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Introduction: COVID‐19 pandemic had a considerable impact among haematological patients. On the other hand, the effect of this disease on patients (pts) affected by Chronic Myeloid Leukemia (CML) is not clearly defined. Objectives: The primary objective of this study was to evaluate mortality‐hospitalization rates and possible protective factors for hospitalization in CML pts affected by COVID. Methods: We collected data from CML patients followed at our institution whotested positive for SARS‐CoV‐2 infection. The following variables were assessed: demographical data, type of TKI therapy, vaccination status, presence of cardiovascular disease (CVD), period of infection, COVID‐19 presenting symptoms, severity and mortality. Data were collected retrospectively and then analysed in univariate and multivariate analysis. Results: Out of a total of 325 CML pts treated at our institution, we recorded 72 SARS‐CoV‐2pts (22%) who tested positive with a SARS‐CoV‐2 PCR assay. Twenty two were infected in 2020 (30%), 16 patients in 2021 (22%) and 34 in 2022 (46%); with a hospitalization rate of 27%, 25% and 3% respectively. Of the 72 confirmed infections, 13 pts (18%; (CI) 10–28) were asymptomatic and 48 (66%; CI: 55–76) had mild symptoms. A total of 11 pts were admitted to hospital and 3 of these required ICU admission. No deaths were recorded. The probability of hospitalization was significantly reduced if patients were vaccinated (odds ratio OR 0.037 with CI: 0–0.33 p 0.002) or treated with Bosutinib (OR 0.06 with CI: 0–0.5 p 0.008). Conclusion: In the present study, no significant increase in mortality was noted among patients with CML as compared to the general population inItaly. Vaccination and treatment with bosutinib were identified as baseline characteristics that were associated with a decreased risk of hospitalitazion resulting from COVID‐19 infection. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of the active phase of labor is a crucial clinical decision, thus requiring an accurate assessment. This study aimed to build and to validate a predictive model, based on maternal signs and symptoms to identify a cervical dilatation ≥4 cm.Methods: A prospective study was conducted from May to September 2018 in a II Level Maternity Unit (development data), and from May to September 2019 in a I Level Maternity Unit (validation data). Women with singleton, term pregnancy, cephalic presentation and presence of contractions were consecutively enrolled during the initial assessment to diagnose the stage of labor. Women < 18 years old, with language barrier or induction of labor were excluded. A nomogram for the calculation of the predictions of cervical dilatation ≥4 cm on the ground of 11 maternal signs and symptoms was obtained from a multivariate logistic model. The predictive performance of the model was investigated by internal and external validation.Results: A total of 288 assessments were analyzed. All maternal signs and symptoms showed a significant impact on increasing the probability of cervical dilatation ≥4 cm. In the final logistic model, "Rhythm" (OR 6.26), "Duration" (OR 8.15) of contractions and "Show" (OR 4.29) confirmed their significance while, unexpectedly, "Frequency" of contractions had no impact. The area under the ROC curve in the model of the uterine activity was 0.865 (development data) and 0.927 (validation data), with an increment to 0.905 and 0.956, respectively, when adding maternal signs. The Brier Score error in the model of the uterine activity was 0.140 (development data) and 0.097 (validation data), with a decrement to 0.121 and 0.092, respectively, when adding maternal signs.Conclusion: Our predictive model showed a good performance. The introduction of a non-invasive tool might assist midwives in the decision-making process, avoiding interventions and thus offering an evidenced-base care. [ABSTRACT FROM AUTHOR]

Background: One cause of poor outcomes in children of low-income countries affected by acute lymphoblastic leukaemia (ALL) is loss to follow-up due to abandonment of treatment. Assuming this type of loss to follow-up as independent censoring, as in standard Kaplan-Meier estimates, ignores the likely association of abandonment with biologic and socio-economic factors related to outcome. Moreover, when comparing treatment protocols adopted in different time periods, possible imbalances in patients' characteristics must be considered. We aim to compare the outcome of children enrolled in two subsequent protocols for ALL treatment (2000-2007 and 2008-2015) in Honduras, taking both dependent censoring due to abandonment of treatment and imbalances between patient characteristics into account.Methods: Marginal structural models based on inverse probability of treatment and censoring (IPTC) weighting allow the estimation of potential event-free survival (EFS) as if no abandonment of treatment occurred and the whole cohort was exposed, or not, to both protocols. An Aalen additive model and a logistic-regression model were used to build abandonment and treatment weights, respectively.Results: The two protocols recruited 514 and 717 patients. Measured baseline covariates in both protocols were gender, age, white blood cell count, central nervous system involvement, tumour histology and socio-economic status. The potential EFS is slightly higher under the more recent protocol in the first 3 years but no difference is estimated in the long period [survival difference at 5 years (95% confidence interval) = 0.1% (-0.97%; 1.13%)]. Both protocols would allow reducing the event rate by 12-13% if there was no abandonment of treatment.Conclusions: Using IPTC weighting, we found a similar potential effect of the two treatment protocols if the imbalance due to the different distribution of potential confounders and to abandonment of therapy was removed. [ABSTRACT FROM AUTHOR]

There is limited information on the prevalence of dyslipidemia in the Italian pediatric population. Aim of the study was to evaluate total cholesterol, high-density lipoprotein (HDL)-cholesterol and triglyceride levels, and associated factors in a large sample of Italian children, applying a micro-sampling procedure in the family pediatrician's office. In a population of 1910 children (50.2% males, age 7–11 years), 27.6% was overweight or obese and 28.3% had at least one parent with referred hypercholesterolemia. Total cholesterol and triglyceride levels were elevated in 4.5% and 23.5% of the subjects, respectively, while HDL cholesterol was below 40 mg/dl in 3.3%. Male gender (OR 1.58, 95% CI 1.01–2.49) and positive family history (OR 2.13, 95% CI 1.36–3.32) were independent predictors of hypercholesterolemia, while BMI z-score was associated with low HDL cholesterol (OR 1.46, 95% CI 1.13–1.88) and high levels of triglycerides (OR 1.39, 95% CI 1.26–1.55). Conclusion: The prevalence of dyslipidemia in our sample is worthy of attention. The study suggests the opportunity and feasibility to check for the presence of dyslipidemia at the family pediatrician's office. Familiarity is associated with high cholesterol levels, regardless of the children's weight class, while weight excess identifies subjects with the typical lipid profile of metabolic syndrome. What is Known: • Few data are available on the lipid profile in Italian children. • Early treatment of hypercholesterolemia is effective in reducing cardiovascular events later in life; there is no agreement on how to screen for dyslipidemia in childhood, however. What is New: • In a large sample of Italian children, familiarity doubles the risk of hypercholesterolemia, while increased BMI is associated with low HDL cholesterol levels and hypertriglyceridemia. • The pediatrician may perform an assessment of plasma lipids in his office as a first step to diagnose familial hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Objective: To investigate women's decision to undergo non-invasive and/or invasive tests for prenatal diagnosis depending on the procedure-related risk and the risk of carrying a foetus with Down syndrome (DS). Both risks are rated in terms of numerical relevance and acceptability.Method: A sample of 448 consecutive women with low-risk pregnancies were interviewed to collect social and clinical variables and to determine their perceptions of the risks of invasive procedure-related miscarriage and carrying a foetus with DS. The risks were scored numerically in terms of their relevance and acceptability using a 10-point rating scale.Results: The factors related to the use of non-invasive tests were age ≥35 years, not being treated at a public service, rating the risk of carrying a foetus with DS as having high numerical relevance and low acceptability, and rating the risk of miscarriage as having high acceptability. These relationships were still present when the use of invasive tests was considered, except in terms of the numerical relevance of the risk of carrying a foetus with DS.Conclusion: Perceived acceptability affects the interpretation of a given risk more than the numerical relevance of the risk. [ABSTRACT FROM AUTHOR]

The influence of feeding patterns on the growth of infants and how salt is included in the diet are unknown in the area of West Bengal, India. A cross-sectional study was carried on 517 infants (median age 6.5 months). Negative Z-scores were observed for all anthropometric parameters. About 72.7% of infants aged 0–6 months received exclusive breastfeeding. In the 6–12-month-old group (n = 235), 91.5% had salt added to foods. In a regression model adjusted for age, a low salt diet resulted a significant factor in increasing weight-for-length and BMI for age z-scores, with increments equal to 0.637 SD (p = 0.037) and 0.650 SD (p = 0.036), respectively. In West Bengal infants showing poor growth, breastfeeding was associated with better anthropometric indexes, but early in life salt is added to their diet. Early life low weight coupled with high salt intake may be a risk factor for arterial hypertension in Indian children. [ABSTRACT FROM PUBLISHER]

Background: In many studies, some information might not be available for the whole cohort, some covariates, or even the outcome, might be ascertained in selected subsamples. These studies are part of a broad category termed two-phase studies. Common examples include the nested case-control and the case-cohort designs. For two-phase studies, appropriate weighted survival estimates have been derived; however, no estimator of cumulative incidence accounting for competing events has been proposed. This is relevant in the presence of multiple types of events, where estimation of event type specific quantities are needed for evaluating outcome.Methods: We develop a non parametric estimator of the cumulative incidence function of events accounting for possible competing events. It handles a general sampling design by weights derived from the sampling probabilities. The variance is derived from the influence function of the subdistribution hazard.Results: The proposed method shows good performance in simulations. It is applied to estimate the crude incidence of relapse in childhood acute lymphoblastic leukemia in groups defined by a genotype not available for everyone in a cohort of nearly 2000 patients, where death due to toxicity acted as a competing event. In a second example the aim was to estimate engagement in care of a cohort of HIV patients in resource limited setting, where for some patients the outcome itself was missing due to lost to follow-up. A sampling based approach was used to identify outcome in a subsample of lost patients and to obtain a valid estimate of connection to care.Conclusions: A valid estimator for cumulative incidence of events accounting for competing risks under a general sampling design from an infinite target population is derived. [ABSTRACT FROM AUTHOR]

Prehospital field triage often fails to accurately identify the need for emergent surgical or non-surgical procedures, resulting in inefficient resource utilization and increased costs. This study aimed to analyze prehospital factors associated with the need for emergent procedures (such as surgery or interventional angiography) within 6 h of hospital admission. Additionally, our goal was to develop a prehospital triage tool capable of estimating the likelihood of requiring an emergent procedure following hospital admission. We conducted a retrospective observational study, analyzing both prehospital and in-hospital data obtained from the Lombardy Trauma Registry. We conducted a multivariable logistic regression analysis to identify independent predictors of emergency procedures within the first 6 h from admission. Subsequently, we developed and internally validated a triage score composed of factors associated with the probability of requiring an emergency procedure. The study included a total of 3985 patients, among whom 295 (7.4%) required an emergent procedure within 6 h. Age, penetrating injury, downfall, cardiac arrest, poor neurological status, endotracheal intubation, systolic pressure, diastolic pressure, shock index, respiratory rate and tachycardia were identified as predictors of requiring an emergency procedure. A triage score generated from these predictors showed a good predictive power (AUC of the ROC curve: 0.81) to identify patients requiring an emergent surgical or non-surgical procedure within 6 h from hospital admission. The proposed triage score might contribute to predicting the need for immediate resource availability in trauma patients. [ABSTRACT FROM AUTHOR]

Background: Cut-point finding is a crucial step for clinical decision making when dealing with diagnostic (or prognostic) biomarkers. The extension of ROC-based cut-point finding methods to the case of censored failure time outcome is of interest when we are in the presence of a biomarker, measured at baseline, used to identify whether there will be the development, or not, of some disease condition within a given time point τ of clinical interest. Methods: Three widely used cut-point finding methods, namely the Youden index, the concordance probability and the point closest to-(0,1) corner in the ROC plane, are extended to the case of censored failure time outcome resorting to non-parametric estimators of the sensitivity and specificity that account for censoring. The performance of these methods in finding the optimal cut-point is compared under Normal and Gamma distributions of the biomarker (in subjects developing or not the disease condition). Normality ensures that estimators point theoretically to the same cut-point. Two motivating examples are provided in the paper. Results: The point closest-to-(0,1) corner approach has the best performance from simulations in terms of mean square error and relative bias. Conclusions: We discuss the use of the Youden index or concordance probability associated to the cut-point identified through the closest-to-(0,1) corner approach to ease interpretability of the classification performance of the dichotomized biomarker. In addition, the achieved performance of the dichotomized biomarker classification associated to the estimated cut-point can be represented through a confidence interval of the point on the ROC curve. [ABSTRACT FROM AUTHOR]

This work focuses on the assessment of the discrimination ability of a binary marker to identify patients that will relapse in time. We consider the cumulative definition of sensitivity and dynamic definition of specificity at a time horizon, that is, the probability of a positive marker in the population that will relapse ( cases) and that will not relapse ( controls). In the presence of censoring, sensitivity and specificity cannot be estimated by proportions because it is not known whether censored subjects should be considered as cases or controls. The solutions proposed do not enable to obtain asymptotic confidence intervals. We explore the use of inverse probability of censoring weighting/imputation (borrowed from the methodology used to correct for verification bias) to adjust the classification matrix for the presence of censoring. The adjustment based on weights estimated conditional on the marker turned to be equivalent to the adjustment based on imputation. These approaches, which address for the presence of marker-dependent censoring, showed a better performance than the adjustment based on weights estimated on the entire sample, even in the case of marker-independent censoring. We derived single intervals and confidence region for sensitivity and 1-specificity using the delta method. The confidence region is particularly useful for a binary marker because the marker has some ability to discriminate among cases and controls only if the region does not intersect the first quadrant bisector. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. Patients and Methods Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (±3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan–Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch–Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ2 distribution. All statistical tests were two-sided. Results A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. Conclusions In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: To evaluate oxidative stress in uremia and dialysis and chromogranin A, a stress hormone that could be related to oxidative processes. Methods: Plasma oxidative stress biomarkers (–SH, 8-OHdG, and ox-LDL) and chromogranin A were measured in 89 outpatients (21 uremic patients, 17 in peritoneal dialysis, and 51 in haemodialysis), and in 18 subjects with normal renal function. Results: –SH groups were significantly reduced in heamodialysis, peritoneal, and uremic patients as compared with the control group (p =0.01), while 8-OHdG was increased (p <0.01). No differences were observed for ox-LDL. Chromogranin A was increased in uremic, peritoneal and haemodialysis patients (p <0.01), showing a positive correlation to 8-OHdG (p <0.01). Conclusion: Oxidative stress biomarkers and chromogranin A levels differ between control subjects when compared to both uremic and dialysis patients. No differences were observed between uremic and dialysis patients, suggesting that uremia is the major source of the increase in oxidative stress and CgA levels in patients with end stage renal disease. [Copyright &y& Elsevier]

Abstract: A common aim of clinical research is the identification of patients at different prognosis, so that future treatment protocols may be tailored to patients’ risk profiles. Establishing a prognostic classification is a difficult process, especially in rare cancers: the availability of a growing number of candidate prognostic factors may lead to competitive stratifications, whose validation may not be feasible due to small numbers and the need for a long follow-up. Our goal is to illustrate a strategy to compare stratifications, based on the performance in clinically relevant subgroups of patients. We investigated different statistical measures and recommend a strategy based on the Brier Score, a measure of prediction inaccuracy on individual survival. Results on an infant leukaemia study show that this method is flexible and easily applied with common statistical software. The method, however, does not overcome the problem of lack of validation on external data. [Copyright &y& Elsevier]

To derive models suitable for outcome prediction, a crucial aspect is the availability of appropriate measures of predictive accuracy, which have to be usable for a general class of models. The Harrell's C discrimination index is an extension of the area under the ROC curve to the case of censored survival data, which owns a straightforward interpretability. For a model including covariates with time-dependent effects and/or time-dependent covariates, the original definition of C would require the prediction of individual failure times, which is not generally addressed in most clinical applications. Here we propose a time-dependent discrimination index Ctd where the whole predicted survival function is utilized as outcome prediction, and the ability to discriminate among subjects having different outcome is summarized over time. Ctd is based on a novel definition of concordance: a subject who developed the event should have a less predicted probability of surviving beyond his/her survival time than any subject who survived longer. The predicted survival function of a subject who developed the event is compared to: (1) that of subjects who developed the event before his/her survival time, and (2) that of subjects who developed the event, or were censored, after his/her survival time. Subjects who were censored are involved in comparisons with subjects who developed the event before their observed times. The index reduces to the previous C in the presence of separation between survival curves on the whole follow-up. A confidence interval for Ctd is derived using the jackknife method on correlated one-sample U-statistics. The proposed index is used to evaluate the discrimination ability of a model, including covariates having time-dependent effects, concerning time to relapse in breast cancer patients treated with adjuvant tamoxifen. The model was obtained from 596 patients entered prospectively at Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano (INT). The model discrimination ability was validated on an independent testing data set of 175 patients provided by Centro Regionale Indicatori Biochimici di Tumore (CRIBT) in Venice. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The area under the receiver operating characteristic curve (overall C) is a widely used measure of a prognostic model discrimination. In this paper, we develop a nonparametric test for the comparison of two correlated C indexes of two different models when applied to the same population. We extend the DeLong's approach and use the theory of the jackknife methodology applied to correlated one sample generalized U-statistics. We derive the distribution of correlated estimators of C indexes as well as a consistent estimate of the asymptotic variance, leading to an asymptotically normal test. [ABSTRACT FROM AUTHOR]

Background: Elevated lipoprotein (Lp(a)) levels are associated with increased risk of atherosclerotic processes and cardiovascular events in adults. The amount of Lp(a) is mainly genetically determined. Therefore, it is important to identify individuals with elevated Lp(a) as early as possible, particularly if other cardiovascular risk factors are present. The purpose of the study was to investigate whether, in a population of children and adolescents already followed for the presence of one or more cardiovascular risk factors (elevated blood pressure (BP), and/or excess body weight, and/or dyslipidemia), the measurement of Lp(a) can be useful for better stratifying their risk profile. Methods: In a sample of 195 children and adolescents, height, body weight, waist circumference and systolic (SBP) and diastolic (DBP) BP were measured. Body Mass Index (BMI) and SBP and DBP z-scores were calculated. Plasma Lp(a), total cholesterol, high-density lipoprotein (HDL), triglycerides, glucose, insulin, uric acid and creatinine were assessed. Low-density lipoprotein (LDL) cholesterol was calculated with the Friedewald formula. High Lp(a) was defined as ≥ 75 nmol/L and high LDL cholesterol as ≥ 3.37 mmol/L. Results: Our sample of children and adolescents (54.4% males, mean age 11.5 years) had median LDL cholesterol and Lp(a) values equal to 2.54 (interquartile range, IQR: 2.07–3.06) mmol/L and 22 (IQR: 7.8–68.6) nmol/L respectively. 13.8% of children had LDL cholesterol ≥ 3.37 mmol/L and 22.6 Lp(a) values ≥ 75 nmol/L. Lp(a) values were higher in children of normal weight than in those with excess weight (p = 0.007), but the difference disappeared if normal weight children referred for dyslipidemia only were excluded from the analysis (p = 0.210). 69.4% of children had normal Lp(a) and LDL cholesterol values and only 6.2% showed both elevated Lp(a) and LDL cholesterol levels. However, 16.6% of the sample, despite having normal LDL cholesterol, had elevated Lp(a) values. Multivariable analyses showed a significant association of LDL cholesterol both with Lp(a) values, and with the presence of elevated Lp(a) levels. For each mmol/L increase in LDL cholesterol the risk of having an elevated Lp(a) value increased by 73%. There was an inverse correlation between BMI z-score and Lp(a). Neither BP z-scores, nor other biochemical parameters were associated with Lp(a). Conclusions: In our population more than one out of five children had elevated Lp(a) values, and in about 17% of children elevated Lp(a) values were present in the absence of increased LDL cholesterol. Our results suggest that Lp(a) measurement can be useful to better define the cardiovascular risk profile in children and adolescents already followed for the presence of other cardiovascular risk factors such as elevated BP, excess body weight and high LDL cholesterol. [ABSTRACT FROM AUTHOR]

Background: The recent progress in medical research generates an increasing interest in the use of longitudinal biomarkers for characterizing the occurrence of an outcome. The present work is motivated by a study, where the objective was to explore the potential of the long pentraxin 3 (PTX3) as a prognostic marker of Acute Graft-versus-Host Disease (GvHD) after haematopoietic stem cell transplantation. Time-varying covariate Cox model was commonly used, despite its limiting assumptions that marker values are constant in time and measured without error. A joint model has been developed as a viable alternative; however, the approach is computationally intensive and requires additional strong assumptions, in which the impacts of their misspecification were not sufficiently studied.Methods: We conduct an extensive simulation to clarify relevant assumptions for the understanding of joint models and assessment of its robustness under key model misspecifications. Further, we characterize the extent of bias introduced by the limiting assumptions of the time-varying covariate Cox model and compare its performance with a joint model in various contexts. We then present results of the two approaches to evaluate the potential of PTX3 as a prognostic marker of GvHD after haematopoietic stem cell transplantation.Results: Overall, we illustrate that a joint model provides an unbiased estimate of the association between a longitudinal marker and the hazard of an event in the presence of measurement error, showing improvement over the time-varying Cox model. However, a joint model is severely biased when the baseline hazard or the shape of the longitudinal trajectories are misspecified. Both the Cox model and the joint model correctly specified indicated PTX3 as a potential prognostic marker of GvHD, with the joint model providing a higher hazard ratio estimate.Conclusions: Joint models are beneficial to investigate the capability of the longitudinal marker to characterize time-to-event endpoint. However, the benefits are strictly linked to the correct specification of the longitudinal marker trajectory and the baseline hazard function, indicating a careful consideration of assumptions to avoid biased estimates. [ABSTRACT FROM AUTHOR]

Aim Design Methods Results Conclusions Implications for the Profession and/or Patient Care Impact Reporting Method Patient or Public Contribution To describe if first‐time parents' expectations of labour and birth, explored during the third trimester of pregnancy, were fulfilled or not when investigated 1 year following birth.Qualitative Husserlian phenomenological approach.The sample comprises 10 parents (five couples), who participated in an online semi‐structured audio‐recorded individual interview conducted 1 year after birth, between September 2020 and October 2020. Parents' expectations of labour and birth, described throughout a focus group discussion on pregnancy, were compared with their experience explored 1 year after birth. A thematic analysis was adopted and member checking was used to validate participants' thoughts.Participants gave birth in a II level maternity unit and one‐to‐one midwifery care was provided. Although during the focus group conducted in pregnancy, women reported being aware of the unpredictable nature of childbirth, they expressed sadness and failure after experiencing some unexpected interventions. The midwife was a reassuring guide, as expected; however, sometimes, the communication was not effective, and women perceived lack of support. Some women partly blame themselves for not being prepared to manage labour pain, which hurt more than expected. Feeling of uncertainty about events were experienced in relation to seeking care at an early stage of labour, which confirmed the fears expressed during pregnancy. During the antenatal focus group discussion, fathers doubted they could be helpful for the labouring women. This negative emotion was confirmed after birth. However, they understood the importance to be present and to support their partner.One year after birth, participants had consistent memories of their birth experience. Professionals might identify fundamental components of quality maternity care that are meaningful for parents, with the potential to generate a long‐term positive health impact on them. Respectful maternity care should be ensured through a family‐centred approach, with the aim to promote satisfaction.The study highlights the importance of taking parents' expectations into account when providing antenatal care to tailor individualized support that addresses their distinct needs and preferences. Healthcare professionals might consider initiating a post‐natal discussion with parents to assess whether their needs and perspectives have been addressed. This perspective may present valuable insights to achieve long‐term positive outcomes, provide high‐quality maternity care, address issues and make improvements.The study showed that 1 year after birth, parents can accurately recall their birth. They might also give significant insights into fundamental components of care that they value as crucial to shape a positive birthing experience. Professionals should use this information to build solutions, promoting long‐term well‐being for parents. Respectful interactions and trusting relationships emerged as key elements in parents' experience. A midwifery care focused on parents' needs may contribute to the achievement of positive birth memories.This study used the Standards for Reporting Qualitative Research checklist.No patient or public contribution. [ABSTRACT FROM AUTHOR]

The vacuolar proton-translocating ATPase (V-ATPase) is a transmembrane multi-protein complex fundamental in maintaining a normal intracellular pH. In the tumoral contest, its role is crucial since the metabolism underlying carcinogenesis is mainly based on anaerobic glycolytic reactions. Moreover, neoplastic cells use the V-ATPase to extrude chemotherapy drugs into the extra-cellular compartment as a drug resistance mechanism. In glioblastoma (GBM), the most malignant and incurable primary brain tumor, the expression of this pump is upregulated, making it a new possible therapeutic target. In this work, the bafilomycin A1-induced inhibition of V-ATPase in patient-derived glioma stem cell (GSC) lines was evaluated together with temozolomide, the first-line therapy against GBM. In contrast with previous published data, the proposed treatment did not overcome resistance to the standard therapy. In addition, our data showed that nanomolar dosages of bafilomycin A1 led to the blockage of the autophagy process and cellular necrosis, making the drug unusable in models which are more complex. Nevertheless, the increased expression of V-ATPase following bafilomycin A1 suggests a critical role of the proton pump in GBM stem components, encouraging the search for novel strategies to limit its activity in order to circumvent resistance to conventional therapy. [ABSTRACT FROM AUTHOR]

As health care workers (HCWs) who care for children, who usually demonstrate milder symptoms than adults, family paediatricians have an increased risk of exposure to coronavirus. In April 2020, the Sindacato Medici Pediatri di Famiglia (SIMPeF), provided its members with rapid tests to detect antibodies against SARS-CoV-2; 1240 individuals, including 377 paediatricians, 108 staff members of pediatric clinics, and 755 cohabitant relatives of paediatricians, were tested in Lombardy, the most affected Italian region. The global prevalence of IgG antibodies in these individuals was 20.7%, which is higher than that of the general population and other HCWs. More than 70% of subjects with IgG antibodies presented symptoms, and 4.9% needed hospitalization. In addition, 64.2% of the study participants reported close contacts with a suspected case of COVID-19, while 72.9% of the family paediatricians reported occupational exposure to the disease. The initiative of the SIMPeF has been useful in assessing the impact of the COVID-19 pandemic on paediatric settings, as well as in raising paediatricians' awareness of the spreading of coronavirus. [ABSTRACT FROM AUTHOR]

Background: Evidence on the safety and appropriateness of vaginal birth after caesarean (VBAC) appears clear, but knowledge about women's choice towards this mode of birth is limited. Aims: To identify variables related to women's decision-making about whether to try for VBAC. Method and findings: Cross-sectional study was conducted. Feelings of body failure towards the previous birth and the desire to have a vaginal birth were associated with maternal choice of VBAC. Women who perceived a repeated section as being dangerous for them opted for a VBAC (p=0.030). Opinion of women with the same experience and information found online were implicated into maternal decision-making. Conclusion: This is the first Italian study to confirm that maternal choice is complex and involves many factors. Midwives and obstetricians should strive to provide an evidence-based midwifery care, in order to offer a VBAC as a safe birth option. [ABSTRACT FROM AUTHOR]

Aim Design Methods Results Conclusion Impact Reporting Method Patient or Public Contribution What does this paper contribute to the wider global clinical community? To evaluate midwives' level of stress and burnout during the COVID‐19 Omicron phase in Italy. Secondary aims were to explore the impact of the pandemic on midwives' personal dimensions and professional activities and potential supporting strategies.A mixed‐methods study was undertaken from July to December 2022.Data were collected using a national online observational survey. Descriptive and inferential analyses were performed to evaluate stress, burnout and the impact of the pandemic on personal and professional dimensions. A deductive qualitative approach was used to analyse open‐ended responses, that were merged with quantitative data following a convergent mixed‐methods approach.A total of 1944 midwives participated in the survey. The stress summary score mean was 10.34, and 562 midwives (28.91%) experienced burnout. The intention to reduce working hours was reported by 202 midwives (10.39%), with 60.40% (n = 122) of them experiencing burnout. The intention to leave clinical practice within the following 2 years was reported by 239 (12.29%), with 68.20% (n = 163) of them experiencing burnout. All the personal dimensions and professional activities considered were defined by more than half of midwives as being impacted ‘Moderately’ or ‘To a great extent’ by pandemic. Stress and burnout frequencies increased when the midwives' perception of the pandemic effects was higher. Potential supporting strategies described by midwives as the most important in increasing their ability to cope with the pandemic were ‘Women's awareness of the midwives' role’ (n = 1072; 55.14%) and ‘Family and friends' emotional support’ (n = 746; 38.38%).Our findings suggested strategies to support a positive and safe working environment for midwives during a pandemic emergency, with potential transferability to similar contexts when human resources are lacking. It is recommended that maternity services provide the necessary resources for a safe and supportive working environment to prevent high stress levels and chronic burnout.Studies conducted during the first COVID‐19 pandemic wave showed an increased level of stress, anxiety, burnout, post‐traumatic stress disorder and depression experienced by healthcare professionals; moreover, midwives experienced drastic changes in care pathways and policies with struggles identified when providing high‐quality woman‐centred care following pandemic restrictions. Although it is recommended, there is lack of knowledge about long‐term psychological effects of COVID‐19 for midwives. Our study highlights that during the Omicron wave midwives experienced a high level of stress and burnout with an impact on individual dimensions and professional activities. Their stress and burnout were influenced by several factors, including restrictions in place, lack of organizational acknowledgement, work overload and need for extra childcare cover. Maternity services should provide the necessary resources for a safe and supportive working environment to prevent high stress levels and chronic burnout. Recommendations on how to facilitate this are suggested.During the writing process, we referred to ‘The Strengthening the Reporting of Observational Studies Epidemiology Statement’, the guidelines for reporting observational studies from the Equator network.No patient or public contribution.Work overload conditions negatively impacted on the quality of maternity services. Improving organizational aspects, reducing working hours, promoting family and friends' emotional support and improving women's awareness of midwife's role were the main strategies reported by midwives. These suggestions for ensuring a positive and safe working environment for midwives during a pandemic emergency could potentially be applied to similar situations where human resources are lacking. [ABSTRACT FROM AUTHOR]

Background: In any single-arm trial on novel treatments, assessment of toxicity plays an important role as occurrence of adverse events (AEs) is relevant for application in clinical practice. In the presence of a non-fatal time-to-event(s) efficacy endpoint, the analysis should be broadened to consider AEs occurrence in time. The AEs analysis could be tackled with two approaches, depending on the clinical question of interest. Approach 1 focuses on the occurrence of AE as first event. Treatment ability to protect from the efficacy endpoint event(s) has an impact on the chance of observing AEs due to competing risks action. Approach 2 considers how treatment affects the occurrence of AEs in the potential framework where the efficacy endpoint event(s) could not occur. Methods: In the first part of the work we review the strategy of analysis for these two approaches. We identify theoretical quantities and estimators consistent with the following features: (a) estimators should address for the presence of right censoring; (b) theoretical quantities and estimators should be functions of time. In the second part of the work we propose the use of alternative methods (regression models, stratified Kaplan-Meier curves, inverse probability of censoring weighting) to relax the assumption of independence between the potential times to AE and to event(s) in the efficacy endpoint for addressing Approach 2. Results: We show through simulations that the proposed methods overcome the bias due to the dependence between the two potential times and related to the use of standard estimators. Conclusions: We demonstrated through simulations that one can handle patients selection in the risk sets due to the competing event, and thus obtain conditional independence between the two potential times, adjusting for all the observed covariates that induce dependence. [ABSTRACT FROM AUTHOR]

Background: It is not known whether, in children and adolescents with alterations in weight and/or blood pressure (BP), lifestyle modifications are associated with an improvement of early cardiac damage. Methods: In a pediatric population referred for excess weight, high BP, or both (n = 278, 10.6 (2.3) years), echocardiography was performed at enrollment and after 15 months of follow-up, during which participants received nonpharmacological treatment, based on correcting unhealthy lifestyles and improving dietary habits. Left ventricular mass was indexed for height (g/m2.7, LVMI), and an LVMI value higher than or equal to age- and gender-specific 95th percentile was the criterion for defining left ventricular hypertrophy (LVH). Multiple linear and logistic regression analyses were carried out to determine associations between changes in BMI and BP z-scores and changes of LVMI values and LVH prevalence, from baseline to follow-up. Results: At baseline, 33.1% of study participants were hypertensive, 52.9% obese, and 36.3% had LVH. At follow-up, the prevalence of hypertension, obesity, and LVH was 18.7%, 30.2%, and 22.3%, respectively (p < 0.001 for all). A decrease in LVMI from 37.1 to 35.2 g/m2.7 (p < 0.001) was observed. Only delta BMI z-score positively related to an improvement of LVMI. Reductions of BMI (OR = 0.22, 95% CI 0.07–0.64) and diastolic BP (OR = 0.64, 95% CI 0.42–0.93) z-scores from baseline to follow-up and family history of hypertension (OR = 0.36, 95% CI 0.16–0.78) were associated with a lower prevalence of LVH. Conclusions: In a pediatric population at cardiovascular risk, changing incorrect lifestyle and dietary habits is associated with both reduction of BMI and BP values and regression of early cardiac damage. [ABSTRACT FROM AUTHOR]

Background: Pulse wave velocity (PWV) assessment represents a simple method to estimate arterial distensibility. At present, carotid-femoral PWV (cf-PWV) is considered the gold standard method in the non-invasive evaluation of the elastic properties of the aorta. On the other hand, the mechanical properties of muscular arteries can be evaluated on the axillo-brachial-radia axis by estimating the carotid-radial PWV (cr-PWV). While a number of studies have addressed these issues in adults, limited information is available on the respective features of cf-PWV and cr-PWV and on their modulating factors in children and adolescents at increased cardiovascular risk. Methods: The mechanical properties of the predominantly elastic (aorta) and muscular (axillo−brachial−radial axis) arteries were evaluated in a pediatric population characterized by either elevated blood pressure (BP) or excess body weight, and the main factors affecting cf-PWV and cr-PWV values in these individuals were investigated. Results: 443 children and adolescents (median age 11.5 years, 43.3% females) were enrolled; 25% had BP values >90th percentile and 81% were excess weight. The cf-PWV values were significantly lower than the cr-PWV values: median (Q1–Q3) = 4.8 m/s (4.3–5.5) and 5.8 m/s (5.0–6.5), respectively (p < 0.001). The pubertal development (p < 0.03), systolic BP and diastolic BP z-scores (p = 0.002), heart rate (p < 0.001), and waist-to-height ratio (p < 0.005) were significantly associated with cf-PWV values. No significant association was found between BMI z-score and cf-PWV. Predictors of high cf-PWV (>95th percentile) were the heart rate (OR 1.07, 95%CI 1.04–1.10, p < 0.001) and waist-to-height ratio (OR 1.06, 95%CI 1.0–1.13, p = 0.04). The variables significantly related with cr-PWV values were diastolic BP z-score (p = 0.001), heart rate (p < 0.01), and HOMA index (p < 0.02). No significant association was found between the cr-PWV and BMI z-score or waist-to-height ratio. Conclusions: Systolic and diastolic BP values and central obesity are associated with aortic stiffness in a population of children and adolescents at increased cardiovascular risk. In contrast, diastolic BP, heart rate, and levels of insulin resistance appear to be related to distensibility of the upper limb vascular district. [ABSTRACT FROM AUTHOR]

The PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Antiplatelet Therapy (PRECISE-DAPT) score has been validated to predict bleeding complications in patients undergoing stent implantation and dual antiplatelet therapy. This score does not include the platelet count (PC), which has been shown to be an independent marker of mortality in patients with acute coronary syndrome (ACS). We assessed the role of the PRECISE-DAPT score calculated on admission for mortality risk prediction and evaluated whether the predictive accuracy of this score improved by adding the PC. In a retrospective cohort study of 1000 patients with ACS, after adjustment for relevant covariates, a PRECISE-DAPT score ≥25 was independently associated with mortality (hazard ratio [HR]: 7.91; 95% confidence interval [CI]: 4.37-14.30). When this score was combined with PC, compared to patients with PRECISE-DAPT <25 and PC ≥150 × 109/L, the adjusted HR was 7.2 (95% CI 2.4-21.6) for those with PRECISE-DAPT <25 and PC <150 × 109/L; 10.7 (95% CI: 5.2-21.9) for those with PRECISE-DAPT ≥25 and PC ≥150 × 109/L; and 17.9 (95% CI 7.0-45.4) for those with PRECISE-DAPT ≥25 and PC <150 × 109/L. Selecting thresholds for high-risk designation, the PRECISE-DAPT score integrated with PC had a higher prediction value, compared to the PRECISE-DAPT and Global Registry of Acute Coronary Events scores. [ABSTRACT FROM AUTHOR]

Tracheal intubation is a high-risk procedure in the critically ill, with increased intubation failure rates and a high risk of other adverse events. Videolaryngoscopy might improve intubation outcomes in this population, but evidence remains conflicting, and its impact on adverse event rates is debated. This is a subanalysis of a large international prospective cohort of critically ill patients (INTUBE Study) performed from 1 October 2018 to 31 July 2019 and involving 197 sites from 29 countries across five continents. Our primary aim was to determine the first-pass intubation success rates of videolaryngoscopy. Secondary aims were characterising (a) videolaryngoscopy use in the critically ill patient population and (b) the incidence of severe adverse effects compared with direct laryngoscopy. Of 2916 patients, videolaryngoscopy was used in 500 patients (17.2%) and direct laryngoscopy in 2416 (82.8%). First-pass intubation success was higher with videolaryngoscopy compared with direct laryngoscopy (84% vs 79%, P =0.02). Patients undergoing videolaryngoscopy had a higher frequency of difficult airway predictors (60% vs 40%, P <0.001). In adjusted analyses, videolaryngoscopy increased the probability of first-pass intubation success, with an OR of 1.40 (95% confidence interval [CI] 1.05–1.87). Videolaryngoscopy was not significantly associated with risk of major adverse events (odds ratio 1.24, 95% CI 0.95–1.62) or cardiovascular events (odds ratio 0.78, 95% CI 0.60–1.02). In critically ill patients, videolaryngoscopy was associated with higher first-pass intubation success rates, despite being used in a population at higher risk of difficult airway management. Videolaryngoscopy was not associated with overall risk of major adverse events. NCT03616054. [ABSTRACT FROM AUTHOR]

In 2007 the International Diabetes Federation (IDF) proposed single blood pressure (BP) cutpoints (systolic: ≥130 mm Hg and diastolic: ≥85 mm Hg) for the diagnosis of high blood pressure (HBP) in adolescents. Before this proposal, HBP had been defined as BP at or above the 95th percentile for age, sex, and height percentile (reference standard). In this study, we evaluated the risk for misclassification when using the IDF single-cutpoints criteria. We first applied the IDF criteria to a reconstructed population with the same age, sex, and height distribution as the population used to develop the reference standard. The proposed single cutpoints corresponded to percentiles from the 81.6th to 99.9th for systolic BP and from the 92.9th to 98.9th for diastolic BP in the reconstructed population. Using IDF criteria, there were high false-negative fractions for both systolic and diastolic BP (from 54% to 93%) in 10- to 12-year-olds and a false-positive fraction up to 35% in older subjects. We then applied the IDF criteria to 1,162 overweight/obese adolescents recruited during 1998-2000 from pediatric clinical centers in Milano, Varese, and Modena in Italy and in Zaragoza, Spain. Overall false-negative and false-positive fractions were 22% and 2%, respectively; negative predictive values were especially low for 10- to 12-year-old subjects. The use of IDF's single cutpoints carries a high risk of misclassification, mostly due to false negatives in younger subjects. The effort to simplify diagnosis could be overcome by the risk of undiagnosed HBP. [ABSTRACT FROM AUTHOR]

Although the relationship among Emotional Intelligence (EI), Attachment Security (AS), and Empathy (E) has been previously established, the mechanism through which these three constructs relate to each other is not wholly understood. Since EI has been found to be predicted by AS and to predict E, we advanced an integrated model according to which EI mediates the relation between AS and E in undergraduate medical students. In a cross-sectional design, the Interpersonal Reactivity Index (IRI), the Emotional Quotient Inventory (EQ-i), the Attachment Style Questionnaire (ASQ), and demographic questions were electronically administrated to 253 second-year medical students (56.13% female) of two medical schools in Northern Italy. Pearson's zero-order correlation coefficients (r) were computed to examine the associations between the three dimensions. To test the indirect effect of AS on E through the variable mediator EI, a mediation analysis was performed using the Structural Equations Modelling (SEM). As was positively related to the IRI dimensions of Empathic Concern (r=0.17, p=0.008) and Perspective Taking (r=0.24, p<0.001), and negatively to Personal Distress (r=-0.33, p<0.001). Individuals with same levels of AS and higher scores on EQ-i had higher scores (?=0.072, p=0.033) on the empathy latent factor (at the basis of Empathic Concern and Perspective Taking) and lower scores (?=-0.290, p<0.001) on Personal Distress than those with lower EQ-i scores. This study shows that EI completely mediated the relationship between AS and empathy dimensions in our study population. Since EI is a dispositional characteristic malleable to modification, this construct should be considered when designing educational interventions and programs to promote medical students' empathy and well-being in interpersonal situations. [ABSTRACT FROM AUTHOR]

Objectives: Erythropoiesis‐stimulating agents (ESA) have an established role in treating anemia in hematological malignancies. However, their role, particularly biosimilar ESA (B‐ESA), in myelofibrosis (MF) is not well established. Methods: This study retrospectively collected data on 96 MF patients treated with B‐ESA (alpha/zeta) for the management of anemia to assess safety, efficacy (anemia response [AR]), and survival. Results: Seventy‐seven patients (80%) obtained AR. The median time to AR was 2.5 months. In multivariate analysis, significant predictive factors of AR were transfusion independency (p =.006) and ferritin levels <200 ng/ml (p =.009) at baseline. After a median follow‐up of 43.8 months from diagnosis, 38 patients (39%) died, 11 (28.9%) from leukemic evolution. Only two patients (2.5%) stopped B‐ESA for toxicity. The 24‐month survival was significantly affected by response to B‐ESA (70.8% in AR vs. 55.3% in non‐responder patients, p =.016). In multivariate analysis, age ≤ 70 years (p =.029) and Hb > 8.5 g/dl (p =.047) at baseline were significantly associated with improved survival, with a trend for longer survival in AR patients (p =.06). Conclusions: B‐ESA seems to be an effective and well‐tolerated option for anemia treatment in the MF setting. This strategy deserves further clinical investigation. [ABSTRACT FROM AUTHOR]

Objective: To describe the Emoty-Com training, its impact on medical students' attitudes towards doctors' emotions and to explore the association between students' empathy, emotional intelligence (EI), and attachment style (AS) with post-training performance scores.Methods: The 16-hour Emoty-Com training was delivered to all second-year medical students of Verona and Milan (Italy) Universities. At pre-training, students filled out three questionnaires assessing empathy, AS and EI and responded to three questions on attitudes towards doctors' emotions in the doctor-patient encounter. The same three questions and a final evaluation test were proposed at post-training.Results: 264 students participated in the study. The training reduced students' worry about managing emotions during doctor-patient relationships. Gender was associated with specific subscales of empathy, EI, and AS. Final performance scores were associated with students' attitudes towards emotions but not with empathy, EI, and AS.Conclusion: The Emoty-Com training increased students' self-efficacy in handling their own emotions during consultations. Students' performance scores were related to their attitude towards doctors' emotions in clinical encounters.Practice Implications: The Emoty-Com training suggests ways to teach and evaluate emotion-handling skills for medical students. Possible links between empathy, EI, AS, and the attitudes towards doctors' emotions during the years of education are highlighted. [ABSTRACT FROM AUTHOR]

Objective: To explore the association of emotional intelligence (EI) and attachment security (AS) with empathy dimensions in medical students by examining the mediating role of EI.Methods: In a cross-sectional design, the Interpersonal Reactivity Index (IRI), the Emotional Quotient Inventory (EQ-i), the Attachment Style Questionnaire (ASQ), and demographic questions were administrated to second-year medical students of two medical schools in Northern Italy.Results: 253 medical students (56.13% female), aged 19-29, participated in this study. AS positively correlated to Empathic Concern (r = 0.17, p = 0.008) and Perspective Taking (r = 0.24, p < 0.001), and negatively to Personal Distress (r = -0.33, p < 0.001). Individuals with the same level of AS and a higher score on EQ-i had a higher score (β = 0.072, p = 0.033) on empathy latent factor (at the basis of Empathic Concern and Perspective Taking) and a lower score (β = -0.290, p < 0.001) on Personal Distress than those with a lower EQ-i score.Conclusion: This study shows that EI completely mediated the relationship between AS and empathy dimensions among medical students.Practice Implications: EI training and workshop should be considered when designing educational interventions and programs to enhance empathy and decrease interpersonal distress in medical students. [ABSTRACT FROM AUTHOR]

Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of a-L-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring a-L-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear. [ABSTRACT FROM AUTHOR]

Frailty is an age-related syndrome that exposes individuals to increased vulnerability. Although it is potentially reversible, in most cases it leads to negative outcomes, including mortality. The different methods proposed identify frailty after the onset of clinical manifestations. An early diagnosis might make it possible to manage the frailty progression better. The frailty pathophysiology is still unclear although mechanisms, in particular, those linked to inflammation and immunosenescence, have been investigated. A common feature of several clinical aspects involved in senescent organisms is the increase of oxidative stress, described as one of the major causes of deoxyribonucleic acid (DNA) damage accumulation in aged cells including the adult stem cell compartment. Likely, this accumulation is implicated in frailty status. The oxidative status of our frail, pre-frail, and non-frail population was characterized. In addition, the DNA damage in hematopoietic cells was evidenced by analyzing the peripheral blood mononuclear cell and their T lymphocyte, monocyte, circulating hematopoietic progenitor stem cell (cHPSC) subpopulations. The phosphorylation of C-terminal of histone H2AX at amino acid Ser 139 (γ-H2AX), which occurs at the DNA double-strand break focus, was evaluated. In our frail population, increased oxidative stress and a high level of DNA damage in cHPSC were found. This study may have potential implications because the increment of DNA damage in cHPSC could be suggestive of an organism impairment preceding the evident frailty. In addition, it may open the possibility for attenuation of frailty progression throughout specific drugs acting on preventing DNA damage or removing damaged cells. [ABSTRACT FROM AUTHOR]

Background: It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID‐19 patients hospitalized in general wards Methods: This is a multicentre, open‐label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. versus 40 mg o.d. enoxaparin in COVID‐19 patients, between April 30 2020 and April 25 2021. Primary efficacy outcome was in‐hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. Results: The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6.5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (ARR 6.5, 95% CI: 1.5–11.6). The absence of concomitant DVT and imaging characteristics suggests that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically nonsignificant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. Conclusions: No DVT developed in COVID‐19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events. [ABSTRACT FROM AUTHOR]

Bladder carcinogenesis is believed to follow two alternative pathways driven by the loss of chromosome 9 and the gain of chromosome 7, albeit other nonrandom copy number alterations (CNAs) were identified. However, confirmation studies are needed since many aspects of this model remain unclear and considerable heterogeneity among cases has emerged. One of the purposes of this study was to evaluate the performance of a targeted test (UroVysion assay) widely used for the detection of Transitional Cell Carcinoma (TCC) of the bladder, in two different types of material derived from the same tumor. We compared the results of UroVysion test performed on Freshly Isolated interphasic Nuclei (FIN) and on Formalin Fixed Paraffin Embedded (FFPE) tissues from 22 TCCs and we didn't find substantial differences. A second goal was to assess the concordance between array-CGH profiles and the targeted chromosomal profiles of UroVysion assay on an additional set of 10 TCCs, in order to evaluate whether UroVysion is an adequately sensitive method for the identification of selected aneuploidies and nonrandom CNAs in TCCs. Our results confirmed the importance of global genomic screening methods, that is array based CGH, to comprehensively determine the genomic profiles of large series of TCCs tumors. However, this technique has yet some limitations, such as not being able to detect low level mosaicism, or not detecting any change in the number of copies for a kind of compensatory effect due to the presence of high cellular heterogeneity. Thus, it is still advisable to use complementary techniques such as array-CGH and FISH, as the former is able to detect alterations at the genome level not excluding any chromosome, but the latter is able to maintain the individual data at the level of single cells, even if it focuses on few genomic regions. [ABSTRACT FROM AUTHOR]

The authors used cancer registry data to assess the incidence rate of second primary cancers among chronic myeloid leukemia (CML) patients and the long-term survival of CML patients before the introduction of tyrosine kinase inhibitors. In the Swedish Cancer Registry, the authors identified 2,753 adult CML patients diagnosed between 1970 and 1995 who were followed through December 2007. Standardized incidence ratios (SIRs) and relative survival ratios were computed. With a total of 145 subsequent primary malignancies, an increased incidence rate of second malignancy was found for stomach cancer (SIR = 2.76, 95% confidence interval (CI): 1.33, 5.08), skin cancer (SIR = 5.36, 95% CI: 3.18, 8.47), urogenital tract cancer (SIR = 1.61, 95% CI: 1.15, 2.21), and lymphoid leukemia (SIR = 5.53, 95% CI: 1.79, 12.89). Long-term relative survival figures showed that CML was related, in the era prior to the introduction of imatinib, to a very steep decline in survival (2 years from diagnosis, relative survival = 51%, 95% CI: 49, 53). This was in spite of a marginal improvement after 1985, possibly related to the introduction of interferon-α for treatment. These estimates constitute a relevant reference for future studies and a benchmark for comparisons with prognosis in CML patients after chronic use of tyrosine kinase inhibitors. [ABSTRACT FROM PUBLISHER]

Purpose: Delayed cord clamping for at least 60 s is recommended to improve neonatal outcomes. The aim of this study is to evaluate whether there are differences in cord BGA between samples collected after double clamping the cord or without clamping the cord, when blood collection occurs within 60 s from birth in both groups. Methods: A cross-sectional study was carried out, collecting data from 6884 high-risk women who were divided into two groups based on the method of cord sampling (clamped vs unclamped). Results: There were significant decrease in pH and BE values into unclamped group compared with the clamped group. This difference remained significant when considering pathological blood gas analysis parameters, with a higher percentage of pathological pH or BE values in the unclamped group. Conclusion: Samples from the unclamped cord alter the acid–base parameters compared to collection from the clamped cord; however, this difference does not appear to be of clinical relevance. Findings could be due to the large sample size, which allowed to achieve a high power and to investigate very small numerical changes between groups, leading to a statistically significant difference in pH and BE between samples even when we could not appreciate any clinical relevant difference of pH or BE between groups. When blood gas analysis is indicated, the priority should be given to the timing of blood collection to allow reliable results, to assess newborns status at birth and intervene when needed. [ABSTRACT FROM AUTHOR]

The altered function of the Hyperpolarization-activated Cyclic-Nucleotide-gated (HCN) ion channels plays an important role in the pathogenesis of epilepsy in humans. In particular, HCN1 missense mutations have been recently identified in patients with different epileptic phenotypes, varying from mild to severe. Their electrophysiological characterization shows that mutated channels can act both with loss-of-function and gain-of-function mechanisms of action, without an evident correlation with the phenotype. In search for a correlation between clinical features and biophysical properties of the mutations, in this work we considered sixteen HCN1 mutations, found in eighteen Early Infantile Epileptic Encephalopathy (EIEE) patients. Statistical analysis did not establish any significant correlation between the clinical parameters and the current properties of the mutant channels. The lack of significance of our results could depend on the small number of mutations analyzed, epilepsy-associated with certainty. With the progressive increase of Next Generation Sequencing in patients with early-onset epilepsy, it is expected that the number of patients with HCN1 mutations will grow steadily. Functional characterization of epilepsy-associated HCN1 mutations remains a fundamental tool for a better understanding of the pathogenetic mechanisms leading to the disease in humans. [ABSTRACT FROM AUTHOR]

Importance: Tracheal intubation is one of the most commonly performed and high-risk interventions in critically ill patients. Limited information is available on adverse peri-intubation events.Objective: To evaluate the incidence and nature of adverse peri-intubation events and to assess current practice of intubation in critically ill patients.Design, Setting, and Participants: The International Observational Study to Understand the Impact and Best Practices of Airway Management in Critically Ill Patients (INTUBE) study was an international, multicenter, prospective cohort study involving consecutive critically ill patients undergoing tracheal intubation in the intensive care units (ICUs), emergency departments, and wards, from October 1, 2018, to July 31, 2019 (August 28, 2019, was the final follow-up) in a convenience sample of 197 sites from 29 countries across 5 continents.Exposures: Tracheal intubation.Main Outcomes and Measures: The primary outcome was the incidence of major adverse peri-intubation events defined as at least 1 of the following events occurring within 30 minutes from the start of the intubation procedure: cardiovascular instability (either: systolic pressure <65 mm Hg at least once, <90 mm Hg for >30 minutes, new or increase need of vasopressors or fluid bolus >15 mL/kg), severe hypoxemia (peripheral oxygen saturation <80%) or cardiac arrest. The secondary outcomes included intensive care unit mortality.Results: Of 3659 patients screened, 2964 (median age, 63 years; interquartile range [IQR], 49-74 years; 62.6% men) from 197 sites across 5 continents were included. The main reason for intubation was respiratory failure in 52.3% of patients, followed by neurological impairment in 30.5%, and cardiovascular instability in 9.4%. Primary outcome data were available for all patients. Among the study patients, 45.2% experienced at least 1 major adverse peri-intubation event. The predominant event was cardiovascular instability, observed in 42.6% of all patients undergoing emergency intubation, followed by severe hypoxemia (9.3%) and cardiac arrest (3.1%). Overall ICU mortality was 32.8%.Conclusions and Relevance: In this observational study of intubation practices in critically ill patients from a convenience sample of 197 sites across 29 countries, major adverse peri-intubation events-in particular cardiovascular instability-were observed frequently. [ABSTRACT FROM AUTHOR]

Individual parameters of complete blood count (CBC) have been associated with worse outcome in patients with acute coronary syndrome (ACS). However, the prognostic role of CBC taken as a whole has never been evaluated for long-term incidence of major adverse cardiovascular events (MACEs). Patients were grouped according to their hematopoietic cells' inflammatory response at different time points during hospital stay. Patients with admission white blood cell count >10 × 109/L, discharge hemoglobin <120 g/L, and discharge platelet count >250 × 109/L were defined as "high-risk CBC." Among 1076 patients with ACS discharged alive, 129 (12%) had a "high-risk CBC" and 947 (88%) had a "low-risk CBC." Patients with "high-risk CBC" were older and had more comorbidities. Over a median follow-up of 665 days, they experienced a higher incidence of MACE compared to "low-risk CBC" patients (18.6% vs 8.1%). After adjustment for age, age-adjusted Charlson comorbidity index, female sex, cardiac arrest, suboptimal discharge therapy, coronary artery bypass, and ejection fraction, a high-risk CBC was significantly associated with increased MACE occurrence (adjusted hazard ratio 1.80; 95% CI: 1.09-3.00). The CBC was a prognostic marker in patients with ACS, and its evaluation at admission and discharge could better classify patient's risk and improve therapeutic management. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type I (MPS-I), a lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase enzyme, results in the progressive accumulation of glycosaminoglycans and consequent multiorgan dysfunction. Despite the effectiveness of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) in correcting clinical manifestations related to visceral organs, complete improvement of musculoskeletal and neurocognitive defects remains an unmet challenge and provides an impact on patients' quality of life. We tested the therapeutic efficacy of combining HSCT and ERT in the neonatal period. Using a mouse model of MPS-I, we demonstrated that the combination therapy improved clinical manifestations in organs usually refractory to current treatment. Moreover, combination with HSCT prevented the production of anti-IDUA antibodies that negatively impact ERT efficacy. The added benefits of combining both treatments also resulted in a reduction of skeletal anomalies and a trend towards decreased neuroinflammation and metabolic abnormalities. As currently there are limited therapeutic options for MPS-I patients, our findings suggest that the combination of HSCT and ERT during the neonatal period may provide a further step forward in the treatment of this rare disease. [ABSTRACT FROM AUTHOR]

At present, very few data are available on the role of iron chelation therapy (ICT) with deferasirox (DFX) in MF (Elli I et al i , [3]; Latagliata I et al i , [5]). Patients received DFX after a median MF duration of 26-8 months [interquartile range (IQR) 2-6-208-7] with a TD latency of 12-5 months (IQR 1-2-146-1). Our preliminary data open new insights regarding the benefit of DFX in MF patients with TD anaemia. [Extracted from the article]

Summary: Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti‐leukaemic effect of L‐asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML‐LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34+CD38+ and CD34+CD38− LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French‐American‐British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients. [ABSTRACT FROM AUTHOR]

The article offers information on human aplastic anaemia-derived mesenchymal stromal cells form functional haematopoietic stem cell niche in vivo. It discusses mesenchymal stromal cells has display decreased proliferation and clonogenic potential. It also mentions patients who had responded to immunosuppressive treatment such as Hematopoietic stem cell transplantation.

The Emoty-Com training is a 16 hours-course based on interactive teaching to increase communication and emotion-handling skills for medical students. The study aimed to describe the Emoty-Com training impact on medical students' attitudes towards patients' emotions and to explore the association between students' empathy, emotional intelligence (EI), attachment style (AS) and attitudes with post-training performance scores. The Emoty-Com training was delivered to all second-year students of Medicine and Surgery Schools in Verona and Milan (Italy) Universities. Empathy, AS and EI were assessed at pre-training; attitudes towards emotions in the doctor-patient encounter were assessed at pre-training and post-training; at post-training, a final test evaluating the knowledge acquired during the training was administered. The Emoty-Com training increased the relevance attributed to doctor emotional involvement, at least by male students, and students' perception of self-efficacy in handling their own emotions during a consultation. Students with higher final test scores were those with less perceived self-efficacy in dealing with patients' emotions before the training, while students with lower final scores were those who tended to give scarce importance to doctors' emotions in the clinical encounter after the training. In contrast with previous literature, the relationship between AS, EI, empathy, and communication skills measured by the final test was not confirmed. Students' acquired knowledge resulted related to their attitude towards emotions, which should be considered in adapting future training to the specific needs of medical students. [ABSTRACT FROM AUTHOR]

The 'landmark' and 'Simon and Makuch' non-parametric estimators of the survival function are commonly used to contrast the survival experience of time-dependent treatment groups in applications such as stem cell transplant versus chemotherapy in leukemia. However, the theoretical survival functions corresponding to the second approach were not clearly defined in the literature, and the use of the 'Simon and Makuch' estimator was criticized in the biostatistical community. Here, we review the 'landmark' approach, showing that it focuses on the average survival of patients conditional on being failure free and on the treatment status assessed at the landmark time. We argue that the 'Simon and Makuch' approach represents counterfactual survival probabilities where treatment status is forced to be fixed: the patient is thought as under chemotherapy without possibility to switch treatment or as under transplant since the beginning of the follow-up. We argue that the 'Simon and Makuch' estimator leads to valid estimates only under the Markov assumption, which is however less likely to occur in practical applications. This motivates the development of a novel approach based on time rescaling, which leads to suitable estimates of the counterfactual probabilities in a semi-Markov process. The method is also extended to deal with a fixed landmark time of interest. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the lates follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. AL mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile. [ABSTRACT FROM AUTHOR]