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•Unsupervised clustering identified optimal HLA matching strategies for pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).•Single HLA-C mismatch in 7/8-matched umbilical cord blood transplantation (UCBT) was associated with poor outcomes in pediatric AML.•Total body irradiation improved relapse-free survival in pediatric ALL regardless of HLA matching.•Antithymocyte globulin was associated with late post-transplantation relapse in pediatric AML and ALL patients.•Tailoring conditioning based on leukemia type and HLA match may optimize UCBT outcomes.

National trends show rapid increases in the use of mechanical circulatory support devices (MCSD) over the last 20 years. While current literature has not proven a mortality benefit in cardiogenic shock as a complication of acute myocardial infarction (AMI-CS) with percutaneous MCSD, these devices are vital to maximizing cardiopulmonary parameters for definitive therapy. To minimize complications, many different techniques have been described including a novel off-pump direct apical cannulation for venoarterial-extracorporeal membrane oxygenation (VA-ECMO). This technique allows early ambulation and avoids peripheral artery access complications but has only been described in small case series. Our case series represents the largest summary of patients (50) using this technique and contains the only comparison data to date. Fifty-four percentage of our patients were Society for Cardiovascular Angiography and Interventions (SCAI) stage D and 22% were arrested before cannulation. We achieved flows on average >5 L/min and most patients required biventricular drainage (86%) and an oxygenator (92%). Thirty day survival was 56% and most survivors were bridged to heart transplant (30%). Our most common complication was bleeding (16%). This technique showed significant improvement in ejection fraction (EF), cardiac output/index (CO/CI), and pulmonary artery pressures. This case series demonstrates the safety and efficacy of this novel technique for central cannulation in cardiogenic shock at large scale within a single institution.

Amyloidosis is a systemic disease due to the accumulation of misfolded amyloid fibrils that damage the heart and worsen the prognosis. Heart failure (HF), a condition frequently linked with an advanced stage of this disease, is the most prevalent clinical manifestation that leads to its diagnosis. However, due to the growing awareness of the occurrence of cardiac amyloidosis (CA), it is now possible to perform an early diagnosis and have a positive impact on its natural course. This study aims to highlight the most compelling issues concerning patients’ clinical management with HF and CA.

Purpose: The management of differentiated thyroid cancer (DTC) is actually based on a dynamic risk stratification based on classes of response to the therapy. Indeterminate response (IR) includes a heterogeneous group of patients with different characteristics, particularly different Tg and AbTg levels and/or imaging findings. The aim of systematic review (SR) is to evaluate the prognosis, diagnostic findings and other characteristics of patients in the IR class. Methods: A wide literature search in the Scopus, PubMed/MEDLINE and Web of Science databases was performed to find published articles on patients with DTC and IR after treatment. The quality assessment of studies was carried out using QUADAS-2 evaluation. Results: Eight articles were included in the systematic review. Six studies evaluated the prognosis and the prognostic factor in patients with IR, one study evaluated the role of 2-[18F]FDG PET-CT in the management of patients with IR and biochemical incomplete response and one study the risk factors for IR. Conclusion: Patients with DTC and IR to therapy have a probability of disease relapse < 15%. Tg value could be a predictor of disease progression. The role of 2-[18F]FDG PET-CT needs to be further investigated.

AbstractPhthalocyanine and hypericin have been previously identified as possible SARS-CoV-2 Spike glycoprotein fusion inhibitors through a virtual screening procedure. In this paper, atomistic simulations of metal-free phthalocyanines and atomistic and coarse-grained simulations of hypericins, placed around a complete model of the Spike embedded in a viral membrane, allowed to further explore their multi-target inhibitory potential, uncovering their binding to key protein functional regions and their propensity to insert in the membrane. Following computational results, pre-treatment of a pseudovirus expressing the SARS-CoV-2 Spike protein with low compounds concentrations resulted in a strong inhibition of its entry into cells, suggesting the activity of these molecules should involve the direct targeting of the viral envelope surface. The combination of computational and in vitroresults hence supports the role of hypericin and phthalocyanine as promising SARS-CoV-2 entry inhibitors, further endorsed by literature reporting the efficacy of these compounds in inhibiting SARS-CoV-2 activity and in treating hospitalized COVID-19 patients.Communicated by Ramaswamy H. Sarma

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiovascular disorder in adults and a significant cause of heart failure and sudden cardiac death. Historically, atrial fibrillation (AF) has been considered as a critical aspect in HCM patients as it is considered to be a marker of disease progression, escalates the frequency of heart failure hospitalisations, increases the risk of thromboembolic events, and worsens quality of life and outcome. Increasing evidence suggests that AF is the result of a subtle long-standing process that starts early in the history of HCM. The process of left atrial dilation accompanied by morphologic and functional remodelling is the quintessential prerequisite for the onset of AF. This review aims to describe the current understanding of AF pathophysiology in HCM, emphasising the role of left atrial myopathy in its development. In addition, we discuss risk factors and management strategies specific to AF in the context of HCM, providing insights into the complexities and challenges of treating this specific patient population.

Healthcare workers handling antineoplastic drugs (ADs) in preparation units run the risk of occupational exposure to contaminated surfaces and associated mutagenic, teratogenic, and oncogenic effects of those drugs. To minimise this risk, automated compounding systems, mainly robots, have been replacing manual preparation of intravenous drugs for the last 20 years now, and their number is on the rise. To evaluate contamination risk and the quality of the working environment for healthcare workers preparing ADs, we applied the Failure Mode Effects and Criticality Analysis (FMECA) method to compare the acceptable risk level (ARL), based on the risk priority number (RPN) calculated from five identified failure modes, with the measured risk level (MRL). The model has shown higher risk of exposure with powdered ADs and containers not protected by external plastic shrink film, but we found no clear difference in contamination risk between manual and automated preparation. This approach could be useful to assess and prevent the risk of occupational exposure for healthcare workers coming from residual cytotoxic contamination both for current handling procedures and the newly designed ones. At the same time, contamination monitoring data can be used to keep track of the quality of working conditions by comparing the observed risk profiles with the proposed ARL. Our study has shown that automated preparation may have an upper hand in terms of safety but still leaves room for improvement, at least in our four hospitals.

Simulating electronic properties and spectral signals requires robust computational approaches that need tuning with the system’s peculiarities. In this paper, we test implicit and fully atomistic solvation models for the calculation of UV–vis and electronic circular dichroism (ECD) spectra of two pharmaceutically relevant molecules, namely, (2S)-captopril and (S)-naproxen, dissolved in aqueous solution. Room temperature molecular dynamics simulations reveal that these two drugs establish strong contacts with the surrounding solvent molecules via hydrogen bonds. Such specific interactions, which play a major role in the spectral response and are neglected in implicit approaches, are further characterized and quantified with natural bond orbital methods. Our calculations show that simulated spectra, and especially ECD, are in good agreement with experiments solely when conformational and configurational dynamics, mutual polarization, and solute–solvent repulsion effects are considered.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with a progressive reduction of functional capacity. The progression of cardiopulmonary exercise testing (CPET) parameters over time is still unknown.

Background: Since primary membranous nephropathy is a heterogeneous disease with variable outcomes and multiple possible therapeutic approaches, all 13 Nephrology Units of the Italian region Emilia Romagna decided to analyze their experience in the management of this challenging glomerular disease. Methods: We retrospectively studied 205 consecutive adult patients affected by biopsy-proven primary membranous nephropathy, recruited from January 2010 through December 2017. The primary outcome was patient and renal survival. The secondary outcome was the rate of complete remission and partial remission of proteinuria. Relapse incidence, treatment patterns and adverse events were also assessed. Results: Median (IQR) follow-up was 36 (24–60) months. Overall patient and renal survival were 87.4% after 5 years. At the end of follow-up, 83 patients (40%) had complete remission and 72 patients (35%) had partial remission. Among responders, less than a quarter (23%) relapsed. Most patients (83%) underwent immunosuppressive therapy within 6 months of biopsy. A cyclic regimen of corticosteroid and cytotoxic agents was the most commonly used treatment schedule (63%), followed by rituximab (28%). Multivariable analysis showed that the cyclic regimen significantly correlates with complete remission (odds ratio 0.26; 95% CI 0.08–0.79) when compared to rituximab (p< 0.05). Conclusions: In our large study, both short- and long-term outcomes were positive and consistent with those published in the literature. Our data suggest that the use of immunosuppressive therapy within the first 6 months after biopsy appears to be a winning strategy, and that the cyclic regimen also warrants a prominent role in primary membranous nephropathy treatment, since definitive proof of rituximab superiority is lacking. Graphic Abstract:

Findings from a novel Primary Care (PC) Mental Health (MH) pathway for children and young people in Northern Ontario, Canada are presented. Overall, 166 MH referrals from PC to a community-based child and youth MH and addictions agency (CB-CYMHA) occurred, with outstanding PC uptake (100%) and faxing referral outcomes (99%) from the CB-CYMHA to the PC provider. Half of referral outcomes (50%) were returned within 2 weeks and 83% of contacted clients reported satisfaction with services received. This successful pilot serves as an example for care pathway improvements and mobilizes knowledge for other pathway sites across Ontario.

•Despite different characteristics and transplant protocols, patients with lymphoma from Europe and Japan have similar outcomes.•TBI–containing regimens positively affected survival in both (European, Japanese) cohorts, whereas the effect of HLA mismatches differed.

The leaders of business are a continued focus of interest in management research and in the broader society. Their attributes speak to social mobility, inequality, and who holds positions of power and influence in society. This article examines the attributes of the ten highest-ranked executives of the largest corporate enterprises in the United States—the Fortune 100—and compares how they have changed over the past 40 years, a period when many assumptions about businesses and the people who run them have changed. While there has been significant change in some areas, such as the increase in the proportion of women and foreign-born executives and the rise in outside hiring, there is no evidence of an increase in younger leaders who advance faster than their predecessors and spend an ever-shorter time with their employer. In fact, top executives now are as old as their peers were in the 1950s, and their tenure with their employer is rising.

Purpose: Preliminary data suggested that bone mineral density (BMD) in transgender adults before initiating gender-affirming hormone therapy (GAHT) is lower when compared to cisgender controls. In this study, we analyzed bone metabolism in a sample of transgender adults before GAHT, and its possible correlation with biochemical profile, body composition and lifestyle habits (i.e., tobacco smoke and physical activity). Methods: Medical data, smoking habits, phospho-calcic and hormonal blood tests and densitometric parameters were collected in a sample of 125 transgender adults, 78 Assigned Females At Birth (AFAB) and 47 Assigned Males At Birth (AMAB) before GAHT initiation and 146 cisgender controls (57 females and 89 males) matched by sex assigned at birth and age. 55 transgender and 46 cisgender controls also underwent a complete body composition evaluation and assessment of physical activity using the International Physical Activity Questionnaire (IPAQ). Results: 14.3% of transgender and 6.2% of cisgender sample, respectively, had z-score values < -2 (p= 0.04). We observed only lower vitamin D values in transgender sample regarding biochemical/hormonal profile. AFAB transgender people had more total fat mass, while AMAB transgender individuals had reduced total lean mass as compared to cisgender people (53.94 ± 7.74 vs 58.38 ± 6.91, p< 0.05). AFAB transgender adults were more likely to be active smokers and tend to spend more time indoor. Fat Mass Index (FMI) was correlated with lumbar and femur BMD both in transgender individuals, while no correlations were found between lean mass parameters and BMD in AMAB transgender people. Conclusions: Body composition and lifestyle factors could contribute to low BMD in transgender adults before GAHT.

Since the beginning of this millennium, frequency comb generators have reshaped frequency metrology and related areas. After more than two decades since their first realization, several other ways to generate frequency combs, in any spectral region, have been demonstrated, each way with its peculiar features. This trend has triggered the need to quantitatively assess how close the new comb realizations are to an ideal comb, a feature that will be called combness throughout this paper. We will briefly review the very dynamic area of novel frequency comb sources and we will describe the techniques that have been recently developed to quantitatively assess the key parameters of old and new frequency combs, in view of the specific applications. Finally, we will try to sketch future steps in this recently born research area.

Purpose: The aim of the study was to analyze the modification of total and regional body composition in early breast cancer patients treated with aromatase inhibitors (AIs). Methods: This is a prospective, single-center, observational, longitudinal study. Four-hundred and twenty-eight patients treated with adjuvant aromatase inhibitors were enrolled at the Medical Oncology and Breast Unit of Spedali Civili Hospital in Brescia from September 2014 to June 2022. Several body composition parameters including total and regional fat and lean body mass were investigated with dual-energy X-ray absorptiometry (DXA) scan at baseline and after 18 months of treatment with aromatase inhibitors. Results: A significant increase in fat body mass (mean + 7.2%, 95% confidence interval [CI]: 5.5;8.9%) and a reduction in lean body mass (mean −3.1%, 95% CI −3.9; −2.4) were documented in this population. The changes in fat and lean body mass varied considerably according to different body districts ranging between + 3.2% to + 10.9% and from−1.3% to −3.9%, respectively. Conclusion: Aromatase inhibitor adjuvant therapy in early breast cancer is associated with changes in body composition, with a wide variability among different body districts, leading to a risk of sarcopenic obesity. Supervised physical exercise that focuses on single body parts that may display detrimental variations may be beneficial for AIs treated patients.

Compliance with principles and guidelines for ethical AI has a significant impact on companies engaged in the development of artificial intelligence (AI) systems. Specifically, ethics is a broad concept that continuously evolves over time and across cultural and geographical boundaries. International organisations (IOs), individual states, and private groups, all have an interest in defining the concept of ethics of AI. IOs, as well as regional and national bodies, have issued many decisions on AI ethics. Developing a system that complies with the ethical framework poses a complex challenge for companies, and the consequences of not complying with ethical principles can have severe consequences, making compliance with these requirements a key issue for companies. Furthermore, there is a shortage of technical tools to ensure that such AI systems comply with ethical criteria. The scarcity of ethics compliance checking tools for AI, and the current focus on defining ethical guidelines for AI development, has led us to undertake a proposal consisting in a semi-automated software model to verify the ethical compliance of an AI system’s code. To implement this model, we focus on the following important aspects: (1) a literature review to identify existing ethical compliance systems, (2) a review of principles and guidelines for ethical AI to determine the international and European views regarding AI ethics, and (3) the identification of commonly accepted principles and sub-principles of AI. These elements served to inform (4) our proposal for the design of a semi-automated software for verifying the ethical compliance of AI systems both at design-time (ethics-by-design perspective) and afterwards on the resulting software.

CKD and HIV infection are two chronic diseases impacting heavily on the survival of the affected patients. The interplay between HIV infection and chronic kidney disease (CKD) is complex and interactions occur at multiple levels. Approach to the management of HIV-infected patients requires special attention to face the numerous therapeutic difficulties ranging from drug-drug interactions to drug-toxicity. The most effective strategy is targeted to suppression of HIV viral load, as it dramatically changes the prognosis of the patients as well as prevents the development of HIV-associated kidney disease. As shown in this review, the approach to the therapeutic management of CKD in the setting of HIV infection varies in relation to the degree of renal impairment.

Exposure to per- and polyfluoroalkyl substances (PFAS) during pregnancy has been linked to maternal complications and exerts a long-term impact on fetal growth. However, information regarding the effects of PFAS on intrahepatic cholestasis of pregnancy (ICP) with hepatic biomarkers underlying the association is nascent. By analyzing 15 PFAS compounds in maternal serum from 78 women with a diagnosis of ICP and 164 healthy participants, this study provided epidemiological associations between PFAS exposure and ICP risks, liver function, and their potential influence on birth outcomes. As a result, the main contributors were perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), which accounted for 21% and 23% of the total PFAS exposure, respectively. Results revealed that each logarithmic increase in serum PFOA was associated with nearly tripled risk of ICP during pregnancy. In contrast, perfluorohexanesulfonic acid (PFHxS), 4:2 fluorotelomer sulfonate (4:2 FTS), and 3H-perfluoro-3-[(3-methoxy-propoxy) propanoic acid] (ADONA) showed negative associations on liver toxicity. In addition, increased estradiol and estriol levels in the serum were observed significantly associated with higher exposure of PFOA, perfluorodecanoic acid (PFDA), and 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA). Concerning the birth outcomes, increased risks for small-for-gestational-age and intrauterine development were found for the higher PFOA, PFOS, and 6:2-Cl-PFESA exposure. Notably, higher levels of PFOA exposure may be linked to an increased risk of intrauterine hypoxia due to impaired transfer of oxygen across the placenta. These findings provide valuable insights for environmental and public health considerations, highlighting the importance of considering maternal PFAS exposure to ICP and birth outcomes.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disorder of the myocardium and is characterized by important gender-related differences: women are typically 5 years older than men at diagnosis, over half are diagnosed >50 years of age and consistently show greater propensity than men for heart failure (HF)-related complications and adverse outcome.Whether pregnancy is a modifier of the long-term course and outcome of women with HCM is unknown.In this study, pregnancy was not a modifier of long-term outcome in women with HCM. In particular: At 10 ±7 years, most patients tolerated pregnancy well and did not show a survival disadvantage compared to women without pregnancies. Only baseline heart failure symptoms and age were associated with adverse outcome.Pregnancy should not be discouraged, except in the presence of severe HF symptoms or high-risk features. Nevertheless, cardio-obstetric counselling and close supervision are key in all instances, particularly in the peri-partum period.Graphical Abstract

ObjectiveThis real-world analysis assessed baseline demographics/characteristics and treatment patterns/effectiveness in patients with rheumatoid arthritis (RA) initiating tofacitinib (TOF) in the US CorEvitas RA Registry.MethodsThe primary analysis of this study included patients with RA initiating TOF with a 12-month follow-up visit from November 2012 to January 2021. Outcomes included baseline demographics/characteristics and TOF initiation/discontinuation reasons, treatment patterns, and effectiveness (disease activity and patient-reported outcomes [PROs] at 12 months); the primary effectiveness outcome was Clinical Disease Activity Index low disease activity (CDAI LDA). All data, analyzed descriptively, were stratified by TOF regimen (monotherapy vs combination therapy), line of therapy (second- to fourth-line), time of initiation (2012-2014, 2015-2017, or 2018-2020), and dose (5 mg twice daily vs 11 mg once daily).ResultsOf 2874 patients with RA who initiated TOF, 1298 had a qualifying 12-month follow-up visit; of these, 43.1% were monotherapy and 66.5% were fourth-line therapy. Overall, tumor necrosis factor inhibitors (40.8%) were the most common treatment immediately prior to TOF initiation. The most common reason for TOF initiation (among those with a reason) was lack/loss of efficacy of prior treatment (67.7%). Overall, at 12 months, 31.9% and 10.1% had achieved CDAI LDA and remission, respectively; 22.4%, 10.4%, and 5% had achieved ≥ 20%, ≥ 50%, and ≥ 70% improvement in modified American College of Rheumatology core set measures, respectively; and improvements in PROs were observed. Effectiveness was generally similar across TOF stratifications.ConclusionTOF effectiveness (CDAI LDA) was observed in a US real-world setting of patients with RA regardless of TOF regimen, line of therapy, time of initiation, and dose. (ClinicalTrials.gov: NCT04721808)

This study shows that plasma-fixed nitrogen applied as an inorganic biostimulant can improve marketable lettuce (Lactuca sativa var. longifolia) yield following delayed harvest. Using just one-tenth of the conventional nitrogen, plasma-fixed nitrogen--which is generated by a dielectric barrier discharge over water--was field-tested against traditional fertilization methods. Although no statistically significant differences were observed in total weight of heads among treatments, plasma-fixed nitrogen--treated plants had significantly increased marketable yields of 250% compared to those grown conventionally, despite reducing applied nitrogen fertilizer. [ABSTRACT FROM AUTHOR]

We study the adsorption process of model peptides, nucleobases, and selected standard ligands on gold through the development of a computational protocol based on fully atomistic classical molecular dynamics (MD) simulations combined with umbrella sampling techniques. The specific features of the interface components, namely, the molecule, the metallic substrate, and the solvent, are taken into account through different combinations of force fields (FFs), which are found to strongly affect the results, especially changing absolute and relative adsorption free energies and trends. Overall, noncovalent interactions drive the process along the adsorption pathways. Our findings also show that a suitable choice of the FF combinations can shed light on the affinity, position, orientation, and dynamic fluctuations of the target molecule with respect to the surface. The proposed protocol may help the understanding of the adsorption process at the microscopic level and may drive the in-silico design of biosensors for detection purposes.

Introduction: To understand factors leading to biologic switches and to develop a readily usable model with data collected in clinical care at preceding visits, with the overall aim to predict the probability of switching biologic at a subsequent clinic visit in patients with rheumatoid arthritis (RA). Methods: Participants were adults with RA participating in the CorEvitas RA registry. The study matched patients who switched biologics or targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) with control patients who had not switched biologics/tsDMARDs; the cohort was divided into a training and test set for prediction model development and validation. Using the training set, the best subset regression, lasso, and elastic net methods were used to determine the best potential models. Area under the ROC curve (AUC) was used for the final selection of the best model, and estimated coefficients of this model were applied to the test dataset to predict switching. Results: A total of 5050 patients were included, of whom 3016 were in the training set and 2034 were in the test dataset. The average age was 59.6 years, the majority were female (3998, 79.2%), and the average duration of RA at the time of switch or control visit was 12.8 years. The final model included prior Clinical Disease Activity Index (CDAI) by category, prior patient pain measurement, change in CDAI from baseline, age group, and number of prior biologics, all of which were significantly associated with switching biologics. The AUC was 0.690 for this model with the training dataset. The model was then applied to the test data with similar performance; the AUC was 0.687. Conclusion: We have developed a simple model to determine the probability of switching biologics for RA at the following clinic visit. This model could be used in practice to provide clinicians with more information about their patient’s trajectory and likelihood of switching to a new biologic.

Objective We sought to evaluate the relationship between social determinants of health and physician-based mental healthcare utilization and virtual care use among children and adolescents in Ontario, Canada, during the COVID-19 pandemic.Methods This population-based repeated cross-sectional study of children and adolescents (3–17 years; N= 2.5 million) used linked health and demographic administrative data in Ontario, Canada (2017–2021). Multivariable Poisson regressions with generalized estimating equations compared rates of outpatient physician-based mental healthcare use during the first year of the COVID-19 pandemic with expected rates based on pre-COVID patterns. Analyses were conducted by socioeconomic status (material deprivation quintiles of the Ontario Marginalization index), urban/rural region of residence, and immigration status.Results Overall, pediatric physician-based mental healthcare visits were 5% lower than expected (rate ratio [RR] = 0.95, 95% confidence interval [CI], 0.92 to 0.98) among those living in the most deprived areas in the first year of the pandemic, compared with the least deprived with 4% higher than expected rates (RR = 1.04, 95% CI, 1.02 to 1.06). There were no differences in overall observed and expected visit rates by region of residence. Immigrants had 14% to 26% higher visit rates compared with expected from July 2020 to February 2021, whereas refugees had similarly observed and expected rates. Virtual care use was approximately 65% among refugees, compared with 70% for all strata.Conclusion During the first year of the pandemic, pediatric physician-based mental healthcare utilization was higher among immigrants and lower than expected among those with lower socioeconomic status. Refugees had the lowest use of virtual care. Further work is needed to understand whether these differences reflect issues in access to care or the need to help inform ongoing pandemic recovery planning.

The paper traces the evolution the concept of socioeconomic vulnerability to climate change has followed in the academic and scientific debate and examines its effects on wellbeing. The recent recognition of vulnerability as a social construction has shifted the focus of the analysis to the dimension of adaptive capacity, restoring a political economy significance to the study of vulnerability. The social origin of vulnerability is related to the presence of structural inequalities, rooted in structural economic and political relationships and reinforced by historical cultural values and praxes. Structural inequalities and power relations in place within a society shape access to resources and capabilities that can enable individuals or population groups to prevent and cope with impacts from extreme weather events, ultimately defining vulnerabilities. Widespread vulnerabilities to climate change can compromise wellbeing in several ways, including an increase in food insecurity, health issues, outbreak of armed conflicts and mass migrations. In addition, the same individual or population group can be vulnerable in more than one wellbeing dimension and, once a dimension is affected, their own vulnerability to other threats is likely to increase.