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A supposedly nonmagnetic 5d^{1} double perovskite oxide is investigated by a combination of spectroscopic and theoretical methods, namely, resonant inelastic x-ray scattering, x-ray absorption spectroscopy, magnetic circular dichroism, and multiplet ligand-field calculations. We found that the large spin-orbit coupling admixes the 5d t_{2g} and e_{g} orbitals, covalency raises the 5d population well above the nominal value, and the local symmetry is lower than O_{h}. The obtained electronic interactions account for the finite magnetic moment of Os in this compound and, in general, of 5d^{1} ions. Our results provide direct evidence of elusive Jahn-Teller distortions, hinting at a strong electron-lattice coupling.

Silicon Photomultipliers (SiPMs) are single photon detectors that gained increasing interest in many applications as an alternative to photomultiplier tubes. In the field of space experiments, where volume, weight and power consumption are a major constraint, their advantages like compactness, ruggedness, and their potential to achieve high quantum efficiency from UV to NIR makes them ideal candidates for spaceborne, low photon flux detectors. During space missions however, SiPMs are usually exposed to high levels of radiation, both ionizing and non-ionizing, which can deteriorate the performance of these detectors over time. The goal of this work is to compare process and layout variation of SiPMs in terms of their radiation damage effects to identify the features that helps reduce the deterioration of the performance and develop the next generation of more radiation-tolerant detectors. To do this, we used protons and X-rays to irradiate several Near Ultraviolet High-Density (NUV-HD) SiPMs with small areas (single microcell, 0.2 × 0.2 mm 2 and 1 × 1 mm 2 ) produced at Fondazione Bruno Kessler (FBK), Italy. We performed online current-voltage measurements right after each irradiation step, and a complete functional characterization before and after irradiation. We observed that the main contribution to performance degradation in space applications comes from proton damage in the form of an increase in primary dark count rate (DCR) proportional to the proton fluence and a reduction in activation energy. In this context, small active area devices show a lower DCR before and after irradiation, and we propose light or charge-focusing mechanisms as future developments for high-sensitivity radiation-tolerant detectors.

In this study, the structural attributes of nanoparticles obtained by a renewable and non-immunogenic "inulinated" analog of the "pegylated" PLA (PEG-PLA) were examined, together with the potential of these novel nanocarriers in delivering poorly water-soluble drugs. Characterization of INU-PLA assemblies, encompassing critical aggregation concentration (CAC), NMR, DLS, LDE, and SEM analyses, was conducted to elucidate the core/shell architecture of the carriers and in vitro cyto- and hemo-compatibility were assayed. The entrapment and in vitro delivery of sorafenib tosylate ( ST ) were also studied. INU-PLA copolymers exhibit distinctive features: (1) Crew-cut aggregates are formed with coronas of 2-4 nm; (2) a threshold surface density of 1 INU/nm 2 triggers a configuration change; (3) INU surface density influences PLA core dynamics, with hydrophilic segment stretching affecting PLA distribution towards the interface. INU-PLA 2 NPs demonstrated an outstanding loading of ST and excellent biological profile, with effective internalization and ST delivery to HepG2 cells, yielding a comparable IC 50 .

Frequent use of pain relief medications among patients with migraine can result in disease worsening and medication-overuse headache (MOH), a painful and debilitating condition. We sought to conduct a cross-sectional survey among adult patients diagnosed with migraine to determine: 1) their awareness of MOH, and 2) their knowledge of the condition and its prevention, and 3) the association of these factors with actual use of pain relief medications. We recruited and interviewed 200 English-speaking adults with migraine who had a clinic visit with a neurologist or primary care provider within the past month. Patients were identified via an electronic health record query. Almost 40% of participants had never heard of the term 'medication-overuse headache.' In bivariate analyses, participants who were Black or Hispanic and those with limited health literacy were less likely to have heard of MOH. Participants scored an average of 2.1 (range: 0-3) on a MOH knowledge measure; older participants, those with limited health literacy, lower education, and little or no migraine-related disability demonstrated less knowledge. Almost a third (31.5%) of patients reported overusing pain relief medication and were at risk for MOH. Overuse was not significantly associated with MOH awareness, knowledge, or sociodemographic factors, but was related to greater migraine-related disability. Our findings suggest that patient awareness and knowledge of MOH is suboptimal, particularly among older adults, racial and ethnic minority groups, and those with limited health literacy. Interventions are needed to prevent MOH and better inform patients about risks associated with frequent use of pain relief medications., Competing Interests: SCB reports grants from Merck, Pfizer, Gordon and Betty Moore Foundation, RRF Foundation for Aging, Lundbeck, Gilead and Eli Lilly through her institution; and personal fees from Gilead, Sanofi, Pfizer, University of Westminster, Lundbeck, and Luto outside the submitted work. APP reports grants from Merck, Pfizer, Gordon and Betty Moore Foundation, RRF Foundation for Aging, Lundbeck, Gilead, and Eli Lilly through her institution; and personal fees from Gilead. MPH and DF are employees of H. Lundbeck A/S and Lundbeck LLC, respectively. SMK was an employee of Lundbeck LLC at the time when this manuscript was written. All other study authors have no conflicts of interest to report., (Copyright: © 2024 Bailey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Polarons and spin-orbit (SO) coupling are distinct quantum effects that play a critical role in charge transport and spin-orbitronics. Polarons originate from strong electron-phonon interaction and are ubiquitous in polarizable materials featuring electron localization, in particular 3d transition metal oxides (TMOs). On the other hand, the relativistic coupling between the spin and orbital angular momentum is notable in lattices with heavy atoms and develops in 5d TMOs, where electrons are spatially delocalized. Here we combine ab initio calculations and magnetic measurements to show that these two seemingly mutually exclusive interactions are entangled in the electron-doped SO-coupled Mott insulator Ba 2 Na 1-x Ca x OsO 6 (0 < x < 1), unveiling the formation of spin-orbital bipolarons. Polaron charge trapping, favoured by the Jahn-Teller lattice activity, converts the Os 5d 1 spin-orbital J eff  = 3/2 levels, characteristic of the parent compound Ba 2 NaOsO 6 (BNOO), into a bipolaron 5d 2 J eff  = 2 manifold, leading to the coexistence of different J-effective states in a single-phase material. The gradual increase of bipolarons with increasing doping creates robust in-gap states that prevents the transition to a metal phase even at ultrahigh doping, thus preserving the Mott gap across the entire doping range from d 1 BNOO to d 2 Ba 2 CaOsO 6 (BCOO)., (© 2024. The Author(s).)

Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring., (© 2024. The Author(s).)

Background: Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC., Methods: We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC., Results: Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells., Conclusions: Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Geometric pattern formation is crucial in many tasks involving large-scale multi-agent systems. Examples include mobile agents performing surveillance, swarms of drones or robots, and smart transportation systems. Currently, most control strategies proposed to achieve pattern formation in network systems either show good performance but require expensive sensors and communication devices, or have lesser sensor requirements but behave more poorly. Methods and result: In this paper, we provide a distributed displacement-based control law that allows large groups of agents to achieve triangular and square lattices, with low sensor requirements and without needing communication between the agents. Also, a simple, yet powerful, adaptation law is proposed to automatically tune the control gains in order to reduce the design effort, while improving robustness and flexibility. Results: We show the validity and robustness of our approach via numerical simulations and experiments, comparing it, where possible, with other approaches from the existing literature., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Giusti, Maffettone, Fiore, Coraggio and di Bernardo.)

HIV pre-exposure prophylaxis (PrEP) uptake among cisgender women in the United States is low. Just4Us, a theory-based counseling and navigation intervention, was evaluated in a pilot randomized controlled trial among PrEP-eligible women (n = 83). The comparison arm was a brief information session. Women completed surveys at baseline, post-intervention, and at three months. In this sample, 79% were Black, and 26% were Latina. This report presents results on preliminary efficacy. At 3 months follow-up, 45% made an appointment to see a provider about PrEP; only 13% received a PrEP prescription. There were no differences in PrEP initiation by study arm (9% Info vs. 11% Just4Us). PrEP knowledge was significantly higher in the Just4Us group at post-intervention. Analysis revealed high PrEP interest with many personal and structural barriers along the PrEP continuum. Just4Us is a promising PrEP uptake intervention for cisgender women. Further research is needed to tailor intervention strategies to multilevel barriers.Clinicaltrials.gov registration NCT03699722: A Women-Focused PrEP Intervention (Just4Us)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The spread of breast cancer to distant sites is the major cause of death in breast cancer patients. Increasing evidence supports the role of the tumor microenvironment (TME) in breast cancers, and its pathologic assessment has become a diagnostic and therapeutic tool. In the TME, a bidirectional interplay between tumor and stromal cells occurs, both at the primary and metastatic site. Hundreds of molecules, including cytokines, chemokines, and growth factors, contribute to this fine interaction to promote tumor spreading. Here, we investigated the effects of Rimonabant and Cannabidiol, known for their antitumor activity, on reprogramming the breast TME. Both compounds directly affect the activity of several pathways involved in breast cancer progression. To mimic tumor-stroma interactions during breast-to-lung metastasis, we investigated the effect of the compounds on growth factor secretion from metastatic breast cancer cells and normal and activated lung fibroblasts. In this setting, we demonstrated the anti-metastatic potential of the two compounds, and the membrane array analyses highlighted their ability to alter the release of factors involved in the autocrine and paracrine regulation of tumor proliferation, angiogenesis, and immune reprogramming. The results enforce the antitumor potential of Rimonabant and Cannabidiol, providing a novel potential tool for breast cancer TME management.

The long-term consequences of the coronavirus disease 19 (COVID-19) are likely to be frequent but results hitherto are inconclusive. Therefore, we aimed to define the incidence of long-term COVID signs and symptoms as defined by the World Health Organization, using a systematic review and meta-analysis of observational studies. A systematic search in several databases was carried out up to 12 January 2022 for observational studies reporting the cumulative incidence of long COVID signs and symptoms divided according to body systems affected. Data are reported as incidence and 95% confidence intervals (CIs). Several sensitivity and meta-regression analyses were performed. Among 11,162 papers initially screened, 196 were included, consisting of 120,970 participants (mean age: 52.3 years; 48.8% females) who were followed-up for a median of six months. The incidence of any long COVID symptomatology was 56.9% (95% CI 52.2-61.6). General long COVID signs and symptoms were the most frequent (incidence of 31%) and digestive issues the least frequent (7.7%). The presence of any neurological, general and cardiovascular long COVID symptomatology was most frequent in females. Higher mean age was associated with higher incidence of psychiatric, respiratory, general, digestive and skin conditions. The incidence of long COVID symptomatology was different according to continent and follow-up length. Long COVID is a common condition in patients who have been infected with SARS-CoV-2, regardless of the severity of the acute illness, indicating the need for more cohort studies on this topic., (© 2022. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

The epidemic spread of obesity is nowadays recognized as a global health and economic burden, arising great interest in the scientific community. The rate of adult obesity steadily increases concomitantly with the cancer incidence. As has been comprehensively reported, obesity is included among the multiple cancer risk factors and can progressively cause and/or exacerbate certain cancer types, as colorectal and breast cancers. The term adiponcosis was forged precisely to emphasize the interconnection between obesity and cancer onset and progression. The underlying mechanisms of adiponcosis have not been fully elucidated yet, may vary on cancer type, and depend on body fat distribution. It has been proposed that insulin resistance and related chronic hyperinsulinemia, increased insulin-like growth factors production, chronic inflammation or increased bioavailability of steroid hormones could be responsible of cancer hallmarks. Additionally, it has been suggested that adipose tissue-derived hormones, cytokines and adipokines, such as leptin, adiponectin and inflammatory markers, may reflect mechanisms linked to tumorigenesis. This review summarizes the current evidence on pathways, hormones, cytokines and low-chronic inflammation subtending adiponconsis, focusing on breast and colorectal cancers. In addition, we analyzed the lifestyle interventions that could attenuate the driving forces of obesity-related cancer incidence and progression. Moreover, current targets and drugs, their pros and cons, as well as new mechanisms and targets with promising therapeutic potential in cancer are discussed. Depicting this complex interconnection will provide insights for establishing new therapeutic approaches to halt the obesity impacts and thwart cancer onset and progression., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background and Objectives: Written discharge instructions help to bridge hospital-to-home transitions for patients and families, though substantial variation in discharge instruction quality exists. We aimed to assess the association between participation in an Institute for Healthcare Improvement Virtual Breakthrough Series collaborative and the quality of pediatric written discharge instructions across 8 US hospitals., Methods: We conducted a multicenter, interrupted time-series analysis of a medical records-based quality measure focused on written discharge instruction content (0-100 scale, higher scores reflect better quality). Data were from random samples of pediatric patients (N = 5739) discharged from participating hospitals between September 2015 and August 2016, and between December 2017 and January 2020. These periods consisted of 3 phases: 1. a 14-month precollaborative phase; 2. a 12-month quality improvement collaborative phase when hospitals implemented multiple rapid cycle tests of change and shared improvement strategies; and 3. a 12-month postcollaborative phase. Interrupted time-series models assessed the association between study phase and measure performance over time, stratified by baseline hospital performance, adjusting for seasonality and hospital fixed effects., Results: Among hospitals with high baseline performance, measure scores increased during the quality improvement collaborative phase beyond the expected precollaborative trend (+0.7 points/month; 95% confidence interval, 0.4-1.0; P < .001). Among hospitals with low baseline performance, measure scores increased but at a lower rate than the expected precollaborative trend (-0.5 points/month; 95% confidence interval, -0.8 to -0.2; P < .01)., Conclusions: Participation in this 8-hospital Institute for Healthcare Improvement Virtual Breakthrough Series collaborative was associated with improvement in the quality of written discharge instructions beyond precollaborative trends only for hospitals with high baseline performance., (Copyright © 2023 by the American Academy of Pediatrics.)

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient-derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an EC/T-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct "education signatures." These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALL/EC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Importance: Investing in educators, educational innovation, and scholarship is essential for excellence in health professions education and health care. Funds for education innovations and educator development remain at significant risk because they virtually never generate offsetting revenue. A broader shared framework is needed to determine the value of such investments., Objective: To explore the value factors using the value measurement methodology domains (individual, financial, operational, social or societal, strategic or political) that health professions leaders placed on educator investment programs, including intramural grants and endowed chairs., Design, Setting, and Participants: This qualitative study used semi-structured interviews with participants from an urban academic health professions institution and its affiliated systems that were conducted between June and September 2019 and were audio recorded and transcribed. Thematic analysis was used to identify themes with a constructivist orientation. Participants included 31 leaders at multiple levels of the organization (eg, deans, department chairs, and health system leaders) and with a range of experience. Individuals who did not respond initially were followed up with until a sufficient representation of leader roles was achieved., Main Outcomes and Measures: Outcomes include value factors defined by the leaders for educator investment programs across the 5 value measurement methodology domains: individual, financial, operational, social or societal, and strategic or political., Results: This study included 29 leaders (5 [17%] campus or university leaders; 3 [10%] health systems leaders; 6 [21%] health professions school leaders; 15 [52%] department leaders). They identified value factors across the 5 value measurement methods domains. Individual factors emphasized the impact on faculty career, stature, and personal and professional development. Financial factors included tangible support, the ability to attract additional resources, and the importance of these investments as a monetary input rather than output. Operational factors identified educational programs and faculty recruitment or retention. Social and societal factors showcased scholarship and dissemination benefits to the external community beyond the organization and to the internal community of faculty, learners, and patients. Strategic and political factors highlighted impact on culture and symbolism, innovation, and organizational success., Conclusions and Relevance: These findings suggest that health sciences and health system leaders find value in funding educator investment programs in multiple domains beyond direct financial return on investment. These value factors can inform program design and evaluation, effective feedback to leaders, and advocacy for future investments. This approach can be used by other institutions to identify context-specific value factors.

The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected racial/ethnic minorities in the United States, who are underrepresented in clinical trials. We assessed the feasibility of using the University of Pennsylvania Health System electronic health record patient portal to diversify the pool of participants in COVID-19 vaccine clinical trials. The patient portal was used to send invitations to eligible individuals living in zip codes with high rates of racial/ethnic minorities. The 5614 invited consisted of 96.7% black, 1.3% Hispanic/Latinx, and 1.5% white. The overall response rate was 5.4%, with lower response rates among Black (3.8%) and Hispanic/Latinx (9.6%) as compared to white individuals (91.6%). Among respondents, black individuals had lower rates of interest in participating (26.7%), as compared to white (65.8%) and Hispanic/Latinx (71.4%) individuals. Of 115 respondents who expressed interest, 9 enrolled in the clinical trial, which included 6 black, 3 white, and 1 Hispanic/Latinx. During phone outreach to nonresponders and decliners, common reasons for declining included mistrust of the COVID-19 vaccine, underlying health conditions, and logistical barriers to trial participation. Because of low rates of patient portal account activation and use, compounded with vaccine hesitancy, this method yielded a small number of interested individuals., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

It is important to determine if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and SARS-CoV-2 mRNA vaccinations elicit different types of antibodies. Here, we characterize the magnitude and specificity of SARS-CoV-2 spike-reactive antibodies from 10 acutely infected health care workers with no prior SARS-CoV-2 exposure history and 23 participants who received SARS-CoV-2 mRNA vaccines. We found that infection and primary mRNA vaccination elicit S1- and S2-reactive antibodies, while secondary vaccination boosts mostly S1 antibodies. Using absorption assays, we found that SARS-CoV-2 infections elicit a large proportion of original antigenic sin-like antibodies that bind efficiently to the spike of common seasonal human coronaviruses but poorly to the spike of SARS-CoV-2. In converse, vaccination modestly boosts antibodies reactive to the spike of common seasonal human coronaviruses, and these antibodies cross-react more efficiently to the spike of SARS-CoV-2. Our data indicate that SARS-CoV-2 infections and mRNA vaccinations elicit fundamentally different antibody responses., Competing Interests: Declaration of interests E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Elstar, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. is an inventor on a patent (US patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S.E.H. has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this report., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the progressions in COVID-19 understanding, the optimization of patient-specific therapies remains a challenge. Statins, the most widely prescribed lipid-lowering drugs, received considerable attention due to their pleiotropic effects, encompassing lipid metabolism control and immunomodulatory and anti-thrombotic effects. In COVID-19 patients, statins improve clinical outcomes, reducing Intensive Care Unit admission, the onset of ARDS, and in-hospital death. However, the safety of statins in COVID-19 patients has been debated, mainly for statins' ability to induce the expression of the ACE2 receptor, the main entry route of SARS-CoV-2. Unfortunately, the dynamic of statins' mechanism in COVID-19 disease and prevention remains elusive. Using different in vitro models expressing different levels of ACE2 receptor, we investigated the role of lipophilic and hydrophilic statins on ACE2 receptor expression and subcellular localization. We demonstrated that the statin-mediated increase of ACE2 receptor expression does not necessarily coincide with its localization in lipid rafts domains, particularly after treatments with the lipophilic atorvastatin that disrupt lipid rafts' integrity. Through a proteomic array, we analyzed the cytokine patterns demonstrating that statins inhibit the release of cytokines and factors involved in mild to severe COVID-19 cases. The results obtained provide additional information to dissect the mechanism underlying the protective effects of statin use in COVID-19., Competing Interests: The authors declare no conflict of interest.

We address the problem of regulating and keeping at a desired balance the relative numbers between cells exhibiting a different phenotype within a monostrain microbial consortium. We propose a strategy based on the use of external control inputs, assuming each cell in the community is endowed with a reversible, bistable memory mechanism. Specifically, we provide a general analytical framework to guide the design of external feedback control strategies aimed at balancing the ratio between cells whose memory is stabilized at either one of two equilibria associated with different cell phenotypes. We demonstrate the stability and robustness properties of the control laws proposed and validate them in silico , implementing the memory element via a genetic toggle-switch. The proposed control framework may be used to allow long-term coexistence of different populations, with both industrial and biotechnological applications. As a representative example, we consider the realistic agent-based implementation of our control strategy to enable cooperative bioproduction of a dimer in a monostrain microbial consortium.

We treated a small cohort of venous ulcers that were very unresponsive to standard and advanced therapies with autologous cultured bone marrow-derived mesenchymal stem cells (MSCs). This pilot clinical trial was randomized, controlled, and double-blinded. Subjects were treated with either normal saline (Group A), fibrin spray alone (Group B), or MSCs in fibrin (1 million cells/cm2 of wound bed surface) (Group C). The control and test materials were applied to the wound using a double-barreled syringe with thrombin and fibrinogen (with or without MSCs) in each barrel, or saline alone in both barrels. The MSCs were separated, cultured in vitro, and expanded in a dedicated Good Manufacturing Practice (GMP) facility from 30-50 ml of bone marrow aspirate obtained from the iliac crest in Group C subjects. To ensure that the study remained controlled and blinded, subjects who were randomized to one of the two control arms (saline or fibrin) underwent sham bone marrow aspiration performed by a hematologist who anesthetized the iliac crest area down to and pushing against the periosteum, but without penetrating the bone marrow. Therefore, both the clinician who evaluated wound progress and the study subjects had no knowledge of whether bone aspiration was actually performed and what treatment had been applied to the wound. The study was performed after full FDA investigational new drug (IND) approval. The primary endpoint was the rate of healing (wound closure as linear healing from the wound margins in cm/week), as measured by the Gilman equation. One-way ANOVA was used to calculate the statistical significance of differences between the mean healing rates of each of the 3 treatment groups every 4 weeks and over the 24 weeks of treatment. Overall, treatment with MSCs accelerated the healing rate by about 10-fold compared to those in the saline and fibrin control groups. Although the total number of patients in this pilot study was small (n=11), the statistical significance was surprisingly promising: p<0.01 and f-ratio of 15.9358. No serious adverse events were noted. This small but carefully performed prospective, controlled, randomized, and double-blinded pilot study in a rare population of totally unresponsive patients adds to previous reports showing the promise of MSCs in the treatment of chronic wounds and provides proof of principle for how to approach this type of very demanding clinical and translational research.

The existence of a close association between disease of the biliary tract and disease of the heart is known from the mists of time. Acute acalculous cholecystitis (AAC) can be defined as an acute necro inflammatory disease of the gallbladder in the absence of cholelithiasis. AAC is a challenging diagnosis. The atypical clinical onset associated to a paucity and similarity of symptoms and to laboratory data mimicking cardiovascular disease (CVD) often results in under and misdiagnosed cases. Moreover, AAC has commonly a fulminant course compared to calculous cholecystitis and it is often associated with gangrene, perforation and empyema as well as considerable morbidity and mortality (up 50%). Early diagnosis is crucial to a prompt treatment in order to avoid complications and to increase survivability. Even today, although scientific evidence dating two hundred years has shown a close association between AAC and CVD, due to the lack of RCT, there is still a lot of confusion regarding the relationship and consequently the clinical management AAC and CVD. In addition, emergency physicians are not always familiar with transient ECG changes with AAC. The aim of this review was to provide evidence regarding epidemiology, pathophysiology, clinical presentation and treatment of the complex association between AAC and CVD. Our main findings indicate that AAC should be suspected after each general disease leading to hypoperfusion such as cardiovascular diseases or cerebrovascular diseases or major heart or aortic surgery. ECG changes in absence of significant laboratory data for IMA (Acute myocardial infarction) could be related to a misdiagnosed AAC. US - Ultrasonography-plays a key role in the early diagnosis and also in the follow up of AAC. Cholecystostomy and cholecystectomy as unique or sequential represent the two prevailing treatment options for AAC., Competing Interests: The authors declare that they have no financial support, no potential conflict of interest., (© 2022 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.)

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, and due to its unique features, its management is certainly one of the most challenging ones among all cancers. N6-isopentenyladenosine (IPA) and its analog N6-benzyladenosine (N6-BA) are modified nucleosides endowed with potent antitumor activity on different types of human cancers, including GBM. Corroborating our previous finding, we demonstrated that IPA and N6-BA affect GBM cell line proliferation by modulating the expression of the F-box WD repeat domain-containing-7 (FBXW7), a tumor suppressor with a crucial role in the turnover of many proteins, such as SREBPs and Mcl1, involved in malignant progression and chemoresistance. Luciferase assay revealed that IPA-mediated upregulation of FBXW7 translates in transcriptional inactivation of its oncogenic substrates (Myc, NFkB, or HIF-1α). Moreover, downregulating MGMT expression, IPA strongly enhances the killing effect of temozolomide (TMZ), producing a favorable sensitizing effect starting from a concentration range much lower than TMZ EC50. Through DNA methyltransferase (DNMT) activity assay, analysis of the global DNA methylation, and the histone modification profiles, we demonstrated that the modified adenosines behave similar to 5-AZA-dC, known DNMT inhibitor. Overall, our results provide new perspectives for the first time, suggesting the modified adenosines as epigenetic tools able to improve chemo- and radiotherapy efficacy in glioblastoma and potentially other cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Proto, Fiore, Piscopo, Laezza, Bifulco and Gazzerro.)

The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo , with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity-driven tumors., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objectives: Pediatric hospital medicine (PHM) fellowships have rapidly developed to meet established needs. The purpose of this research was to describe the research and career outcomes of PHM fellowship graduates. We hypothesized that graduates would report significant research and academic productivity., Methods: This was an institutional review board-approved, cross-sectional survey of PHM fellowship graduates in 2018. The 88-item survey was modified from an existing survey, developed by experts to address study objectives and pilot tested, and it included quantitative and qualitative items to assess characteristics of fellowship training and research and career outcomes., Results: A total of 63% of PHM fellowship graduates (143 of 228) completed the survey (graduation dates, 2000-2018). In total, 89% graduated from dedicated PHM fellowship programs, with 59% completing a 2-year fellowship and 78% now practicing primarily at a university or children's hospital. Fellows conducted research in clinical research (53%), quality improvement (41%), health services (24%), and medical education (19%). A total of 77% of graduates continued to do research after graduation, with 63% publishing and 25% obtaining grant funding. Graduates of 2- and 3-year fellowships and those with a master's degree were significantly more productive. Graduates now hold important roles in academic and health systems leadership. Graduates are highly satisfied with their decision to do PHM fellowship and identified 5 themes regarding how fellowship impacted their career outcomes., Conclusions: In this study, we document robust research activity and leadership positions among PHM fellowship graduates and can serve as a benchmark for metrics that PHM educational leaders can use to assess outcomes and improve training regarding research and career development., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Some studies suggest that recent common coronavirus (CCV) infections are associated with reduced COVID-19 severity upon SARS-CoV-2 infection. We completed serological assays using samples collected from health care workers to identify antibody types associated with SARS-CoV-2 protection and COVID-19 symptom duration. Rare SARS-CoV-2 cross-reactive antibodies elicited by past CCV infections were not associated with protection; however, the duration of symptoms following SARS-CoV-2 infections was significantly reduced in individuals with higher common betacoronavirus (βCoV) antibody titers. Since antibody titers decline over time after CCV infections, individuals in our cohort with higher βCoV antibody titers were more likely recently infected with common βCoVs compared with individuals with lower antibody titers. Therefore, our data suggest that recent βCoV infections potentially limit the duration of symptoms following SARS-CoV-2 infections through mechanisms that do not involve cross-reactive antibodies. Our data are consistent with the emerging hypothesis that cellular immune responses elicited by recent common βCoV infections transiently reduce symptom duration following SARS-CoV-2 infections.

Using a mobile research facility, we enrolled 141 opioid users from a neighborhood of Philadelphia, an urban epicenter of the opioid epidemic. Nearly all (95.6%) met DSM-5 criteria for severe opioid use disorder. The prevalence of HIV infection (8.5%) was more than seven times that found in the general population of the city. Eight of the HIV-positive participants (67.0%) reported receiving antiretroviral treatment but almost all of them had unsuppressed virus (87.5%). The majority of participants (57.4%) reported symptoms consistent with major depressive disorder. Severe economic distress (60.3%) and homelessness were common (57%). Polysubstance use was nearly universal, 72.1% had experienced multiple overdoses and prior medication for opioid use disorder (MOUD) treatment episodes (79.9%), but few currently engaged in addiction care. The prevalence, multiplicity and severity of chronic health and socioeconomic problems highlight consequences of the current opioid epidemic and underscore the urgent need to develop integrated models of treatment.

Background: Cognitive impairment is a prominent feature of multiple sclerosis (MS). However, the impact that cognitive symptoms have on daily life, and the effect this has on persons with MS and their relationships with spouses/partners, remains unclear. This qualitative study sought information on the nature of cognitive impairments experienced and the impact of cognitive impairments on the daily lives of adults with MS and their partners to gain further insights into how health care professionals can best support families., Methods: Fifteen persons with MS and their spouses/partners participated in separate semistructured telephone interviews., Results: Six themes and several subthemes were identified: the social impact of cognitive impairments in MS, changes to daily living, relationship quality, communication, ways of coping with MS, and the desire for help in managing MS., Conclusions: These results identified types of support that couples needed and wanted; ways that MS affects couples' social lives; that there are difficulties negotiating changes in roles due to cognitive challenges; that there are difficulties coping with the impact of cognitive challenges on daily living; that couples often have difficulty communicating about the impact of cognitive changes on daily living and related issues, which also contributes to relationship strain; and finally, that most participants felt that they did not understand enough about the cognitive symptoms of MS. We outline key areas to address these identified needs., Competing Interests: Financial Disclosures: Dr Halstead and Mr Stanley were employed by Healios LLC at the time of the study. Dr Fiore is employed by Genentech Inc. Dr Mueser is a consultant for Healios LLC., (© 2021 Consortium of Multiple Sclerosis Centers.)

The cell cycle is the process by which eukaryotic cells replicate. Yeast cells cycle asynchronously with each cell in the population budding at a different time. Although there are several experimental approaches to synchronise cells, these usually work only in the short-term. Here, we build a cyber-genetic system to achieve long-term synchronisation of the cell population, by interfacing genetically modified yeast cells with a computer by means of microfluidics to dynamically change medium, and a microscope to estimate cell cycle phases of individual cells. The computer implements a controller algorithm to decide when, and for how long, to change the growth medium to synchronise the cell-cycle across the population. Our work builds upon solid theoretical foundations provided by Control Engineering. In addition to providing an avenue for yeast cell cycle synchronisation, our work shows that control engineering can be used to automatically steer complex biological processes towards desired behaviours similarly to what is currently done with robots and autonomous vehicles.

This paper focuses on the understanding of the Random Telegraph Signal (RTS) in Single-Photon Avalanche Diodes (SPAD). We studied the RTS of two different SPAD layouts, designed and implemented in a 150-nm CMOS process, after proton irradiation. The two structures are characterized by different junction types: the first structure is constituted by a P+/Nwell junction, while the second is formed by a Pwell/Niso junction. RTS occurrence has been measured in about one thousand SPAD pixels and the differences addressed in two layouts are motivated and discussed. Hypotheses on the RTS origin are drawn by analyzing the RTS time constants and the RTS occurrence evolution as a function of the annealing temperature.

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Despite encouraging progresses achieved in the management of viral diseases, efficient strategies to counteract infections are still required. The current global challenge highlighted the need to develop a rapid and cost-effective strategy to counteract the SARS-CoV-2 pandemic. Lipid metabolism plays a crucial role in viral infections. Viruses can use the host lipid machinery to support their life cycle and to impair the host immune response. The altered expression of mevalonate pathway-related genes, induced by several viruses, assures survival and spread in host tissue. In some infections, statins, HMG-CoA-reductase inhibitors, reduce cholesterol in the plasma membrane of permissive cells resulting in lower viral titers and failure to internalize the virus. Statins can also counteract viral infections through their immunomodulatory, anti-inflammatory and anti-thrombotic effects. Beyond statins, interfering with the mevalonate pathway could have an adjuvant effect in therapies aimed at mitigating endothelial dysfunction and deregulated inflammation in viral infection. In this review we depicted the historical and current evidence highlighting how lipid homeostasis and mevalonate pathway targeting represents a valid approach to rapidly neutralize viruses, focusing our attention to their potential use as effective targets to hinder SARS-CoV-2 morbidity and mortality. Pros and cons of statins and Mevalonate-pathway inhibitors have been also dissected., (Copyright © 2021. Published by Elsevier Ltd.)

In the hemato-oncology field, remarkable scientific progress has been achieved, primarily propelled by the discovery of new technologies, improvement in genomics, and novel in vitro and in vivo models. The establishment of multiple cell line collections and the development of instrumental mouse models enhanced our ability to discover effective therapeutics. However, cancer models that faithfully mimic individual cancers are still imperfect. Patient-derived tumor xenografts (PDTXs) have emerged as a powerful tool for identifying the mechanisms which drive tumorigenesis and for testing potential therapeutic interventions. The recognition that PDTXs can maintain many of the donor samples' properties enabled the development of new strategies for discovering and implementing therapies. Described in this article are protocols for the generation and characterization of lymphoma PDTXs that may be used as the basis of shared procedures. Universal protocols will foster the model utilization, enable the integration of public and private repositories, and aid in the development of shared platforms. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Tissue handling and cryopreservation of primary and PDTX samples Basic Protocol 2: Performing tumor implant in immunocompromised mice PDTX models Alternate Protocol 1: Intra-medullary femoral injection Alternate Protocol 2: Intravenous injection Alternate Protocol 3: Intraperitoneal injection Support Protocol 1: Phenotypical characterization of PDTXs by flow cytometry Support Protocol 2: Biological and molecular characterization of PDTX tumors by PCR detection of IGK, IGH, and TCR rearrangements Basic Protocol 3: Harvesting PDTX-derived tumor cells for ex vivo experiments Basic Protocol 4: In vivo testing of multiple compounds in a PDTX mouse model., (© 2021 Wiley Periodicals LLC.)

Nausea and vomiting are common for runners during ultramarathons and often contribute to non-finishes. We aimed to determine the efficacy of ondansetron, a commonly used antiemetic, to treat nausea and vomiting in runners during an ultramarathon. Runners who had a previous history of frequent nausea or vomiting during races and entered in 160, 80, and 55 km ultramarathons in 2018 and 2019 were randomized in a double-blind fashion to 4 mg ondansetron or placebo capsules to use if they developed nausea or vomiting during the race with the ability to take three additional doses. Study participants completed a post-race online survey to assess medication use and efficacy. Of 62 study participants, 31 took either ondansetron (20) or placebo (11). In this small study, there were no group differences in those reporting any improvement in nausea and vomiting ( p = 0.26) or in the amount of improvement ( p = 0.15). We found no evidence that ondansetron capsules improve nausea and vomiting during ultramarathons.

Abstract: In the United States, pre-exposure prophylaxis (PrEP) uptake among eligible cisgender women has been slow, despite the availability of oral PrEP since 2012. Although women make up nearly 20% of those living with HIV, there are currently few PrEP uptake interventions for cisgender women at elevated risk for acquiring HIV. Here we describe the process used to design and pre-pilot test Just4Us, a theory-based behavioral intervention to promote PrEP initiation and adherence among PrEP-eligible cisgender women. This work was part of a multiphase study conducted in New York City and Philadelphia, two locations with HIV rates higher than the national average. The counselor-navigator component of the intervention was designed to be delivered in a 60- to 90-min in-person session in the community, followed by several phone calls to support linkage to care. An automated text messaging program was also designed for adherence support. Just4Us addressed personal and structural barriers to PrEP uptake using an empowerment framework by building on women's insights and resources to overcome barriers along the PrEP cascade. Usability pre-pilot testing results were favorable and provided valuable feedback used to refine the intervention., (Copyright © 2021 Association of Nurses in AIDS Care.)

This perspective paper aims at discussing theoretical principles that could explain how emotion regulation and physical diseases mutually influence each other in the context of borderline personality disorder (BPD). Furthermore, this paper discusses the clinical implications of the functional relationships between emotion regulation, BPD and medical conditions considering dialectical behavior therapy (DBT) as a well-validated therapeutic intervention, which encompasses these issues. The inflexible use of maladaptive emotion regulation strategies (e.g., suppression, experiential avoidance, and rumination) might directly increase the probability of developing physical diseases through a physiological pathway, or indirectly through a behavioral pathway. Some metabolic and chronic medical conditions could significantly impact emotional functioning through biological alterations involved in emotion regulation. Several empirical studies have shown high co-occurrence rates between BPD and several chronic physical diseases, especially ones linked to emotion-based maladaptive behaviors. DBT addresses physical diseases reported by individuals with BPD reducing problematic behaviors functionally associated to emotion dysregulation and identifying physical health as a goal for Building a Life Worth Living ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cavicchioli, Barone, Fiore, Marchini, Pazzano, Ramella, Riccardi, Sanza and Maffei.)

The effects of mental health comorbidities and social support on the HIV pre-exposure prophylaxis (PrEP) care continuum are unknown. We conducted a cross-sectional study of men and transgender individuals, ≥ 18 years-old, with ≥ 2 male or transgender partners, or recent condomless anal intercourse. Surveys assessed demographics, mental health treatment, depressive symptomatology, social support, and PrEP-related social contacts. Logistic regression assessed associations between these factors and PrEP uptake and persistence. Participants (n = 247) were 89% cis-male and 46% African-American. Median age was 27 (IQR:23-33). Thirty-seven percent had ever used PrEP, of whom 18% discontinued use. High depressive symptomology was identified in 11% and 9% were receiving mental health treatment. There were no significant associations between depressive symptoms or mental health treatment on the odds of PrEP uptake or discontinuation. Each additional PrEP contact conferred a greater odds of uptake (aOR:1.24, 95% CI: 1.09-1.42). Network-level targets may produce fruitful interventions to increase PrEP uptake.

Prior sexually transmitted infections (STIs) are associated with higher rates of subsequent human immunodeficiency virus (HIV) infection, but the influence of prior STIs on perceived vulnerability to HIV remains unclear. We aimed to assess this relationship, hypothesizing that a prior STI diagnosis is associated with higher self-assessed vulnerability to HIV. We performed a cross-sectional study of men and transgender individuals who have sex with men screening for HIV prevention trials in Philadelphia. An unadjusted regression analysis found no significant association between prior STI and HIV risk perception ( p  = 0.71) or HIV anxiety ( p  = 0.32). Multivariate logistic regression models that controlled for predetermined potential cofounders known to impact HIV risk-such as condom use, preexposure prophylaxis use, and demographics-also failed to show statistically significant associations between prior STI and HIV risk perception ( p  = 0.87) or HIV anxiety ( p  = 0.10). Furthermore, there was no effect modification by HIV preventive behaviors on the relationship between prior STI and HIV vulnerability. These data suggest that a gap exists between how clinicians may attribute individual HIV risk and how individuals view their own vulnerability at a given moment in time. Future research should focus on the dynamic relationship between perceived HIV vulnerability, STI diagnosis, and adoption of preventive behavior to determine better, individualized targets for HIV prevention interventions.

The molecular mechanisms leading to the transformation of anaplastic lymphoma kinase negative (ALK - ) anaplastic large cell lymphoma (ALCL) have been only in part elucidated. To identify new culprits which promote and drive ALCL, we performed a total transcriptome sequencing and discovered 1208 previously unknown intergenic long noncoding RNAs (lncRNAs), including 18 lncRNAs preferentially expressed in ALCL. We selected an unknown lncRNA, BlackMamba, with an ALK - ALCL preferential expression, for molecular and functional studies. BlackMamba is a chromatin-associated lncRNA regulated by STAT3 via a canonical transcriptional signaling pathway. Knockdown experiments demonstrated that BlackMamba contributes to the pathogenesis of ALCL regulating cell growth and cell morphology. Mechanistically, BlackMamba interacts with the DNA helicase HELLS controlling its recruitment to the promoter regions of cell-architecture-related genes, fostering their expression. Collectively, these findings provide evidence of a previously unknown tumorigenic role of STAT3 via a lncRNA-DNA helicase axis and reveal an undiscovered role for lncRNA in the maintenance of the neoplastic phenotype of ALK - ALCL.

Background: Resilience is a protective factor that emerges when individuals are faced with challenges and stressors. Multiple sclerosis (MS) is a chronic neurological disease that introduces a great deal of stress for the individual and his/her support partner. We designed a telehealth resilience-building dyadic program for persons with MS (PwMS) and their support partners., Objectives: To evaluate the feasibility of the resilience intervention. The secondary objective was to assess the benefits of the intervention., Methods: Sixty-two participants ( M  = 49.5 years, 31 dyads of PwMS) and support partners) were recruited to participate. Out of the 31 dyads, 26 were spouses, 2 were cohabiting partners, and 3 were parent-child dyads., Results: The feasibility goals of the intervention were met, as determined by high participant satisfaction and acceptable completion rates. Preliminary outcomes relating to resilience were positive, suggesting that this intervention had a positive impact on participants., Conclusions: To the best of our knowledge, this is the first resilience-building intervention delivered via telehealth for both PwMS and their support partners. The study showed an increase in resilience-building skills for addressing the challenges faced by PwMS and their support partners. These skills can be promoted and taught, clinically supported by telehealth, an affordable, accessible healthcare solution. Trial Registration at ClinicalTrials.gov (NCT03555253)., (© The Author(s) 2020.)

Women comprise 19% of those newly diagnosed with HIV in the U.S. There is a wide gap between recommended use of pre-exposure prophylaxis (PrEP) and actual uptake among women who are eligible for PrEP. In order to identify women's beliefs and intentions about starting PrEP, a survey, informed by the reasoned action approach, was administered to 160 cisgender PrEP-eligible women, age 18-55, in Philadelphia and New York City. The mean age was 40.2 years (SD = 11.78), 44% had completed high school, 75% were unemployed, and 85% experienced financial instability in the past 3 months. Multivariate linear regression analyses identified sets of behavioral and normative beliefs associated with intention to start PrEP in the next 3 months. Behavioral beliefs reflected views about PrEP benefits such as preventing HIV, and normative beliefs reflected perceptions of support or lack thereof from others including partners, friends, mother, and children. These findings can be used to inform interventions to foster greater PrEP uptake among women.

We present a combined experimental and computational study of the effect of charge doping in the osmium based double perovskite Ba 2 Na 1- x Ca x OsO 6 for 0 ≤ x ≤ 1 in order to provide a structural and electronic basis for understanding this complex Dirac-Mott insulator material. Specifically, we investigate the effects of the substitution of monovalent Na with divalent Ca, a form of charge doping or alloying that nominally tunes the system from Os 7+ with a 5d 1 configuration to Os 6+ with 5d 2 configuration. After an X-ray diffraction characterization, the local atomic and electronic structure has been experimentally probed by X-ray absorption fine structure at all the cation absorption edges at room temperature; the simulations have been performed using ab initio density functional methods. We find that the substitution of Na by Ca induces a linear volume expansion of the crystal structure which indicates an effective alloying due to the substitution process in the whole doping range. The local structure corresponds to the expected double perovskite one with rock-salt arrangement of Na/Ca in the B site and Os in the B' one for all the compositions. X-ray absorption near edge structure measurements show a smooth decrease of the oxidation state of Os from 7+ (5d 1 ) to 6+ (5d 2 ) with increasing Ca concentration, while the oxidation states of Ba, Na, and Ca are constant. This indicates that the substitution of Na by Ca gives rise to an effective electron transfer from the B to the B' site. The comparison between X-ray absorption measurements and ab initio simulations reveals that the expansion of the Os-O bond length induces a reduction of the crystal field splitting of unoccupied Os derived d states., Competing Interests: The authors declare no competing financial interest.

Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II.

Breast implant-associated lymphoma (BIA-ALCL) has recently been recognized as an independent peripheral T-cell lymphoma (PTCL) entity. In this study, we generated the first BIA-ALCL patient-derived tumor xenograft (PDTX) model (IL89) and a matching continuous cell line (IL89&#95;CL#3488) to discover potential vulnerabilities and druggable targets. We characterized IL89 and IL89&#95;CL#3488, both phenotypically and genotypically, and demonstrated that they closely resemble the matching human primary lymphoma. The tumor content underwent significant enrichment along passages, as confirmed by the increased variant allele frequency (VAF) of mutations. Known aberrations (JAK1 and KMT2C) were identified, together with novel hits, including PDGFB, PDGFRA, and SETBP1. A deep sequencing approach allowed the detection of mutations below the Whole Exome Sequencing (WES) sensitivity threshold, including JAK1G1097D, in the primary sample. RNA sequencing confirmed the expression of a signature of differentially expressed genes in BIA-ALCL. Next, we tested IL89's sensitivity to the JAK inhibitor ruxolitinib and observed a potent anti-tumor effect, both in vitro and in vivo. We also implemented a high-throughput drug screening approach to identify compounds associated with increased responses in the presence of ruxolitinib. In conclusion, these new IL89 BIA-ALCL models closely recapitulate the primary correspondent lymphoma and represent an informative platform for dissecting the molecular features of BIA-ALCL and performing pre-clinical drug discovery studies, fostering the development of new precision medicine approaches.

Cutaneous melanoma, the most aggressive form of skin cancer, is characterized by activating BRAF mutations. Despite the initial success of selective BRAF inhibitors, only few patients exhibited complete responses, whereas many showed disease progression. Melanoma is one of the few types of cancer in which p53 is not frequently mutated, but p53 inactivation can be indirectly achieved by a stable activation of MDM2 induced by a deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) locus, encoding for p16 INK4A and p14 ARF , two tumor suppressor genes. In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives, 8 g, 8 h and 8i, in melanoma cell lines, and we compared the effects of the most active of these, the 8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that 8i potentiates the inhibitory effect of Nutlin 3 and the combined use of 8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the 8i compound reduces p53-MDM2 interaction and induces p53-HSP90 complex formation, suggesting that the observed raise in p53 transcriptional activity could be mediated by HSP90. Because the main feature of melanoma is the resistance to most chemotherapeutics, our studies suggest that the 8i tetra-substituted pyrrole derivative, restoring p53 functions and its transcriptional activities, may have potential application, at least as adjuvant, in the treatment of human melanoma.

Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of orphan neoplasms. Despite the introduction of anthracycline-based chemotherapy protocols, with or without autologous haematopoietic transplantation and a plethora of new agents, the progression-free survival of patients with PTCLs needs to be improved. The rarity of these neoplasms, the limited knowledge of their driving defects and the lack of experimental models have impaired clinical successes. This scenario is now rapidly changing with the discovery of a spectrum of genomic defects that hijack essential signalling pathways and foster T cell transformation. This knowledge has led to new genomic-based stratifications, which are being used to establish objective diagnostic criteria, more effective risk assessment and target-based interventions. The integration of genomic and functional data has provided the basis for targeted therapies and immunological approaches that underlie individual tumour vulnerabilities. Fortunately, novel therapeutic strategies can now be rapidly tested in preclinical models and effectively translated to the clinic by means of well-designed clinical trials. We believe that by combining new targeted agents with immune regulators and chimeric antigen receptor-expressing natural killer and T cells, the overall survival of patients with PTCLs will dramatically increase.

The problem of controlling cells endowed with a genetic toggle switch has been recently highlighted as a benchmark problem in synthetic biology. It has been shown that a carefully selected periodic forcing can balance a population of such cells in an undifferentiated state. The effectiveness of these control strategies, however, can be hindered by the presence of stochastic perturbations and uncertainties typically observed in biological systems and is therefore not robust. Here, we propose the use of feedback control strategies to enhance robustness and performance of the balancing action by selecting in real-time both the amplitude and the duty-cycle of the pulsatile inputs affecting the toggle switch behavior. We show, via in silico experiments and realistic agent-based simulations, the effectiveness of the proposed strategies even in the presence of uncertainties, stochastic effects, cell growth, and inducer diffusion. In so doing, we confirm previous observations made in the literature about coherence of the population when pulsatile forcing inputs are used, but, contrary to what was proposed in the past, we leverage feedback control techniques to endow the balancing strategy with unprecedented robustness and stability properties. We compare via in silico experiments different external control solutions and show their advantages and limitations from an in vivo implementation viewpoint.

The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention.