mean pulsatility index at 11\u201341 weeks of gestation. Ultrasound Obstet Gynecol 2008; 32:128-132. 8. von Bertalanffy L. Quantitative laws in metabolism and growth. Q Rev Biol 1957; 32:217-231 9. Marubini E. Mathematical handling of long-term longitudinal data. In Human Growth, vol.1: Principles and Prenatal Growth; Falkner F, Tanner JM(eds). Plenum Press: New York 1978; 209-225 10. Bertino E, Spada E, Occhi L, et al. Neonatal anthropometric charts: the Italian neonatal study compared with other European studies. J Pediatr Gastroenterol Nutr 2010; 51:353-361

Modelling the progression of cervical dilatation in spontaneous labour

Introduction The first attempt to model the progression of cervical dilation during spontaneous labour of pregnant women dates back to 1955 [1]. From the graphical analysis of the time profiles of dilation observed in 500 women aged 13 to 42 years, the Author derived a mean labour sigmoid curve, consisting in a latent phase followed by an active phase ending in a deceleration phase. This cervimetric graph, or cervicogram, is still reported in current manuals of obstetrics. Zhang et al [2, 3] fitted cervical dilation profiles with mixed models based on 10th or 8th degree polynomials, and concluded that the duration of latent and active phases largely differs from woman to woman, and that there is no deceleration at the end of the active phase. For this reason, these Authors supply charts reporting the empirical 95th centile of the distribution of labour duration for different values of cervical dilation at admission to labour room, thus abandoning the idea of modelling the progression of cervical dilation. The aim of this presentation is to show the use of parsimonious nonlinear mixed models to trace cervimetric charts, reporting current cervical dilation vs time to full dilation. Data and methods Data here used derive from an observational study including 328 low-risk women (146 primiparae and 182 multiparae), who delivered at Buzzi Children\u2019s Hospital between April and June 2013 [4]. All women delivered vaginally at term, after uncomplicated single pregnancy and spontaneous labour managed by midwives, without any kind of medical intervention. We had to take into account a lot of difficulties and hindrances to construct a model for the progression of cervical dilation. The time of the beginning of labour is unknown (1); women are admitted to labour room at different degrees of dilation (2); cervical dilation measures are taken at irregular intervals as required by clinical practice (3); midwives usually assess cervical dilation with fingers, though the measure is reported in cm, from 0 (no dilation) to 10 (full dilation) (4); full cervical dilation is not indicated with a measure, but with a value of 10 cm, arbitrarily assigned to all women (5); individual dilation profiles are largely incomplete, a maximum of 5 measures per woman was recorded before full dilation, and only 60 women (18%) were assessed twice or more (6); the progression of cervical dilation is extremely erratic (7). Since dilation cannot be related to the unknown time from the onset of labour, we considered, as already suggested by Zhang et al [2], the time remaining to the attainment of full cervical dilation (t, time to full dilation), and expressed current dilation (yi(t), from 1 to 9 cm) observed in the ith woman as a function of a parsimonious nonlinear model (3 parameters only), instead of the 9 to 11 parameters of the polynomials used by Zhang et al [2, 3]: i i i i i(t) logit(y (t)/10) \u3b1= 7\u3b2+ log(t \u3b4+ ) \u3b5+ In {1}, logit(yi(t)/10) is a linear function of the log-transformation of time: parameter \u3b2i is the dilation velocity constant, the ratio \u3b1 \u3b2ii determines the time at maximum dilation velocity, and \u3b4i modulates the shape of the log-transformation of time; intra-individual random terms \u3b5i(t) were assumed to approximate a normal distribution, with variance proportional to {[E(yi(t))/10][1\u2013E(yi(t))}-1. When back-transformed to the original scale, expression {1} defines a family of strongly asymmetrical never-decreasing (since cervical dilation is an irreversible process) sigmoid curves, with a slight slowdown of dilation velocity a little before, or at full dilation, in this latter case the curve presents an exponential shape. Because cervical dilation profiles were largely incomplete, we could not resort to the usual two-stage models [5] to trace cervimetric charts, but we were forced to adopt a nonlinear mixed model [6], which can obtain estimates of the parameters of the individual cervical dilation curves also for the women with profiles made up by a number of observations lower the number of paramtes (in our case 1 or 2 assesments only): i 0 i P 0 i P 0 P i(t) logit(y (t)/10) \u3b1= \u3b1+ \u3b1+ x (\u3b2+ \u3b2+\u3b2+ x)log(t \u3b4+ \u3b4+ x) \u3b5+ {2} Parity (x=0 for primiparae, x=1 for multiparae) was included as a covariate into model {2}, since multiparae are known to progress somewhat faster in active-phase labour [7]. Parameters \u3b10 and \u3b20 refer to primiparae, \u3b1P and \u3b2P refer to the difference between multiparae and primiparae, whereas \u3b40 and \u3b4P modulate the log-transformation of time by parity. Random terms \u3b1i and \u3b2i, which model inter-individual differences, are assumed to have bivariate normal distribution with E(\u3b1i)=E(\u3b2i)=0 and unstructered covariance matrix Cov(\u3b1i,\u3b2i)=[ ] 2 2 \u3c3\u3b1 \u3c3\u3b1\u3b2 \u3c3\u3b2 , , . Models {1} and {2} were fitted using PROC NLIN and NLMIXED of SAS/STAT\uae software (SAS Institute, Cary, NC; v.9.4, 2013). Results Although based on 3 parameters only, model {1} proved to be flexible enough to describe cervical dilation profiles of rather different shape. As shown in figure 1 (left), concerning primiparous women, profiles may present an inflection point (i.e. a maximum dilation velocity) already 4 hours before the attainment of full dilation (orange curve) or at about 1 hour (dark red and green curves) or in the last half hour of the dilation process (the remaining profiles). Ten hours before the attainment of full dilation there are women with no more than 1 cm dilation and women with so much as 4 cm dilation. During the labour, dilation velocity may vary considerably from woman to woman: 10 hours before the attainment of full dilation, dilation velocity is always less than 0.5 cm/hr, but maximum velocity may be more than 3.5 cm/hr when initial dilation is 1 cm (red and blue curves) or be about 1 cm/hr when initial dilation is 4 cm (green curve). It is worth noting that women with different initial dilation (red curve: 1.7 cm, olive green curve: 2.7 cm) may present the same maximum velocity (1.7 cm/hr), since their dilation profiles differ in convexity. Figure 1 (right) shows, plotted on the cervicometric charts traced with mixed model {2}, the cervical dilation profiles (green lines) of the 95 primiparous women with 2 or more assessments and the dilation values (green dots) of the 51 women with 1 assessment only, predicted on the basis of model {2}. Green dots As expected, though individual profiles differ largely, the large majority of them lies completely within the interval 3rd \u2013 97th centile of the cervicometric charts. At 10 hours, the distribution of dilation values conditional on time to full dilation is highly right skewed, then positive skewness decreases and the distribution becomes symmetrical when median dilation is 5 cm, and left skewed subsequently. The same results were observed in the 182 multiparous women included in the study. We observe that a 4 cm dilation is the 97th centile 10 hours before the attainment of full dilation, and is the 3 rd centile at 0.5 hours. This means that, at 10 hours, 3% of women present more than 4 cm dilation, but that another 3% of women still present a 4 cm dilation half an hour before the end of dilation process. So a 4 cm dilation observed from 10 to 0.5 hours before the attainment of full dilation cannot be regarded as unusual. Analogously, at 10 hours, 10% and 25% of women present more than 3 and 2 cm dilation, respectively, but 10% and 25% of women still present a 3 or 2 cm dilation, 1 and 3 hours before the end of dilation process. Our data confirm that labour progresses faster in multiparae than in primiparae: e.g. a 5 cm dilation is achieved 45 min vs 1 hour and half before the end of dilation process in multiparae. Primiparae present a wider variability (+30% in terms of interquartile range) in the distribution of dilation values conditional on time to full dilation. Conclusions In 1955 Friedman [1] wrote: \u201cThe dynamic nature of parturitional change has, in the past, rendered exceedingly difficult the detailed and critical analysis of its vagaries\u201d. Actually, try to model the kinetics of the cervical dilation process turned out still to be a very hard task. Nonetheless some important points were established: (1) a parsimonious nonlinear parametric model is suitable to describe very different shapes of the dilation process, (2) mixed nonlinear models allow to trace plausible cervimetric charts even in the case of dilation profiles largely incomplete, (3) the above model provide quantitative estimates of the inter-individual variability and of the difference in the progression of cervical dilation between primiparae and multiparae. Unfortunately, the classical cervicograms give an unrealistic and useless picture of labour progression when referred to a single patient, the course of cervical dilation being largely erratic even in the case of spontaneous labour in uncomplicated pregnancies. In the first place, during labour the time remaining to the attainment of full cervical dilation is unknown, so the charts cannot be used in obstetric practice; in the second place a subsequent value of dilation cannot be predicted on the basis of the previous assessments. For these reasons, Ferrazzi et al [4] proposed cervimetric charts reporting the distribution of time needed to gain 1 cm in cervical dilation as a function of current dilation. Although theoretically usable, the practical value of these charts remains very low. In primiparous women, the time needed to gain 1 cm in dilation ranges from 10 (10th centile) to 110 min (90th centile) when current dilation is 1 cm, and from 5 to 70 min when current dilation is 9 cm. In multiparous women, the reference interval is somewhat narrower, the time needed ranging from 3 to 70 min when current dilation is 1 cm, and from 2 to 45 min when current dilation is 9 cm. On the basis of these results they concluded that the progression of cervical dilatation in normal human labour is unpredictable. References 1. Friedman EA. Primigravid labor. A graphicostatistical analysis. Obstetrics and Gynecology 1955; 6:567-589. 2. Zhang J, Troendle JF, Yancey MK. Reassessing the labor curve in nulliparous women. American Journal of Obstetrics and Gynecology 2002; 187:824-828. 3. Zhang J, Landy HJ, Branch DW, et al. Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstetrics and Gynecology 2010; 116:1281-1287. 4. Ferrazzi E, Milani S, Cirillo F, at al. Progression of cervical dilatation in normal human labor is unpredictable. Acta Obstet Gynecol Scand 2015; 94:1136-1144. 5. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics 1982; 38:963-974. 6. Goldstein H. Nonlinear multilevel models, with an application to discrete response data. Biometrika 1991; 78:45-51. 7. Friedman EA. An objective approach to the diagnosis and management of abnormal labor. Bull N Y Acad Med 1972; 48:842-858

Determining the reference range of blood presepsin in term and preterm neonates

Introduction Sepsis is still a major cause of morbidity and mortality in neonates, especially in preterm infants. Mortality can reach 60-70% in very low birth weight infants (birthweight 0.20). This reduced model explains 3.8% of the total sum of squares. After adjustment for all the factors in the model, presepsin levels appear to be significantly lower in twins (496 pg/ml \uf0b1 65.5 vs 655 pg/ml \uf0b1 11.8) and in neonates with Apgar at 1 min 658 (644 pg/ml \uf0b1 11.8 vs 774 pg/ml \uf0b1 56.2). So none of the above factors seems worth to be taken into account in determining the reference limits for presepsin blood levels in healthy term neonates. Preterm neonates. The largest differences in presepsin level are observed between small for gestational age (SGA) (903 pg/ml \uf0b1 57.1) and adequate for gestational age (AGA) neonates (703 pg/ml \uf0b1 26.7), between neonates with and without mechanical ventilation at blood sampling (1090 pg/ml \uf0b1 86.9 vs 711 pg/ml \uf0b1 24.7) and at delivery (855 pg/ml \uf0b1 87.3 vs 729 pg/ml \uf0b1 25.8), between neonates with and without venous catether (801 pg/ml \uf0b1 47.5 vs 716 pg/ml \uf0b1 28.9), between neonates who underwent blood sampling after the 4th day or before (797 pg/ml \uf0b1 46.2 vs 716 pg/ml \uf0b1 29.2), between males and females (778 pg/ml \uf0b1 35.1 vs 701 pg/ml \uf0b1 34.7). All these factors, when simultaneously introduced into a multivariable linear model, explain only 18.8% of the total sum of squares. A second multivariable linear model was fitted after removing the factors that showed the lowest effect on presepsin level (those associated with a p-value >0.50). This reduced model explains 13.4% of the total sum of squares. A third and more parsimonious multivariable linear model was fitted after removing the factors that showed the lowest effect on presepsin level (those associated with a p-value >0.20). This reduced model explains 12.3% of the total sum of squares. After adjustment for all the factors in the model, presepsin levels result to be significantly lower in AGA neonates (706 pg/ml \uf0b1 25.7 vs 890 pg/ml \uf0b1 55.0) and between neonates with and without mechanical ventilation at blood sampling (1074 pg/ml \uf0b1 85.3 vs 712 pg/ml \uf0b1 24.2). Even in this case, none of the above factors is expected to substantially affect the reference limits for presepsin blood levels in preterm neonates. Conclusion Presepsin blood levels seem to be quite independent of most of maternal and neonatal conditions examined in this study both in preterm and term neonates. The factors exerting significant effects (multiple birth and Apgar at 1 min, in term neonates, weight by gestational age and mechanical ventilation in preterm neonates) are expected to affect presepsin reference limits only to minor extent. References [1] Evaluation of a newly identified soluble CD14 subtype as a marker for sepsis. Yaegashi Y., Shirakawa K., Sato N., Suzuki Y., Kojika M., Imai S., Takahashi G., Miyata M., Furusako S., Endo S. J Infect Chemother. 2005;11:234-8. [2] CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infection in the acute care setting. Horan T.C., Andrus M., Dudeck M.A. Am J Infect Control. 2008;36:309-32

Usefulness of Presepsin (Soluble CD14 Subtype) in the Diagnosis of Neonatal Sepsis

Background: Sepsis is a major cause of morbidity and mortality in neonates. Recently, presepsin (soluble CD14 subtype) has been shown to be beneficial as sepsis marker in adults. Nevertheless, few data are available in neonates. Objective: To evaluate the diagnostic accuracy of presepsin as a marker of sepsis in the neonatal period. Design/Methods: All neonates with clinical signs of sepsis admitted to our Unit during a 18\uacmonths period were consecutively enrolled. CDC criteria were used to identify neonates with a suspected sepsis. The subjects enrolled in the study were then classified into 3 groups according to Goldstein's and Wynn's definitions: group 1, infection\u37e group 2, sepsis\u37e group 3, septic shock. To measure presepsin, 100 microliters of blood were collected at the following times: at the onset of clinical signs of sepsis (T0), every 12 h for the next 48 h (T1, T2, T3, T4), and at the end of antibiotic therapy (T5). C\uacreactive protein (CRP) was determined at the same times. Presepsin levels were determined using PathfastTM System (LSI Medience Corporation, Japan/Mitsubishi Chemical Europe). Results: We enrolled 110 neonates: 36 in group 1 (mean GA 34.6 wks, mean BW 2403 g), 59 in group 2 (mean GA 31 wks, mean BW 1615 g) and 15 in group 3 (mean GA 30.2 wks, mean BW 1441 g). Overall, median presepsin value was 1146 pg/ml at T0, higher than the values we previously reported in healthy neonates (PAS Meeting 2015), and decreased over time to 726 pg/ml at T5. Presepsin levels were significantly higher in neonates with sepsis and in those with septic shock than in the others at T0, T1, T2, T3, and T4 (p < .05). Additionally, neonates with septic shock had higher levels of presepsin than those with sepsis at all times. At enrollment, median presepsin value was 874 pg/ml, 1277 pg/ml, and 1928 pg/ml in group 1, 2, and 3 respectively. No significant difference was found in CRP values among the 3 groups at enrollment. The area under the ROC curve for presepsin at enrollment was 0.839 (95% CI: 0.79\uac0.88). Maximum Youden index was at a cut\uacoff value of 865 pg/ml, corresponding to 75% sensitivity and 80% specificity. Conclusions: According to our results, presepsin appears an accurate biomarker for the diagnosis of neonatal sepsis and it seems to be earlier than CRP in identifying sepsis and septic shock

Impaired photosystem I oxidation induces STN7-dependent phosphorylation of the light-harvesting complex I protein Lhca4 in Arabidopsis thaliana

Reduction of the plastoquinone (PQ) pool is known to activate phosphorylation of thylakoid proteins. In the Arabidopsis thaliana mutants psad1-1 and psae1-3, oxidation of photosystem I (PSI) is impaired, and the PQ pool is correspondingly over-reduced. We show here that, under these conditions, the antenna protein Lhca4 of PSI becomes a target for phosphorylation. Phosphorylation of the mature Lhca4 protein at Thr16 is suppressed in stn7 psad1 and stn7 psae1 double mutants. Thus, under extreme redox conditions, hyperactivation of thylakoid protein kinases and/or reorganization of thylakoid protein complex distribution increase the susceptibility of PSI to phosphorylation

Incidence, mortality, and survival of hematological malignancies in Northern Italian patients: an update to 2020

BackgroundHematological malignancies (HMs) represent a heterogeneous group of diseases with diverse etiology, pathogenesis, and prognosis. HMs' accurate registration by Cancer Registries (CRs) is hampered by the progressive de-hospitalization of patients and the transition to molecular rather than microscopic diagnosis. Material and methodsA dedicated software capable of automatically identifying suspected HMs cases by combining several databases was adopted by Reggio Emilia Province CR (RE-CR). Besides pathological reports, hospital discharge archives, and mortality records, RE-CR retrieved information from general and biomolecular laboratories. Incidence, mortality, and 5-year relative survival (RS) reported according to age, sex, and 4 HMs' main categories, were noted. ResultsOverall, 7,578 HM cases were diagnosed from 1996 to 2020 by RE-CR. HMs were more common in males and older patients, except for Hodgkin Lymphoma and Follicular Lymphoma (FL). Incidence showed a significant increase for FL (annual percent change (APC)=3.0), Myeloproliferative Neoplasms (MPN) in the first period (APC=6.0) followed by a significant decrease (APC=-7.4), and Myelodysplastic Syndromes (APC=16.4) only in the first period. Over the years, a significant increase was observed in 5-year RS for Hodgkin -, Marginal Zone -, Follicular - and Diffuse Large B-cell-Lymphomas, MPN, and Acute Myeloid Leukemia. The availability of dedicated software made it possible to recover 80% of cases automatically: the remaining 20% required direct consultation of medical records. ConclusionsThe study emphasizes that HM registration needs to collect information from multiple sources. The digitalization of CRs is necessary to increase their efficiency