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Introduction: Infertility related to polycystic ovary syndrome (PCOS) represents a significant challenge for women of reproductive age. Over the last few years, evidence-based medicine has driven new approaches for treating infertility in patients with PCOS, changing rapidly and deeply the clinical practice., Areas Covered: The authors provide an in-depth examination of recent developments in drug treatment strategies that have impacted the clinical practice and changed the previous approach to infertility in patients with PCOS., Expert Opinion: The authors identify four primary areas of interest that have impacted clinical practice in the last few years. Specifically, they discuss the current role of metformin administration in women with PCOS and infertility, the choice for using clomiphene citrate or letrozole as first-line treatment for ovulation induction, the use of new gonadotropin formulations for in vitro fertilization (IVF) program, and the elective embryo transfer in IVF cycles as golden standard treatment for patients with PCOS at high-risk for ovarian hyperstimulation syndrome.

Exosomes are promising therapeutics for tissue repair and regeneration to induce and guide appropriate immune responses in dystrophic pathologies. However, manipulating exosomes to control their biodistribution and targeting them in vivo to achieve adequate therapeutic benefits still poses a major challenge. Here we overcome this limitation by developing an externally controlled delivery system for primed annexin A1 myo-exosomes (Exo myo ). Effective nanocarriers are realized by immobilizing the Exo myo onto ferromagnetic nanotubes to achieve controlled delivery and localization of Exo myo to skeletal muscles by systemic injection using an external magnetic field. Quantitative muscle-level analyses revealed that macrophages dominate the uptake of Exo myo from these ferromagnetic nanotubes in vivo to synergistically promote beneficial muscle responses in a murine animal model of Duchenne muscular dystrophy. Our findings provide insights into the development of exosome-based therapies for muscle diseases and, in general, highlight the formulation of effective functional nanocarriers aimed at optimizing exosome biodistribution., (© 2024. The Author(s).)

Background: Hesitancy about vaccination during pregnancy posed challenges to SARS-CoV-2 vaccination efforts. We aimed to examine rates of SARS-CoV-2 vaccination among Ontario residents who gave birth in early 2022, and to compare rates of SARS-CoV-2 vaccine uptake with rates of tetanus, diphtheria, and pertussis (Tdap) and influenza vaccination during pregnancy in 2019, 2021, and 2022., Methods: We conducted a population-based retrospective cohort study to describe vaccination rates among pregnant and comparable nonpregnant populations in Ontario using linked administrative data. Provincially insured females who had a live, in-hospital birth from Jan. 1 to Mar. 31 in 2019, 2021, or 2022 were our primary cohort. Using log-binomial regression, we tested associations between SARS-CoV-2 (2022) and Tdap and influenza (2019, 2021, 2022) vaccination status, with birth group and covariates. We compared SARS-CoV-2 vaccination status with the status of a matched cohort of nonpregnant females and conducted subgroup analyses by age and prenatal clinician type., Results: Among birthing people, 78.7% received their first SARS-CoV-2 vaccine dose and 74.2% received a second dose. The rate was significantly higher among nonpregnant comparators (dose 1: relative risk [RR] 0.94, 95% confidence interval [CI] 0.93-0.94; dose 2: RR 0.91, 95% CI 0.90-0.91). However, the rate of SARS-CoV-2 vaccination uptake among birthing people was higher than uptake of Tdap or influenza vaccination. Tetanus, diphtheria, and pertussis vaccination increased over time from 22.2% in 2019 to 32.6% in 2022, and influenza vaccination rose to 35.3% in 2021 but returned to prepandemic levels in 2022 (27.7%). Vaccination rates were lower among pregnant people who were young, multiparous, or residents of rural or economically deprived areas for all 3 vaccines., Interpretation: Rates of SARS-CoV-2 vaccination were lower among pregnant people than among nonpregnant comparators but were higher than rates of routinely recommended Tdap and influenza vaccinations. Pandemic urgency may have overcome a great deal of hesitancy about vaccinating against SARS-CoV-2 during pregnancy in 2022, but uptake of routinely recommended vaccines in pregnancy remains a challenge., Trial Registration: Clinicaltrials.gov, no. NCT05663762., Competing Interests: Competing interests:: Devon Greyson reports support for other research from the Canadian Institutes of Health Research (CIHR), British Columbia Immunization Committee, Canadian Immunization Research Network, BC Children’s Hospital Research Canucks for Kids Fund, University of British Columbia (UBC) Hampton Fund, UBC Faculty of Medicine, and Social Sciences and Humanities Research Council. Dr. Greyson also reports honoraria from the University of Sydney and University of Oulu, and unpaid membership with the Association for Information Science and Technology Special Interest Group on Health Information Executive Committee. Meredith Vanstone reports CIHR salary support from Canada Research Chairs program, Banting Postdoctoral Fellowships, Michael Smith Health Research BC Scholar Award, and CIHR/Public Health Agency of Canada (PHAC) Applied Public Health Chair., (© 2024 CMA Impact Inc. or its licensors.)

A cancer diagnosis in patients who are parents of minor children is uniquely stressful for both parents and children. Children need developmentally appropriate information and support to help reduce their fears and worries. Child life specialists (CLSs) are health professionals who work in pediatric environments to support children and families with the stress and uncertainty of illnesses. Increasingly, CLSs have been called upon to support children of patients in adult clinical environments. Our objective was to elucidate CLS caregiving narratives related to working with children of adult cancer patients. We used narrative inquiry to interview four CLSs working in adult oncology. Canadian CLSs who have experience providing care for children and families affected by parental cancer were recruited via convenience sampling. We used narrative analysis methods that included multiple close reads of the data, generating narrative themes, and noting conflicts or tensions in the data. CLSs' caregiving stories often highlighted the complexities of working in an adult oncology environment. Their narratives included challenges in providing optimal care to the children, including family-level barriers (such as parental wishes to withhold information from their children) and systemic barriers (such as late referrals and limited options for bereavement support). CLS participants identified several challenges of working with families in adult oncology. The CLSs highlighted a desire for additional institutional support for children of adult oncology patients and for themselves working in these environments in order to achieve what they believed to be optimal care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Examining institutional data from seven cohorts of students intending to major in biology across five research-intensive institutions, this work analyzes opportunity gaps-defined as the difference between the grade received by students from the dominant and nondominant sociodemographic groups in institutions of higher education-at the course-section level across mathematics, physics, biology, and chemistry disciplines. From this analysis, we find that the majority of course sections have large opportunity gaps between female and male students, students who are Black, Latino/a/e/x, or indigenous to the United States and its territories and students who are White or Asian, first-generation and non-first-generation students, and low-income and non-low-income students. This work provides a framework to analyze equity across institutions using robust methodology, including: using multiple approaches to measure grades, quantile regression rankscores which adjust for previous academic performance, and cluster analysis. Recommendations are provided for institutions to identify faculty who have equitable course sections, automate equity analyses, and compare results to other institutions to make a change toward more equitable outcomes., Competing Interests: Conflicts of interest: The authors declare no conflicts of interest.

Radiotherapy is an invaluable tool in the treatment of cancer. However, when used as a monotherapy, it fails to provide curative outcomes. Chemotherapy drugs are often included to boost the effects of radiation. Key classes of radiosensitizing drugs include platinum compounds, anthracyclines, antimetabolites, taxanes, topoisomerase inhibitors, alkylating agents, and DNA damage repair inhibitors. Chemoradiotherapy suffers from not only systemic toxicities from chemotherapy drugs but also synergistic radiation toxicity as well. It is critical to deliver radiosensitizing molecules to tumor cells while avoiding adjacent healthy tissues. Currently, nanomedicine provides an avenue for tumor specific delivery of radiosensitizers. Nanoscale delivery vehicles can be synthesized from lipids, polymers, or inorganic materials. Additionally, nanomedicine encompasses stimuli responsive particles including prodrug formulation for tumor specific activation. Clinically, nanomedicine and radiotherapy are intertwined with approved formulation including DOXIL and Abraxane. Though many challenges remain, the ongoing progress evidences a promising future for both nanomedicine and chemoradiotherapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies., (© 2024 The Author(s). WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

The gut microbiota plays a pivotal role in maintaining the dynamic balance of intestinal epithelial and immune cells, crucial for overall organ homeostasis. Dysfunctions in these intricate relationships can lead to inflammation and contribute to the pathogenesis of various diseases. Recent findings uncovered the existence of a gut-muscle axis, revealing how alterations in the gut microbiota can disrupt regulatory mechanisms in muscular and adipose tissues, triggering immune-mediated inflammation. In the context of Duchenne muscular dystrophy (DMD), alterations in intestinal permeability stand as a potential origin of molecules that could trigger muscle degeneration via various pathways. Metabolites produced by gut bacteria, or fragments of bacteria themselves, may have the ability to migrate from the gut into the bloodstream and ultimately infiltrate distant muscle tissues, exacerbating localized pathologies. These insights highlight alternative pathological pathways in DMD beyond the musculoskeletal system, paving the way for nutraceutical supplementation as a potential adjuvant therapy. Understanding the complex interplay between the gut microbiota, immune system, and muscular health offers new perspectives for therapeutic interventions beyond conventional approaches to efficiently counteract the multifaceted nature of DMD.

Bioactive glass has been employed in several medical applications since its inception in 1969. The compositions of these materials have been investigated extensively with emphasis on glass network formers, therapeutic transition metals, and glass network modifiers. Through these experiments, several commercial and experimental compositions have been developed with varying chemical durability, induced physiological responses, and hydroxyapatite forming abilities. In many of these studies, the concentrations of each alkali and alkaline earth element have been altered to monitor changes in structure and biological response. This review aims to discuss the impact of each alkali and alkaline earth element on the structure, processing, and biological effects of bioactive glass. We explore critical questions regarding these elements from both a glass science and biological perspective. Should elements with little biological impact be included? Are alkali free bioactive glasses more promising for greater biological responses? Does this mixed alkali effect show increased degradation rates and should it be employed for optimized dissolution? Each of these questions along with others are evaluated comprehensively and discussed in the final section where guidance for compositional design is provided.

The majority of triple negative breast cancers (TNBCs) are basal-like breast cancers (BLBCs), which tend to be more aggressive, proliferate rapidly, and have poor clinical outcomes. A key prognostic biomarker and regulator of BLBC is the Forkhead box C1 (FOXC1) transcription factor. However, because of its functional placement inside the cell nucleus and its structural similarity with other related proteins, targeting FOXC1 for therapeutic benefit, particularly for BLBC, continues to be difficult. We envision targeted nonviral delivery of CRISPR/Cas9 plasmid toward the efficacious knockdown of FOXC1. Keeping in mind the challenges associated with the use of CRISPR/Cas9 in vivo, including off-targeting modifications, and effective release of the cargo, a nanoparticle with context responsive properties can be designed for efficient targeted delivery of CRISPR/Cas9 plasmid. Consequently, we have designed, synthesized, and characterized a zwitterionic amino phospholipid-derived transfecting nanoparticle for delivery of CRISPR/Cas9. The construct becomes positively charged only at low pH, which encourages membrane instability and makes it easier for nanoparticles to exit endosomes. This has enabled effective in vitro and in vivo downregulation of protein expression and genome editing. Following this, we have used EpCAM aptamer to make the system targeted toward BLBC cell lines and to reduce its off-target toxicity. The in vivo efficacy, biodistribution, preliminary pharmacokinetics, and biosafety of the optimized targeted CRISPR nanoplatform is then validated in a rodent xenograft model. Overall, we have attempted to knockout the proto-oncogenic FOXC1 expression in BLBC cases by efficient delivery of CRISPR effectors via a context-responsive nanoparticle delivery system derived from a designer lipid derivative. We believe that the nonviral approach for in vitro and in vivo delivery of CRISPR/Cas9 targeted toward FOXC1, studied herein, will greatly emphasize the therapeutic regimen for BLBC.

A significant amount of progress in nanotechnology has been made due to the development of engineered nanoparticles. The use of metallic nanoparticles for various biomedical applications has been extensively investigated. Biomedical research is highly focused on them because of their inert nature, nanoscale structure, and similar size to many biological molecules. The intrinsic characteristics of these particles, including electronic, optical, physicochemical, and surface plasmon resonance, that can be altered by altering their size, shape, environment, aspect ratio, ease of synthesis, and functionalization properties, have led to numerous biomedical applications. Targeted drug delivery, sensing, photothermal and photodynamic therapy, and imaging are some of these. The promising clinical results of NBTXR3, a high-Z radiosensitizing nanomaterial derived from hafnium, have demonstrated translational potential of this metal. This radiosensitization approach leverages the dependence of energy attenuation on atomic number to enhance energy-matter interactions conducive to radiation therapy. High-Z nanoparticle localization in tumor issue differentially increases the effect of ionizing radiation on cancer cells versus nearby healthy ones and mitigates adverse effects by reducing the overall radiation burden. This principle enables material multifunctionality as contrast agents in X-ray-based imaging. The physiochemical properties of hafnium (Z = 72) are particularly advantageous for these applications. A well-placed K-edge absorption energy and high mass attenuation coefficient compared to elements in human tissue across clinical energy ranges leads to significant attenuation. Chemical reactivity allows for variety in nanoparticle synthesis, composition, and functionalization. Nanoparticles such as hafnium oxide exhibit excellent biocompatibility due to physiochemical inertness prior to incidence with ionizing radiation. Additionally, the optical and electronic properties are applicable in biosensing, optical component coatings, and semiconductors. The wide interest has prompted extensive research in design and synthesis to facilitate property fine-tuning. This review summarizes synthetic methods for hafnium-based nanomaterials and applications in therapy, imaging, and biosensing with a mechanistic focus. A discussion and future perspective section highlights clinical progress and elaborates on current challenges. By focusing on factors impacting applicational effectiveness and examining limitations this review aims to support researchers and expedite clinical translation of future hafnium-based nanomedicine.

Mounting evidence underscores the intricate interplay between the immune system and skeletal muscles in Duchenne muscular dystrophy (DMD), as well as during regular muscle regeneration. While immune cell infiltration into skeletal muscles stands out as a prominent feature in the disease pathophysiology, a myriad of secondary defects involving metabolic and inflammatory pathways persist, with the key players yet to be fully elucidated. Steroids, currently the sole effective therapy for delaying onset and symptom control, come with adverse side effects, limiting their widespread use. Preliminary evidence spotlighting the distinctive features of T cell profiling in DMD prompts the immuno-characterization of circulating cells. A molecular analysis of their transcriptome and secretome holds the promise of identifying a subpopulation of cells suitable as disease biomarkers. Furthermore, it provides a gateway to unraveling new pathological pathways and pinpointing potential therapeutic targets. Simultaneously, the last decade has witnessed the emergence of novel approaches. The development and equilibrium of both innate and adaptive immune systems are intricately linked to the gut microbiota. Modulating microbiota-derived metabolites could potentially exacerbate muscle damage through immune system activation. Concurrently, genome sequencing has conferred clinical utility for rare disease diagnosis since innovative methodologies have been deployed to interpret the functional consequences of genomic variations. Despite numerous genes falling short as clinical targets for MD, the exploration of Tdark genes holds promise for unearthing novel and uncharted therapeutic insights. In the quest to expedite the translation of fundamental knowledge into clinical applications, the identification of novel biomarkers and disease targets is paramount. This initiative not only advances our understanding but also paves the way for the design of innovative therapeutic strategies, contributing to enhanced care for individuals grappling with these incapacitating diseases.

Background: Large introductory lecture courses are frequently post-secondary students' first formal interaction with science, technology, engineering, and mathematics (STEM) disciplines. Grade outcomes in these courses are often disparate across student populations, which, in turn, has implications for student retention. This study positions such disparities as a manifestation of systemic inequities along the dimensions of sex, race/ethnicity, income, and first-generation status and investigates the extent to which they are similar across peer institutions., Results: We examined grade outcomes in a selected set of early STEM courses across six large, public, research-intensive universities in the United States over ten years. In this sample of more than 200,000 STEM course enrollments, we find that course grade benefits increase significantly with the number of systemic advantages students possess at all six institutions. The observed trends in academic outcomes versus advantage are strikingly similar across universities despite the fact that we did not control for differences in grading practices, contexts, and instructor and student populations. The findings are concerning given that these courses are often students' first post-secondary STEM experiences., Conclusions: STEM course grades are typically lower than those in other disciplines; students taking them often pay grade penalties. The systemic advantages some student groups experience are correlated with significant reductions in these grade penalties at all six institutions. The consistency of these findings across institutions and courses supports the claim that inequities in STEM education are a systemic problem, driven by factors that go beyond specific courses or individual institutions. Our work provides a basis for the exploration of contexts where inequities are exacerbated or reduced and can be used to advocate for structural change within STEM education. To cultivate more equitable learning environments, we must reckon with how pervasive structural barriers in STEM courses negatively shape the experiences of marginalized students., Supplementary Information: The online version contains supplementary material available at 10.1186/s40594-024-00474-7., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2024.)

Purpose: Learning to navigate difficult clinical conversations is an essential feature of residency training, yet much of this learning occurs "on the job," often without the formative, multisource feedback trainees need. To generate insight into how on-the-job training influences trainee performance, the perspectives of parents and health care providers (HCPs) who engaged in or observed difficult conversations with Neonatal Intensive Care Unit (NICU) trainees were explored., Method: The iterative data generation and analysis process was informed by constructivist grounded theory. Parents (n = 14) and HCPs (n = 10) from 2 Canadian NICUs were invited to participate in semistructured interviews informed by rich pictures-a visual elicitation technique useful for exploring complex phenomena like difficult conversations. Themes were identified using the constant comparative approach. The study was conducted between 2018 and 2021., Results: According to participants, misalignment between parents' and trainees' communication styles, HCPs intervening to protect parents when trainee-led communication went awry, the absence of feedback, and a culture of sole physician responsibility for communication all conspired against trainees trying to develop communication competence in the NICU. Given beliefs that trainees' experiential learning should not trump parents' well-being, some physicians perceived the art of communication was best learned by observing experts. Sometimes, already limited opportunities for trainees to lead conversations were further constricted by perceptions that trainees lacked the interest and motivation to focus on so-called "soft" skills like communication during their training., Conclusions: Parents and NICU staff described that trainees face multiple barriers against learning to navigate difficult conversations that may set them up to fail. A deeper understanding of the layered challenges trainees face, and the hierarchies and sociocultural norms that interfere with teaching, may be the start of breaking down multiple barriers trainees and their clinician supervisors need to overcome to succeed., Competing Interests: Other disclosures: The authors have no conflicts of interest to declare., (Copyright © 2023 by the Association of American Medical Colleges.)

Introduction: The mistreatment or abuse (maltreatment) of medical learners by their peers and supervisors has been documented globally for decades, and there is significant research about the prevalence, sequelae and strategies for intervention. However, there is evidence that learners experience maltreatment as being less clear cut than do researchers, educators and administrators. This definitional ambiguity creates problems for understanding and addressing this issue. The objective of this study was to understand how medical learners and educators make sense of less-than-ideal interactions in the clinical learning environment, and to describe which factors influenced their perception that the encounter constituted maltreatment., Methods: Using constructivist grounded theory, we interviewed 16 medical students, 15 residents or fellows, and 18 educators associated with a single medical school (n = 49). Data collection began with the most junior learners, iterating with analysis as we progressed through the project. Constant comparative analysis was used to gather and compare stories of 'definitely', 'maybe' and 'definitely not' maltreatment across a variety of axes including experience level, clinical setting and type of interaction., Results: Our data show that learners and educators have difficulty classifying their experiences of negative interpersonal interaction, except in the most severe and concrete cases. While there was tremendous variation in the way they categorised similar experiences, there was consistency in the elements drawn upon to make sense of those experiences. Participants interpreted negative interpersonal interactions on an individual basis by considering factors related to the interaction, initiator and recipient., Conclusions: Only the most negative behaviour is consistently understood as maltreatment; a complex process of individual sense-making is required to determine the acceptability of each interaction. The differences between how individuals judge these interactions highlight an opportunity for administrative, research and faculty development intervention., (© 2023 The Authors. Medical Education published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Objectives: Stress has deleterious effects on teachers' well-being and interactions with students. While in-person mindfulness programs have demonstrated benefits for teachers' mental health, in-person classes are often not feasible due to teachers' busy schedules. This study assessed four components of feasibility (implementation, demand, acceptability, and limited-efficacy testing) for an online mindfulness intervention for teachers., Method: A volunteer sample of 50 primary school teachers was recruited across three urban public schools and was offered a 9-week online mindfulness program (DeStress Monday at School). The program provided weekly mindfulness practices for (1) self-care and (2) classroom use to promote teacher and student stress management. Surveys and focus group discussions assessed program feasibility. Paired t -tests were used to evaluate pre-post changes in teacher well-being., Results: Most participants had no technical problems, providing general support for implementation. Support for program demand was mixed; while 85% of participants used practices at least once, some never used practices, and over half used practices only 1-3 times. Those who used practices generally rated their acceptability favorably. Qualitative analyses showed significant pre-post improvements in work-related and overall stress, depressive and anxiety symptoms, and sleep; those who used practices reported more benefits than those who did not. Qualitative data corroborated these findings, with teachers describing improved stress- and emotion-management following program use., Conclusions: Our findings suggest mindfulness can be delivered online to teachers and may enhance mental health and wellness. Next steps include conducting more rigorous research with a control condition to better understand potential program impact., Preregistration: This study is not preregistered., Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-023-02142-3., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

A growing body of the literature shows the influence of cognitive styles, which capture the ways individuals share, encode, and process information, and their implications for collaboration. We build on this literature to investigate the special contributions of individuals with cognitive style versatility, or facility in more than one cognitive style, for improving teams' collaborative performance. In two studies, including a total of 452 participants in 132 teams, we observe that the presence of cognitively versatile individuals has direct (Study 1) and indirect (Study 2) effects on team performance. In an exploratory analysis, we observe that the presence of cognitively versatile individuals facilitates the task and social processes necessary for effective team information processing, specifically reducing team process conflict and task conflict and enhancing team social integration, with social integration mediating the relationship between cognitive style versatility and team performance. Importantly, these effects remain even when accounting for team cognitive ability and other measures of team surface- and deep-level diversity. Our findings contribute to the emerging literature on team composition and its implications for collaboration and teamwork. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background and Objective: Hydroxychloroquine was widely used during the severe acute respiratory syndrome coronavirus 2 pandemic as an antiviral drug. Most previous pharmacokinetic/pharmacodynamic studies on hydroxychloroquine were conducted on healthy volunteers or patients receiving long-term therapy. There are no studies on the elimination of hydroxychloroquine after short-term treatments. Hydroxychloroquine is known to have a pro-arrhythmic effect through QT interval prolongation, but data in this setting are not conclusive. Our aims were to estimate the time needed for hydroxychloroquine concentrations (C HCQ ) to drop to a safe concentration (500 ng/mL) after a short-term therapeutic cycle and to correlate the corrected QT interval with C HCQ ., Methods: We collected blood samples and electrocardiograms of patients who underwent short-term therapy with hydroxychloroquine during drug intake and after discontinuation. Hydroxychloroquine concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and analysed with a linear regression model to estimate the elimination time of the drug after its discontinuation. We conducted a multivariate analysis of the corrected QT interval correlation with C HCQ ., Results: Our data suggest that short-term hydroxychloroquine courses can generate significant C HCQ persisting above 500 ng/mL up to 16 days after discontinuation of treatment. Corrected QT interval prolongation significantly correlates with C HCQ ., Conclusions: The study confirms the long half-life of hydroxychloroquine and its effect on the corrected QT interval even after short-term courses of the drug. This can inform the clinician using hydroxychloroquine treatments that it would be safer to start or re-initiate treatments with corrected QT interval-prolonging potential 16 days after hydroxychloroquine discontinuation., (© 2022. The Author(s).)

Abstract: Individualization of vancomycin dosing based on therapeutic drug monitoring (TDM) data is known to improve patient outcomes compared with fixed or empirical dosing strategies. There is increasing evidence to support area-under-the-curve (AUC24)-guided TDM to inform vancomycin dosing decisions for patients receiving therapy for more than 48 hours. It is acknowledged that there may be institutional barriers to the implementation of AUC24-guided dosing, and additional effort is required to enable the transition from trough-based to AUC24-based strategies. Adequate documentation of sampling, correct storage and transport, accurate laboratory analysis, and pertinent data reporting are required to ensure appropriate interpretation of TDM data to guide vancomycin dosing recommendations. Ultimately, TDM data in the clinical context of the patient and their response to treatment should guide vancomycin therapy. Endorsed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology, the IATDMCT Anti-Infectives Committee, provides recommendations with respect to best clinical practice for vancomycin TDM., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Major depressive disorder (MDD) and alcohol use disorder (AUD) are highly comorbid, with greater clinical complexity and psychosocial impairment. Several antidepressants have been used in this population, with mixed results. This preliminary study aims to investigate the effects of the multimodal antidepressant vortioxetine in MDD + AUD subjects., Methods: We retrospectively evaluated 57 MDD + AUD and 56 MDD outpatients, matched for baseline characteristics. Patients were assessed after 1, 3, and 6 months treatment with vortioxetine (10-20 mg/d, flexibly dosed) in combination with continuous psychosocial support. The primary outcome was improvement in depressive symptoms measured by the Montgomery-Åsberg Depression Rating Scale. We also investigated changes in anxiety, anhedonia, cognition, functioning, quality of life, and clinical global severity using the following instruments: Hamilton Anxiety Rating Scale, Snaith-Hamilton Pleasure Scale, Digit Symbol Substitution Test, Perceived Deficits Questionnaire-Depression, Functioning Assessment Short Test, Quality of Life Index, and Clinical Global Impression-Severity Scale., Results: Vortioxetine significantly improved mood in MDD + AUD patients (P < .001), with no differences when compared to MDD (P = .36). A substantial rate (45.6%) of comorbid subjects obtained clinical remission at endpoint (P = .36 vs MDD). We additionally observed baseline to endpoint improvements on all secondary outcomes (P < .001), with no significant difference between groups. Overall, vortioxetine was safe and well tolerated., Conclusions: Given its effectiveness on mood, cognition, and functioning, its good safety and tolerability profile, and low potential for abuse, vortioxetine could represent a valid pharmacological intervention in MDD + AUD patients as part of an integrated therapeutic-rehabilitation program.

Background: The coronavirus disease 2019 pandemic represents an unprecedented traumatic stressor to mental health. Psychological distress is considered a reliable proxy for psychopathology and can be negatively influenced by childhood trauma through sensitization effects. Emotion dysregulation has been proposed as a potential mediator of this mechanism. We aimed to test this hypothesis in a national Italian sample assessed in the early phase of the coronavirus disease 2019 outbreak., Methods: We investigated the relationship between psychological distress and childhood trauma in 500 healthy participants assessed through a survey-based study, after the coronavirus disease 2019 pandemic lockdown in Italy. Levels of psychological distress and history of childhood trauma were obtained using the Kessler-10 (K10) and the Childhood Trauma Questionnaire, respectively. We used bootstrapped mediation analysis to test the mediator role of emotional dysregulation, measured through the Difficulties in Emotion Regulation Scale, on the effect of childhood trauma on psychological distress., Results: In total, 190 (38%) reported psychological distress related to the coronavirus disease 2019 outbreak. Individuals with psychological distress experienced more childhood trauma, specifically emotional abuse ( F  = 23.51, df  = 1, p  < 0.001) and neglect ( F  = 10.98, df  = 1, p  = 0.001). After modelling the effect of emotional dysregulation, the impact of childhood trauma on coronavirus disease 2019-related psychological distress resulted in indirect effects and mediated by deficits in emotion regulation mechanisms (bootstrapped lower level of confidence interval = 0.345, upper level of confidence interval = 0.598)., Conclusion: Childhood trauma is associated with increased vulnerability to the stressful effect of the coronavirus disease 2019 outbreak. Our data suggest that emotional dysregulation may represent a dimension mediating the impact of childhood trauma on coronavirus disease 2019-related psychological distress and may be considered as specific target for interventions aiming at empowering resilience.

Depression is common among people living with HIV. Multiple studies demonstrate a link between depression and cognitive dysfunction in adults with HIV, but the association has been minimally investigated in children and adolescents with HIV in Africa. We conducted a cross-sectional analysis as part of the HIV-associated Neurocognitive Disorders in Zambia study, a prospective cohort study in Lusaka, Zambia. We included 208 perinatally-infected children with HIV ages 8-17 taking antiretroviral therapy and 208 HIV-exposed uninfected (HEU) controls. Cognition was assessed with a comprehensive neuropsychological battery. Depressive symptoms were evaluated using self-report and parent-report versions of the NIH Toolbox Sadness module and the Patient Health Questionnaire-9 (PHQ-9). Risk factors for depression and associations between depressive symptoms and cognition were evaluated in bivariable and multivariable regression models. Participants with HIV demonstrated higher levels of depressive symptoms than controls (mean NIH Toolbox Sadness T-Score 50 vs. 44, p < 0.01; mean PHQ-9 score 2.0 vs. 1.5, p = 0.03), and were more likely to have cognitive impairment (30% vs. 13%, p < 0.001). Risk factors for depressed mood included self-reported poor health (OR 7.8, p < 0.001) and negative life events (OR 1.3, p = 0.004) Depressed mood was associated with cognitive impairment in participants with HIV (OR = 2.9, 95% CI 1.2-7.2, p = 0.02) but not in HEU participants (OR 1.7, 95% CI 0.18-15.7, p = 0.6). In conclusion, depressed mood is common among youth with HIV in Zambia, and is associated with cognitive impairment. Depression may be a result of HIV-related stress and stigma, or may be part of the spectrum of HIV-associated neurocognitive disorders. The causal relationship between depressed mood and cognitive impairment is unclear and should be evaluated in future longitudinal studies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Abstract: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

To study the long-term psychological effects of Covid-19 disease, we recruited 61 patients older than 60 years of age and administered the Kessler questionnaire K10 to assess psychological distress and classify them according to mental health risk groups. Patients' affective temperaments were assessed with the 39-item form of the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-A-39) and emotional dysregulation with the Difficulties in Emotion Regulation Scale (DERS). Patients were divided in two samples according to their scores on the K10, i.e., a high likelihood of psychological distress group ( N = 18) and a low likelihood of psychological distress group ( N = 43). The two groups differed on their gender composition, in that more women ( N = 11) were in the former and more men in the latter ( N = 29) (χ 2 = 4.28; p = 0.039). The high likelihood of psychological distress group scored higher on the Cyclothymic (3.39 ± 3.45 vs. 0.93 ± 1.08, p < 0.001) and the Depressive (2.28 ± 2.82 vs. 0.65 ± 1.09, p = 0.01) affective temperaments of the TEMPS and on the lack of Impulse control (12.67 ± 4.04 vs. 9.63 ± 3.14, p = 0.003) and lack of Clarity (15.00 ± 5.56 vs. 9.85 ± 4.67, p = 0.004) scales of the DERS. Our results show that having had Covid-19 may be related with high likelihood for psychological distress in advanced-age people and this may in turn be associated with impaired emotional regulation and higher scores on depressive and cyclothymic temperaments., (Copyright © 2020 Janiri, Kotzalidis, Giuseppin, Molinaro, Modica, Montanari, Terenzi, Carfì, Landi, Sani and the Gemelli Against COVID-19 Post-acute Care Study Group.)

Recent studies report strategies for analysing immunosuppressive drugs in brain, liver and renal tissue, mostly in animals: we developed and validated a two steps combined enzymatic digestion/mass spectrometry assay to quantify Tacrolimus (TAC) in heart biopsies. Our aims were to avoid sample loss and sample contamination during the laboratory preparation, and to limit matrix effects in the electrospray ionization source (ESI) of the mass spectrometer. Enzymatic tissue digestion followed by a liquid-liquid drug extraction in the same vial of reaction allowed us to reach both our aims. The assay was assessed for selectivity, matrix effect, linearity, Lower Limit of Quantification (LLOQ) and Detection (LOD), accuracy and precision, according to the "Guideline on Bioanalytical Method Validation (EMA). A stable isotopically labelled (SIL) analogue ( 13 CD 2 -TAC) was used as internal standard. The chromatographic separation of the analyte took 6 min. The observed linear range of quantification was 0.0162-0.520 ng in terms of TAC added to the biopsies (by 50 μL of the corresponding working solutions). The limit of detection and the lower limit of quantification (LLOQ) were 0.008 and 0.0162 ng, respectively. Both the mobile phases contained ammonium acetate and formic acid that promote the formation of ammoniated precursor ions that can be easily fragmented ([M + NH 4 ] + , TAC m/z 821.3; 13 CD 2 -TAC m/z 824.3). The calibration curves were generated by plotting analyte-to-internal standard peak area ratios versus TAC amount (ng) added to the biopsies, and using a weighted (1/x) linear regression. Curves were not forced to pass through the origin. Swine hearts were employed as blank matrix for all the analytical method validation procedures but, after approval by the ethics committee (by "Fondazione IRCCS Policlinico San Matteo": Protocol 20190032933), TAC was also quantified in endomyocardial biopsies from informed and consenting heart transplant patients. The study was funded by Fondazione IRCCS Policlinico San Matteo (RC08017617), as a part of the clinical studies on the maintenance of immunosuppressive therapy in cardiac transplant patients. Tacrolimus concentrations in patients biopsies were expressed as ratio between the detected amount of TAC (ng) in the tissue and the weight of the tissue itself (mg)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The outbreak of COVID-19 is severely affecting mental health worldwide, although individual response may vary. This study aims to investigate the psychological distress perceived by the Italian general population during the early phase of the COVID-19 pandemic, and to analyze affective temperament and adult attachment styles as potential mediators. Through an online survey, we collected sociodemographic and lockdown-related information and evaluated distress, temperament, and attachment using the Kessler 10 Psychological Distress Scale (K10), the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire short version (TEMPS-A) and the Attachment Style Questionnaire (ASQ). In our sample (n = 500), 62% of the individuals reported no likelihood of psychological distress, whereas 19.4% and 18.6% displayed mild and moderate-to-severe likelihood. Cyclothymic (OR: 1.24; p < 0.001), depressive (OR: 1.52; p < 0.001) and anxious (OR: 1.58; p = 0.002) temperaments, and the ASQ "Need for approval" (OR: 1.08; p = 0.01) were risk factors for moderate-to-severe psychological distress compared to no distress, while the ASQ "Confidence" (OR: 0.89; p = 0.002) and "Discomfort with closeness" were protective (OR: 0.92; p = 0.001). Cyclothymic (OR: 1.17; p = 0.008) and depressive (OR: 1.32; p = 0.003) temperaments resulted as risk factors in subjects with moderate-to-severe psychological distress compared to mild distress, while the ASQ "Confidence" (OR: 0.92; p = 0.039) and "Discomfort with closeness" (OR: 0.94; p = 0.023) were protective. Our data indicated that a relevant rate of individuals may have experienced psychological distress following the COVID-19 outbreak. Specific affective temperament and attachment features predict the extent of mental health burden. To the best of our knowledge, these are the first data available on the psychological impact of the early phase of the COVID-19 pandemic on a sizeable sample of the Italian population. Moreover, our study is the first to investigate temperament and attachment characteristics in the psychological response to the ongoing pandemic. Our results provide further insight into developing targeted intervention strategies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives: Gambling disorder (GD) leads to impaired socioeconomical functioning and increased social costs. Although the research on GD has been rising over the years, approved treatment guidelines are currently not available. The aim of this study was to systematically review the literature on the pharmacological and psychosocial treatment of adults with GD, and to identify possible agreed-upon standards of care., Methods: MEDLINE, PubMed, Cochrane, Web of Science, Embase, and CINAHL electronic databases were searched up to April 2019 for systematic reviews on pharmacological, psychosocial, and combined treatment of adults with GD. Twenty-six studies were eventually included in this meta-review., Results: Studies reported promising results of opioid antagonists and mood stabilizers in reducing GD-related symptomatology. Lithium was particularly effective in subjects with comorbid bipolar disorders. Cognitive behavioral therapy (CBT) was the most commonly used psychological intervention and reduced global severity, gambling frequency, and financial loss. Motivational interviewing (MI) seemed to improve several GD domains, alone or in combination with CBT. Self-help interventions (SHIs) showed some efficacy in promoting treatment-seeking, and in combination with other treatments., Conclusions: We found moderate evidence of effect for CBT, but weaker evidence for pharmacotherapy and SHIs. Results suggested some efficacy for MI in the short but not in the long term. It is likely that certain interventions might be more effective than others on specific features of GD. Further studies are needed to compare the efficacy and acceptability of individual and combined psychosocial and pharmacological interventions, to deliver patient-tailored treatments.

Objective: To examine receptive language growth in children with cerebral palsy (CP) and anarthria using a parent-reported measure of vocabulary., Method: Scores from 47 children (29 males) with CP and anarthria were obtained from the vocabulary checklists on the MacArthur-Bates Communication Development Inventories (MCDI) and analyzed to examine the distribution of receptive language growth. Linear trajectories of word composite scores were created using a linear-mixed model, incorporating between two and ten data points per child., Results: Three different growth trajectories emerged: approximately 23% grew by 100 or more words per year, 13% grew by 50-100 words per year, and 64% grew by 50 words per year or less. Age-four vocabulary was strongly correlated with rate of increase in vocabulary., Conclusion: Receptive vocabulary scores from the MCDI are increasing at a reduced pace for most children with CP and anarthria. More sensitive measures of language assessment are necessary to gain a complete picture of their language ability levels.

Background: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs). It is therefore likely that solid organ transplant recipients will be treated with these experimental antivirals., Methods: This article is not intended to provide a systematic literature review on investigational treatments tested against COVID-19; rather, the authors aim to provide recommendations for therapeutic drug monitoring of ISDs in transplant recipients infected with SARS-CoV-2 based on a review of existing data in the literature., Results: Management of drug-drug interactions between investigational anti-SARS-CoV-2 drugs and immunosuppressants is a complex task for the clinician. Adequate immunosuppression is necessary to prevent graft rejection while, if critically ill, the patient may benefit from pharmacotherapeutic interventions directed at limiting SARS-CoV-2 viral replication. Maintaining ISD concentrations within the desired therapeutic range requires a highly individualized approach that is complicated by the pandemic context and lack of hindsight., Conclusions: With this article, the authors inform the clinician about the potential interactions of experimental COVID-19 treatments with ISDs used in transplantation. Recommendations regarding therapeutic drug monitoring and dose adjustments in the context of COVID-19 are provided.

Background: We assessed the utility of the International HIV Dementia Scale (IHDS) in detecting HIV-associated neurocognitive disorder (HAND) in Uganda in antiretroviral (ART)-naïve and ART-experienced adults., Setting: A longitudinal observational cohort study in Rakai, Uganda., Methods: Three hundred ninety-nine HIV+ ART-naïve adults underwent neurological, functional status, and neuropsychological assessments including the IHDS. Three hundred twelve participants who initiated ART were re-evaluated after 2 years. HAND stages [asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia (HAD)] were determined based on Frascati criteria using local normative data. Sensitivity, specificity, and area under the ROC curve were determined for various IHDS thresholds (≤9, ≤ 9.5, and ≤10)., Results: At baseline, the participants' mean age was 35 years (SD ± 8), 53% were men, and 84% had less than a high school education. At baseline, sensitivity for detecting any HAND stage, symptomatic HAND [mild neurocognitive disorder, HAD], and HAD alone were maximized at IHDS ≤10 (81%, 83%, 92%, respectively). Among 312 individuals who returned for the 2-year follow-up and had initiated ART, a score of ≤10 provided a lower or equal sensitivity for detecting different stages of HAND (all HAND: 70%; symptomatic HAND: 75%; HAD: 94%). The area under the ROC curve was higher for ART-experienced versus ART-naïve individuals., Conclusions: The IHDS is a potentially useful screening tool for neurocognitive impairment in rural Uganda for both ART-naïve and ART-experienced adults. A cutoff ≤10 demonstrates higher sensitivity for more severe HAND stages compared with less severe HAND. Future studies should focus on potential modifications to the IHDS to improve its specificity.

We analyzed the use of isavuconazole (ISA) as treatment or prophylaxis for invasive fungal disease (IFD) in children with hemato-oncologic diseases. A multicentric retrospective analysis was performed among centers belonging to the Italian Association for Pediatric Hematology and Oncology (AIEOP). Pharmacokinetic (PK) monitoring was applied by a high-performance liquid chromatography-tandem mass spectrometry (HLPC-MS/MS) assay. Twenty-nine patients were studied: 10 during chemotherapy and 19 after allogeneic hematopoietic stem cell transplantation (HSCT). The patients consisted of 20 males and 9 females with a median age of 14.5 years (age range, 3 to 18 years) and a median body weight of 47 kg (body weight range, 15 to 80 kg). ISA was used as prophylaxis in 5 patients and as treatment in 24 cases (20 after therapeutic failure, 4 as first-line therapy). According to European Organization for Research and Treatment of Cancer (EORTC) criteria, we registered 5 patients with proven IFD, 9 patients with probable IFD, and 10 patients with possible IFD. Patients with a body weight of <30 kg received half the ISA dose; the others received ISA on the adult schedule (a 200-mg loading dose every 8 h on days 1 and 2 and a 200-mg/day maintenance dose); for all but 10 patients, the route of administration switched from the intravenous route to the oral route during treatment. ISA was administered for a median of 75.5 days (range, 6 to 523 days). The overall response rate was 70.8%; 12 patients with IFD achieved complete remission, 5 achieved partial remission, 5 achieved progression, and 3 achieved stable IFD. No breakthrough infections were registered. PK monitoring of 17 patients revealed a median ISA steady-state trough concentration of 4.91 mg/liter (range, 2.15 to 8.54 mg/liter) and a concentration/dose (in kilograms) ratio of 1.13 (range, 0.47 to 3.42). Determination of the 12-h PK profile was performed in 6 cases. The median area under the concentration-time curve from 0 to 12 h was 153.16 mg·h/liter (range, 86.31 to 169.45 mg·h/liter). Common Terminology Criteria for Adverse Events grade 1 to 3 toxicity (increased transaminase and/or creatinine levels) was observed in 6 patients, with no drug-drug interactions being seen in patients receiving immunosuppressants. Isavuconazole may be useful and safe in children with hemato-oncologic diseases, even in the HSCT setting. Prospective studies are warranted., (Copyright © 2020 American Society for Microbiology.)

Monoclonal antibody (mAb) therapy does not usually lead to a clinical response in all patients and resistance may increase over time after repeated mAb administration. This lack or loss of response to the treatment may originate from different and little-known epigenetic, biomolecular, or pathophysiological mechanisms, although an inadequate serum concentration is perhaps the most likely cause, even if not widely recognized and investigated yet. Patient factors that influence the pharmacokinetics (PK) of a mAb should be taken into account. Multiple analyses of patient-derived PK data have identified various factors influencing the clearance of mAbs. These factors include the presence of antidrug antibodies, low serum albumin, high serum levels of C-reactive protein, high body weight, and gender differences among others. The same clearance processes involved in systemic clearance after intravenous administration are also involved in local first-pass catabolism after subcutaneous administration of mAbs. Therapeutic drug monitoring has been proposed as a way to understand and respond to the variability in clinical response and remission. For both classes of mAbs with anti-inflammatory and antitumor effects, dose-guided optimization based on the measurement of serum concentrations in individual patients could be the next step for a personalized and targeted mAb therapy.

Background: The pharmacokinetic properties and clinical advantages of the local anesthetic chloroprocaine are well known. Here, we studied the pharmacokinetic profile of a new hydrogel device loaded with chloroprocaine to investigate the potential advantages of this new strategy for postoperative pain (POP) relief., Materials and Methods: We performed both in vitro and in vivo analyses by considering plasma samples of four piglets receiving slow-release chloroprocaine. To quantify chloroprocaine and its inactive metabolite 4-amino-2-chlorobenzoic acid (ACBA), a HPLC-tandem mass spectrometry (HPLC-MS/MS) analytical method was used. Serial blood samples were collected over 108 hours, according to the exposure time to the device., Results: Chloroprocaine was consistently found to be below the lower limit of quantification, even though a well-defined peak was observed in every chromatogram at an unexpected retention time. Concerning ACBA, we found detectable plasma concentrations between T 0 and T 12h , with a maximum plasma concentration (C max ) observed 3 hours after the device application. In the in vitro analyses, the nanogel remained in contact with plasma at 37°C for 90 minutes, 3 hours, 1 day, and 7 days. Chloroprocaine C max was identified 1 day following exposure and C min after 7 days, respectively. Additionally, ACBA reached the C max following 7 days of exposure., Conclusion: A thorough review of the literature indicates that this is the first study analyzing both in vivo and in vitro pharmacokinetic profiles of a chloroprocaine hydrogel device and is considered as a pilot study on the feasibility of including this approach to the management of POP., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level., Methods: A total of 97 hematology-oncology pediatric patients with ≥1 posaconazole plasma concentration level (PPC) assessment in the first 6 weeks after the start of posaconazole treatment were included., Results: Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12 mg in the prophylaxis group and 12.5 to 16.5 mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8 μg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4 μg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04., Conclusions: Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: A monocentric, single-dose, open-label, 2-way, crossover randomized study was conducted by the San Matteo Phase I Clinical Trial Unit and Experimental Therapy (Pavia, Italy) to assess the bioequivalence and the systemic tolerability of a new oral formulation of levosulpiride (tablet 25 mg: test) versus a commercially available formulation on the Italian market (tablet 25 mg: reference)., Methods: Thirty-five healthy adult volunteers, men (n = 19) and women (n = 16), aged between 18 and 55 years were screened and 32 of them were enrolled in the study. After having signed the written informed consent, each subject received a single oral dose of Test or Reference product with 250 mL of natural mineral water, in fasting conditions, interspersed with a 6-day washout period Blood samples were collected up to 36 hours after drug administration: the drug plasma levels were determined by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The pharmacokinetic parameters included peak plasma concentration (Cmax), time corresponding to Cmax (tmax), area under the plasma concentration-time curve from zero to infinity (AUC0-∞) or to the last sampling time assessment (AUC0-36), the elimination rate constant (ke), and the terminal half-life (t1/2). Safety was measured by pre- and post-treatment specific biochemical investigations, physical examination, electrocardiogram, occurrence of adverse events, and any information on patients' withdrawal., Results: The geometric mean ratio Test/Reference (90% confidence interval) for levosulpiride was 103.0% (95.8-110.8) for AUC0-36, 103.6% (95.9-111.9) for AUC0-∞, and 104.3% (94.9-114.6) for Cmax. ke and t1/2 were 0.07 (SD: 0.02) and 9 hours (8-12) for both the formulations. Clearance (L/h) was 29.6 (±13.5) and 30.7 (±14.2) for the test and the reference product, respectively., Conclusions: Because the acceptance criteria required by the drug regulatory agency (European Medicines Agency, EMA) for bioequivalence prescribe limits of 80%-120% for untransformed data and 80%-125% for "ln" transformed data, we can confirm that the 2 formulations are bioequivalent, in terms of the rate and extent of absorption.

Background: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%., Objectives: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients., Methods: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations., Results: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively., Conclusions: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Preterm infants are at high risk of neonatal sepsis. We report a case of a preterm infant under prophylaxis with Lactobacillus Rhamnosus for necrotizing enterocolitis; the child develops neonatal sepsis by Lactobacillus Rhamnosus. The infection is improved after probiotic withdrawal and had complete remission after 20 days of specific antibiotic therapy.

Unlabelled: High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor μ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P = .007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy., Perspective: This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Reactive oxygen species and reactive nitrogen species are produced endogenously by cardiomyocytes and are fundamental signaling molecules that regulate cellular function. Production of ROS and RNS is finely tuned to maintain proper myocardial function, but is altered in many pathophysiological conditions, therefore contributing to worsening myocardial dysfunction and ultimately heart failure. Indeed, an excess of ROS and RNS is central in many pathways leading to cardiac hypertrophy and failure, and the correct regulation of the nitroso-redox balance is fundamental for the function of the main components of the EC-coupling machinery. Broad antioxidant therapies have been proposed to improve myocardial function, but these therapies blunt even physiological ROS and RNS signaling, bringing limited, if any, beneficial effect. On the other hand, more targeted interventions on specific sources or pathways may produce promising results.

Along with the improvement of survival after cancer, cardiotoxicity due to antineoplastic treatments has emerged as a clinically relevant problem. Potential cardiovascular toxicities due to anticancer agents include QT prolongation and arrhythmias, myocardial ischemia and infarction, hypertension and/or thromboembolism, left ventricular (LV) dysfunction, and heart failure (HF). The latter is variable in severity, may be reversible or irreversible, and can occur soon after or as a delayed consequence of anticancer treatments. In the last decade recent advances have emerged in clinical and pathophysiological aspects of LV dysfunction induced by the most widely used anticancer drugs. In particular, early, sensitive markers of cardiac dysfunction that can predict this form of cardiomyopathy before ejection fraction (EF) is reduced are becoming increasingly important, along with novel therapeutic and cardioprotective strategies, in the attempt of protecting cardiooncologic patients from the development of congestive heart failure.

Measurement of inosine-monophosphate dehydrogenase (IMPDH) activity or gene expression was used as a further approach in pharmacokinetics (PK)/pharmacodynamic (PD)-guided mycophenolate mofetil (MMF) therapy. Forty-four de novo kidney transplant patients were enrolled; 35 of these completed the study, and were followed for 24 weeks for clinical status, PK parameters, IMPDH activity and IMPDH1/2 gene expression. IMPDH activity and expression were measured in peripheral blood mononuclear cells before transplant and at week 2,4,12 and 24, drawn before (t0) and 2 h (t2 h) after MMF administration. No significant correlation was found between IMPDH activity/expression and PK parameters. For both genes, significant enhancement in t2 h expression was observed, then decreases towards week 24 with a trend following steroid dosages. Seven patients experienced acute rejection (AR) and exhibited significantly higher pre-transplant expression of both IMPDH1 (median 3.42 vs. 0.84; p=0.0025), and IMPDH2 genes (135 vs. 104; p=0.0218) with respect to non-rejecting patients. A significant association was also found between pre-transplant IMPDH1 mRNA and haematological complications (p=0.032). This study suggests that high steroid dosages may influence IMPDH1/2 expression, hampering their use as a PD biomarker, particularly during the early post-transplant period. The measurement of pre-transplant levels of IMPDH1/2 may contribute to prediction of individual drug responsiveness to improve the clinical management of patients in MMF therapy.

Skeletal muscle has a remarkable capacity to regenerate after mechanical or pathological injury. We show that the V1a receptor (V1aR) for vasopressin, a potent myogenic-promoting factor that stimulates differentiation and hypertrophy in vitro, is expressed in mouse skeletal muscle and modulated during regeneration after experimental injury. We used gene delivery by electroporation to overexpress the myc-tagged vasopressin V1aR in specific muscles, thus sensitizing them to circulating vasopressin. The correct localization on the surface of the fibers of the recombinant product was demonstrated by confocal immunofluorescence directed against the myc tag. V1aR overexpression dramatically enhanced regeneration. When compared with mock-transfected controls, V1aR overexpressing muscles exhibited significantly accelerated activation of satellite cells and increased expression of differentiation markers. Downstream of V1aR activation, calcineurin was strongly up-regulated and stimulated the expression of IL-4, a potent mediator of myogenic cell fusion. The central role of calcineurin in mediating V1aR-dependent myogenesis was also demonstrated by using its specific inhibitor, cyclosporine A. This study identifies skeletal muscle as a physiological target of hormones of the vasopressin family and reveals a novel in vivo role for vasopressin-dependent pathways. These findings unveil several steps, along a complex signaling pathway, that may be exploited as potential targets for the therapy of diseases characterized by altered muscle homeostasis and regeneration.

Fusion of mononucleated myoblasts to form multinucleated myofibers is an essential phase of skeletal myogenesis, which occurs during muscle development as well as during postnatal life for muscle growth, turnover, and regeneration. Many cell adhesion proteins, including integrins, have been shown to be important for myoblast fusion in vertebrates, and recently focal adhesion kinase (FAK), has been proposed as a key mediator of myoblast fusion. Here we focused on the possible role of PKC, the PKC isoform predominantly expressed in skeletal muscle, in myoblast fusion. We found that the expression of PKC is strongly up-regulated following freeze injury-induced muscle regeneration, as well as during in vitro differentiation of satellite cells (SCs; the muscle stem cells). Using both PKC knockout and muscle-specific PKC dominant-negative mutant mouse models, we observed delayed body and muscle fiber growth during the first weeks of postnatal life, when compared with wild-type (WT) mice. We also found that myofiber formation, during muscle regeneration after freeze injury, was markedly impaired in PKC mutant mice, as compared with WT. This phenotype was associated with reduced expression of the myogenic differentiation program executor, myogenin, but not with that of the SC marker Pax7. Indeed in vitro differentiation of primary muscle-derived SCs from PKC mutants resulted in the formation of thinner myotubes with reduced numbers of myonuclei and reduced fusion rate, when compared with WT cells. These effects were associated to reduced expression of the profusion genes caveolin-3 and β1D integrin and to reduced activation/phosphorylation of their up-stream regulator FAK. Indeed the exogenous expression of a constitutively active mutant form of PKC in muscle cells induced FAK phosphorylation. Moreover pharmacologically mediated full inhibition of FAK activity led to similar fusion defects in both WT and PKC-null myoblasts. We thus propose that PKC signaling regulates myoblast fusion by regulating, at least in part, FAK activity, essential for profusion gene expression.

In this paper we report the development of two attachments to a commercial cell phone that transform the phone's integrated lens and image sensor into a 350x microscope and visible-light spectrometer. The microscope is capable of transmission and polarized microscopy modes and is shown to have 1.5 micron resolution and a usable field-of-view of 150 x 50 with no image processing, and approximately 350 x 350 when post-processing is applied. The spectrometer has a 300 nm bandwidth with a limiting spectral resolution of close to 5 nm. We show applications of the devices to medically relevant problems. In the case of the microscope, we image both stained and unstained blood-smears showing the ability to acquire images of similar quality to commercial microscope platforms, thus allowing diagnosis of clinical pathologies. With the spectrometer we demonstrate acquisition of a white-light transmission spectrum through diffuse tissue as well as the acquisition of a fluorescence spectrum. We also envision the devices to have immediate relevance in the educational field.

Background: Ischemia-reperfusion (I/R) is present at various degrees in kidney transplants. I/R plays a major role in early function and long-term survival of renal allograft. The purpose of our study was to determine if immunosuppressants modulate I/R in a model that separates I/R from all immune responses., Methods: Sprague-Dawley rats with monolateral renal I/R received daily cyclosporine (A), tacrolimus (B), sirolimus (C) or saline (D). Sham-operated rats received saline (E). After 30 days, glomerular filtration rate for each kidney was measured by inulin clearance. Kidney injury was examined, and TGF-β, fibronectin and metalloproteases were evaluated by real-time PCR, Western blot and zymography., Results: Sirolimus, but not cyclosporine and tacrolimus, prevented a glomerular filtration rate decrease in I/R kidneys (403 ± 303 vs. 1,006 ± 484 μl/min, p < 0.05; 126 ± 170 vs. 567 ± 374 μl/min, p < 0.05; 633 ± 293 vs. 786 ± 255; A, B and C group, respectively, I/R vs. contralateral kidneys). Sirolimus reduced ED-1+ cell infiltrate, interstitial fibrosis and intimal thickening of small vessels observed in I/R kidneys of controls and calcineurin inhibitor-treated rats. Tacrolimus and cyclosporine increased fibronectin and TGF-β expression and matrix deposition. Only sirolimus increased metalloprotease activity., Conclusions: Sirolimus but not calcineurin inhibitors prevented I/R-induced kidney injury., (Copyright © 2011 S. Karger AG, Basel.)

Protein kinase Cs (PKCs) constitute a family of serine/threonine kinases, which has distinguished and specific roles in regulating cardiac responses, including those associated with heart failure. We found that the PKCθ isoform is expressed at considerable levels in the cardiac muscle in mouse, and that it is rapidly activated after pressure overload. To investigate the role of PKCθ in cardiac remodeling, we used PKCθ(-/-) mice. In vivo analyses of PKCθ(-/-) hearts showed that the lack of PKCθ expression leads to left ventricular dilation and reduced function. Histological analyses showed a reduction in the number of cardiomyocytes, combined with hypertrophy of the remaining cardiomyocytes, cardiac fibrosis, myofibroblast hyper-proliferation and matrix deposition. We also observed p38 and JunK activation, known to promote cell death in response to stress, combined with upregulation of the fetal pattern of gene expression, considered to be a feature of the hemodynamically or metabolically stressed heart. In keeping with these observations, cultured PKCθ(-/-) cardiomyocytes were less viable than wild-type cardiomyocytes, and, unlike wild-type cardiomyocytes, underwent programmed cell death upon stimulation with α1-adrenergic agonists and hypoxia. Taken together, these results show that PKCθ maintains the correct structure and function of the heart by preventing cardiomyocyte cell death in response to work demand and to neuro-hormonal signals, to which heart cells are continuously exposed.

What Is Already Known About This Subject: * Mycophenolic acid (MPA) is a potent, selective and reversible inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for de novo guanosine triphosphate biosynthesis. * The large IMPDH interindividual variability could be responsible for the differences in therapeutic effects and side-effects observed with MPA. * Induction of IMPDH activity has been observed in whole blood during immunosuppressive therapy., What This Study Adds: * Our data were acquired in long-term mycophenolate mofetil-treated renal transplant recipients on different combinations of immunosuppressive agents (ciclosporin, tacrolimus, sirolimus) and with different treatment duration (up to 8.8 years post transplant). * The increasing trend in IMPDH activity that we observed throughout our 12-month observation period was significantly higher in rejecting than in nonrejecting subjects., Aims: Long-term mycophenolate mofetil (MMF) therapy may induce inosine 5'-monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells (PBMCs), thus decreasing MMF immunosuppressive properties. Pharmacodynamic monitoring was used to investigate whether biological activity is altered after long-term therapy., Methods: IMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t(0)) and 2 h after (t(2)) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations., Results: During the 15 months' monitoring, t(0) IMPDH activity in transplant recipients increased from 5.9 +/- 3.7 nmol h(-1) mg(-1)[95% confidence interval (CI) 4.9, 6.9] to 9.0 +/- 3.9 nmol h(-1) mg(-1) (95% CI 7.2, 10.8), with an intra- and interpatient variability of 28% and 42%. Five patients experienced acute rejection during the follow-up: t(0) IMPDH activity was increased during rejection vs. nonrejection, and the trend was significantly higher in rejecting than in nonrejecting subjects for the whole monitoring period., Conclusions: Even though a correlation has been found between IMPDH activity and rejection, its efficacy as a predictive tool in long-term transplant outcomes may be affected by high interpatient variability; on the other hand, continuous monitoring of the IMPDH trend could make an effective prognostic parameter of rejection. Other trials also including pre-transplant data on both IMPDH expression and activity are warranted to better assess their role as biomarkers for MPA effect in clinical practice.

The antioxidant enzyme superoxide dismutase 1 (SOD1) is a critical player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1(G93A)) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, associated with a significant reduction in muscle strength, alterations in the contractile apparatus, and mitochondrial dysfunction. The analysis of molecular pathways associated with muscle atrophy revealed that accumulation of oxidative stress served as signaling molecules to initiate autophagy, one of the major intracellular degradation mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1(G93A) -mediated toxicity and disclose the molecular mechanism whereby oxidative stress triggers muscle atrophy.