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This paper was initiated by a multidisciplinary Topic Workshop in the frame of the Deutsche Forschungsgemeinschaft Priority Program 1158 “Antarctic Research with Comparative Investigations in Arctic Ice Areas”, and hence it represents only the national view without claiming to be complete but is intended to provide awareness and suggestions for the current discussion on so-called big data in many scientific fields. The importance of the polar regions and their essential role for the Earth system are both undoubtedly recognized. However, dramatic changes in the climate and environment have been observed first in the Arctic and later in Antarctica over the past few decades. While important data have been collected and observation networks have been built in Antarctica and the Southern Ocean, this is a relatively data-scarce region due to the challenges of remote data acquisition, expensive labor, and harsh environmental conditions. There are many approaches crossing multiple scientific disciplines to better understand Antarctic processes; to evaluate ongoing climatic and environmental changes and their manifold ecological, physical, chemical, and geological consequences; and to make (improved) predictions. Together, these approaches generate very large, multivariate data sets, which can be broadly classified as “Antarctic big data”. For these large data sets, there is a pressing need for improved data acquisition, curation, integration, service, and application to support fundamental scientific research. Based on deficiencies in crossing disciplines and to attract further interest in big data in Antarctic sciences, this article will (i) describe and evaluate the current status of big data in various Antarctic-related scientific disciplines, (ii) identify current gaps, (iii) and provide solutions to fill these gaps.

The ExoClock project has been created to increase the efficiency of the Ariel mission. It will achieve this by continuously monitoring and updating the ephemerides of Ariel candidates, in order to produce a consistent catalog of reliable and precise ephemerides. This work presents a homogenous catalog of updated ephemerides for 450 planets, generated by the integration of ∼18,000 data points from multiple sources. These sources include observations from ground-based telescopes (the ExoClock network and the Exoplanet Transit Database), midtime values from the literature, and light curves from space telescopes (Kepler, K2, and TESS). With all the above, we manage to collect observations for half of the postdiscovery years (median), with data that have a median uncertainty less than 1 minute. In comparison with the literature, the ephemerides generated by the project are more precise and less biased. More than 40% of the initial literature ephemerides had to be updated to reach the goals of the project, as they were either of low precision or drifting. Moreover, the integrated approach of the project enables both the monitoring of the majority of the Ariel candidates (95%), and also the identification of missing data. These results highlight the need for continuous monitoring to increase the observing coverage of the candidate planets. Finally, the extended observing coverage of planets allows us to detect trends (transit-timing variations) for a sample of 19 planets. All the products, data, and codes used in this work are open and accessible to the wider scientific community.

Ethnopharmacological Relevance: The flowers of Nyctanthes arbor-tristis (L.) heals mouth ulcers. Its tinctures promote gastric secretions, and improve lung expectoration when taken orally. It has traditionally been used to treats scabies and other skin problems. The leaves of NAT(L.) plant are used in Ayurvedic medicine to treat sciatica, chronic fever, rheumatism, internal worm infections, and as a laxative, diaphoretic, and diuretic. The bark used in treatment of snakebite and bronchitis. In addition to traditional uses, pharmacologically this plant has potent antimalarial, antiarthritic, anticancer and antidiabetic activity. However, the mechanistic antiproliferative potentials of NAT(L.) flower as anticancer therapeutics has not yet been explored., Aim of the Study: The current study is based on a broad range of scientific literature that highlights the nutritional and therapeutic benefits of NAT (L.). Present investigation was carried out to determine the therapeutic efficacy of NAT (L.) against breast adenocarcinoma cells and T-cell lymphoma., Materials and Methods: The ethyl-acetate extract of NAT(L.) was tested against breast cancer cells to assess the anticancer potential. To evaluate apoptosis, intracellular ROS levels and mitochondrial dynamics, fluorescence microscopy and flow cytometry were employed. Additionally, cell cycle analysis and western blotting were also performed. Furthermore, in vivo antitumor efficacy of flower extracts was investigated in T-cell lymphoma-bearing BALB/c mice model., Results: Our present study revealed that NAT (L.) exert anticancer activity against breast cancer cells effectively at IC 50 320 μg/ml while having less impact on normal cells with IC 50 more than 480 μg/ml. Fluorescence imaging showed that NAT (L.) treatment elicits a concentration-dependent rise in the occurrence of apoptotic cell deaths with altered mitochondrial dynamics and was subsequently confirmed by flow cytometry. Further, flow cytometric analysis delineates ethyl acetate flower extract exposure promotes arrest of cells in S phase of the cell cycle. The differential expression of apoptotic proteins such as Bax, Bcl-2, cleaved PARP-1, cleaved caspase 3, Cytochrome-c, p53 and VEGF A were influenced by NAT (L.) treatment. The in vivo antitumor activity study delineates that NAT(L.) therapy significantly increased the life span of T-cell lymphoma bearing mice while reducing tumor load and belly size growth pattern without causing significant other distinct side effects as evident by histopathological studies., Conclusion: Our current findings unveil that NAT(L.) ethyl acetate flower extract potentially induces mitochondrial pathway of apoptosis, promote cell cycle arrest, reduces tumor load of mice, enhances survivability and could be a promising agent against the triple negative breast cancer and lymphoma., 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 © 2024 Elsevier B.V. All rights reserved.)

A novel ferrocene conjugated Mn(I)-tricarbonyl complex viz [Mn(Fc-tpy)(CO)3Br] (Mn2) where, Fc-tpy = 4'-ferrocenyl-2,2':6',2''-terpyridine was synthesized and fully characterized along with its non-ferrocene analog [Mn(Ph-tpy)(CO)3 Br] Ph-tpy = 4'-phenyl-2,2':6',2''-terpyridine (Mn1) for ultrasound (US) activated anticancer applications. The X-ray structure of Mn2 confirmed its distorted octahedral geometry. Mn1 and Mn2, for the first time, showed US-triggered release of CO and ROS generation (1O2 and •OH) in an aqueous solution from any Mn(I)-tricarbonyl complexes, indicating its potential for synergetic CO gas therapy and sonodynamic therapy. The above-mentioned in-solution chemistry was successfully translated into in vitro cellular models. These complexes showed unprecedented US-triggered toxicity against T-cell lymphoma and human breast cancer cells (IC50 for Mn2 < 1 μM) while were minimally toxic without US or against normal spleen cells. Mn2 was ca. 12 fold more anticancer active than Mn1, indicating that the ferrocene conjugation augmented the US sensitivity. The apoptotic sonotoxicity of Mn2 was due to US-promoted mitochondrial depolarization via ROS generation and CO release. The apoptosis was triggered by caspase 3 activation. This is the first report of Mn(I)-tricarbonyl-based sonosensitizers for cancer SDT. Overall, this study, for the first time, establishes the effectiveness of 3d metal carbonyls in SDT., (© 2024 Wiley‐VCH GmbH.)

The present investigation focuses on synthesizing eco-friendly and cost-effective silver nanoparticles (CsAgNP) utilizing Camellia sinensis ethanolic extract (CsE) as a reducing agent and investigating the potential enhancement in its anticancer efficacy as compared to CsE. The CsAgNP formation was confirmed through the color change from pale green to dark brown and further validated using UV-visible spectroscopy in the 400-450 nm range. The optimal CsAgNP synthesis parameters include 1:4 ratio of CsE: 1 mM AgNO 3 , 60 min of duration and 50 °C reaction temperature. The morphology and the size of nanoparticles were estimated using AFM, SEM and TEM where the results showed a smooth topography with a size <100 nm. The CsAgNP crystalline form was confirmed through SAED pictures and silver's presence confirmed through EDX analysis. FTIR study ascertained the capping agents and distortion in functional groups compared to CsE. The anticancer potency of CsAgNP and crude extract (CsE) was assessed against the T-47D breast cancer cells by MTT assay. CsAgNP displayed strong activity towards T-47D cells (IC 50 8 μg/ml) compared to CsE and relatively low activity towards the normal HEK-293 cells. Further, fluorescence microscopy and flow cytometry data revealed that the CsAgNP promotes apoptosis and also induces G2-M phase cell cycle arrest. Furthermore, CsAgNP treatment decreases p53 and Bcl-2 protein expression, while increasing Bax, Cytochrome c and Caspase-3 levels, indicating mitochondrial-mediated apoptotic pathway activation. Thus, our research aims to investigate the potential of using Camellia sinensis to synthesize CsAgNP, a potent drug delivery system, to enhance anticancer effectiveness and advance cancer therapy in the future., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diorganotin complexes of the compositions [Me 2 Sn(L)] (1), [n-Bu 2 Sn(L)] (2), [Ph 2 Sn(L)]⋅C 6 H 6 (3), [Bz 2 Sn(L)]⋅C 6 H 6 (4) and [n-Oct 2 Sn(L)] (5) were synthesized by reacting R 2 SnO (R = Me, n-Bu, Ph, Bz or n-Oct) with the N 2 ,N 6 -di(thiazol-2-yl)pyridine-2,6-dicarboxamide (H 2 L, where H 2 denotes the two acidic protons) in refluxing toluene. Additionally, the mono-n-butyltin complex [n-BuSn(HL)Cl 2 ]·H 2 O (6) was synthesized from n-BuSnCl 3 and H 2 L in acetonitrile. Compounds were characterized by FT-IR, 1 H, 13 C and 119 Sn NMR spectroscopy, while their solid-state structures were examined using single-crystal X-ray diffraction studies. In diorganotin compounds 1-5, the dianionic tridentate ligands (N py , N - , N - ) act as κ-N 3 chelators. In 6, the L moiety (O, N py , N - ) acts as a κ-ON 2 tridentate chelator, with involvement of one of the carboxamide oxygen atoms. The coordination polyhedron around the Sn(IV) ion is completed either by two axial Sn-R ligands in compounds 1-5 or by n-Bu and Cl ligands in compound 6, giving rise to distorted trigonal bipyramid or octahedral structures, respectively. The tin NMR results show that the penta-coordinated structures of compounds 1-5 and the hexacoordinated structure of compound 6, observed in the solid-state, are retained in solution. The in vitro antitumor activities of 1-5 were tested on T-47D breast cancer cells. Of these, diphenyltin compound 3 showed the highest anti-proliferative effect, with an IC 50 of 10 ± 1.60 μM. Compound 3 exhibited selective toxicity, potentially inducing apoptosis via reactive oxygen species generation and nuclear changes, indicating promise as a breast cancer treatment. This study is the first to explore thiazole-appended organotin compounds for cytotoxicity., 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 © 2024 Elsevier Inc. All rights reserved.)

Background: Patients presenting to Emergency Departments (ED) with opioid use disorder may be candidates for buprenorphine treatment, making EDs an appropriate setting to initiate this underused, but clinically proven therapy. Hospitals are devoting increased efforts to routinizing buprenorphine initiation in the ED where clinically appropriate, with the greatest successes occurring in academic medical centers. Overall, however, clinician participation in these efforts is suboptimal. Hospitals need more information to inform the standardized implementation of these programs nationally. Using an implementation science framework, we investigated ED providers' concerns about ED buprenorphine programs and their willingness to prescribe buprenorphine in the ED., Methods: We conducted Consolidated Framework for Implementation Research (CFIR)-informed interviews with 11 ED staff in Nevada and analyzed the transcripts using a six-step thematic approach. Results were organized within the CFIR 1.0 domains of inner setting, outer setting, intervention characteristics, and individual characteristics; potential implementation strategies were recommended., Results: Physicians expressed that the ED is a suitable location for prescribing buprenorphine. However, they expressed concerns about: information gaps in the prescribing protocols (inner setting), patient outcomes beyond the ED, buprenorphine effectiveness and appropriate timing of treatment initiation (intervention characteristics), and their own competence in managing opioid withdrawal (individual characteristics). Some were anxious about patients' outcomes and continuity of care in the community (outer setting), others desired access to prospective data that demonstrate buprenorphine effectiveness. Additional concerns included a lack of availability of the required support to prescribe buprenorphine, a lack of physicians' experience and competence, and concerns about opioid withdrawal. Recommended implementation strategies to address these concerns include: designating personnel at the ED to bridge the information gap, engaging emergency physicians through educational meetings, creating a community of practice, facilitating mentorship opportunities, and leveraging existing collaborative learning platforms., Conclusion: Overall, physicians in our study believed that implementing a buprenorphine program in the ED is appropriate, but had concerns. Implementation strategies could be deployed to address concerns at multiple levels to increase physician willingness and program uptake., (© 2024. The Author(s).)

Objectives: We described age, gender, race, and ethnicity associations with filling buprenorphine prescriptions post-emergency department (post-ED) visits., Methods: We analyzed 1.5 years (July 1, 2020-December 31, 2021) of encounter-level Medicaid ED and retail pharmacy claims data obtained from the Nevada Department of Health and Human Services. We studied ED patients with an opioid use disorder (OUD) diagnosis who did not fill a prescription for OUD medications within 6 months before the ED encounter. Using logistic regression, we modeled the associations between the patient's demographic characteristics and the outcome, filling a buprenorphine prescription at a community pharmacy within 14 or 30 days of the ED encounter., Results: Among 2781 ED visits, representing 2094 patients, the median age was 39 years, 54% were male, 18.5% were Black, 11.7% were Hispanic, and 62.3% were White. Only 4% of the ED visits were followed by a filled buprenorphine prescription. Increasing age (14-day window: adjusted odds ratio (aOR) = 0.965, 95% confidence interval [CI]: 0.948-0.983) and being a Black patient (14-day window: aOR: 0.114, 95% CI 0.036-0.361) were both associated with lower odds of filled buprenorphine prescriptions. These results were similar within 30 days of an ED visit., Conclusions: Initiation of buprenorphine following an ED visit remains low among Nevadan Medicaid patients and is less likely with increasing age and among Black patients, despite strong evidence supporting its use. Overburdened EDs, lack of attention from managers, and substance use stigma are among possible explanations. When ED clinicians do write buprenorphine prescriptions, peer recovery support could increase the fill rates., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Effective targeting of breast tumors is critical for improving therapeutic outcomes in breast cancer treatment. Additionally, hypoxic breast cancers are difficult to treat due to resistance toward chemotherapeutics, poor vascularity, and enhanced angiogenesis, which complicate effective drug delivery and therapeutic response. Addressing this formidable challenge requires designing a drug delivery system capable of targeted delivery of the anticancer agent, inhibition of efflux pump, and suppression of the tumor angiogenesis. Here, we have introduced Palbociclib (PCB)-loaded PLGA nanoparticles (NPs) consisting of chitosan-folate (CS-FOL) for folate receptor-targeted breast cancer therapy. The developed NPs were below 219 nm with a smooth, spherical surface shape. The entrapment efficiencies of NPs were achieved up to 85.78 ± 1.8%. Targeted NPs demonstrated faster drug release at pH 5.5, which potentiated the therapeutic efficacy of NPs due to the acidic microenvironment of breast cancer. In vitro cellular uptake study in MCF-7 cells confirmed the receptor-mediated endocytosis of targeted NPs. In vivo ultrasound and photoacoustic imaging studies on rats with hypoxic breast cancer showed that targeted NPs significantly reduced tumor growth and hypoxic tumor volume, and suppressed angiogenesis.

Background: The prevalence of anticoagulation treatment is increasing as an aging global population faces a high burden of cardiovascular comorbidities. Direct oral anticoagulants, including factor Xa inhibitors (FXai), are replacing vitamin K antagonists as the most commonly prescribed treatment for reducing risk of thrombotic events. While the risk of FXai-associated spontaneous bleeds is established, less is understood about their management and the effect of treatment on clinical and patient-reported outcomes. The primary objectives of the REVERXaL study are to describe patient characteristics, health care interventions during the acute-care phase, in-hospital outcomes, and associations between timing of reversal/replacement agent administration and in-hospital outcomes. Secondary/exploratory objectives focus on clinical assessments and patient-reported outcome measures (PROMs) at 30 and 90 days., Methods: REVERXaL is a multinational, observational study of hospitalized patients with FXai-associated major bleeds in Germany, Japan, the United Kingdom, and the United States. The study includes 2 cohorts of approximately 2000 patients each. Cohort A is a historic cohort for whom medical chart data will be collected from hospitalization to discharge for patients admitted for major bleeds during FXai use within 2 years prior to enrollment of Cohort B. Cohort B will prospectively enroll patients administered any reversal/replacement agent during hospitalization to manage FXai-associated major bleeds and will include the collection of clinical outcomes and PROMs data over 3 months., Conclusions: REVERXaL will generate insights on patient characteristics, treatment approaches, and associated outcomes in patients hospitalized with FXai-associated major bleeds. These data may inform clinical practice and streamline treatment pathways in this population., Registration: URL: https://www., Clinicaltrials: gov; unique identifier: NCT06147830., Competing Interests: Declaration of competing interest MN and SY have no conflicts of interest to disclose. RA has received fees for consulting work from AstraZeneca, Alexion, Bristol Myers Squibb, Pfizer, Bayer, and Daiichi. RO-A, SA-C, HC, and BK are employees of AstraZeneca. MY has received lecture, advisory, and travel fees from AstraZeneca, Bristol Myers Squibb, Nippon Boehringer Ingelheim, Bayer, Daiichi Sankyo, and CSL Behring; and scholarship funds or nonrestricted grants from Nippon Boehringer Ingelheim. VS has served as a consultant for Apollo Endosurgery, Pentax, Medtronic, Pharmacosmos, Microtech, and AstraZeneca; has served on advisory boards for Pharmacosmos and Microtech; and has received educational grants from Apollo Endosurgery, Pentax, and Medtronic. AT has received consulting fees from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sobi; has received payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sobi; and has received support for attending meetings and/or travel from Bayer, Biomarin, Biotest, Chugai, Roche, Takeda, CSL Behring, Novo Nordisk, Octapharma, Pfizer, and Sobi. BDC has served as a consultant for AstraZeneca. MM has received lecture honoraria, payment for participation in expert and advisory panels, and financial support for scientific meeting participation from AstraZeneca, Baxter, Bayer, Biotest, CSL Behring, IL-Werfen/TEM-International, LFB Biomedicaments France, Octapharma, and Portola. AJS has served on an advisory board for Alexion and AstraZeneca; has served on the speakers bureau of Alexion and AstraZeneca; and his institution has received research funding from Alexion., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: β-Lactams are the most widely used antibiotics in children. Their optimal dosing is essential to maximize their efficacy, while minimizing the risk for toxicity and the further emergence of antimicrobial resistance. However, most β-lactams were developed and licensed long before regulatory changes mandated pharmacokinetic studies in children. As a result, pediatric dosing practices are poorly harmonized and off-label use remains common today., Areas Covered: β-Lactam pharmacokinetics and dose optimization strategies in pediatrics, including fixed dose regimens, therapeutic drug monitoring, and model-informed precision dosing are reviewed., Expert Opinion/commentary: Standard pediatric doses can result in subtherapeutic exposure and non-target attainment for specific patient subpopulations (neonates, critically ill children, e.g.). Such patients could benefit greatly from more individualized approaches to dose optimization, beyond a relatively simple dose adaptation based on weight, age, or renal function. In this context, Therapeutic Drug Monitoring (TDM) and Model-Informed Precision Dosing (MIPD) emerge as particularly promising avenues. Obstacles to their implementation include the lack of strong evidence of clinical benefit due to the paucity of randomized clinical trials, of standardized assays for monitoring concentrations, or of adequate markers for renal function. The development of precision medicine tools is urgently needed to individualize therapy in vulnerable pediatric subpopulations.

Background and Aims: Clinical trials support injectable opioid agonist treatment (iOAT) for individuals with opioid use disorder (OUD) for whom other pharmacological management approaches are not well-suited. However, despite substantial research indicating that person-centered care improves engagement, retention and health outcomes for individuals with OUD, structural requirements (e.g. drug policies) often dictate how iOAT must be delivered, regardless of client preferences. This study aimed to quantify clients' iOAT delivery preferences to improve client engagement and retention., Design: Cross-sectional preference elicitation survey., Setting: Metro Vancouver, British Columbia, Canada., Participants: 124 current and former iOAT clients., Measurements: Participants completed a demographic questionnaire package and an interviewer-led preference elicitation survey (case 2 best-worst scaling task). Latent class analysis was used to identify distinct preference groups and explore demographic differences between preference groups., Findings: Most participants (n = 100; 81%) were current iOAT clients. Latent class analysis identified two distinct groups of client preferences: (1) autonomous decision-makers (n = 73; 59%) and (2) shared decision-makers (n = 51; 41%). These groups had different preferences for how medication type and dosage were selected. Both groups prioritized access to take-home medication (i.e. carries), the ability to set their own schedule, receiving iOAT in a space they like and having other services available at iOAT clinics. Compared with shared decision-makers, fewer autonomous decision-makers identified as a cis-male/man and reported flexible preferences., Conclusions: Injectable opioid agonist treatment (iOAT) clients surveyed in Vancouver, Canada, appear to prefer greater autonomy than they currently have in choosing OAT medication type, dosage and treatment schedule., (© 2024 The Author(s). Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Increasing the effectiveness of psychosomatic rehabilitation by prolonging the treatment is a subject of controversial debate. The number of sessions over time defines the dosage in psychotherapy. While the dose-response model assumes an optimal therapy dose, the good-enough level model assumes a correlation of the rate of change with the total sessions. A randomized control group study was conducted to investigate the extent to which an adaptive therapy concept with a two-week intensive phase and early intervention could increase rehabilitation success., Method: A total of 494 rehabilitants between the ages of 21 and 64 (47% women) who completed a classical or an integrative psychosomatic rehabilitation at the Rehazentrum Oberharz between 2020 and 2022 were analysed. Rehabilitation success was mapped by the Reliable Change Index of individual symptom reduction (depression severity or psychological and somatoform disorders) and as a socio-medical parameter (physician's assessment of potential work ability (WA) after two weeks). Two-factorial ANOVAs and hierarchical binary logistic regressions were calculated, and sick leave before rehabilitation was statistically controlled., Results: Dosage showed no effect on symptom reduction (p = 0.29) and potential WA after two weeks (p = 0.90). However, when stratified by disease severity, there was a mean effect of dosage (p = 0.05) and twice the probability of WA after two weeks (odds 2.13; p = 0.01) for those with mild disease at the start of measure (p = 0.05)., Discussion: In the early stages of an affective disorder, early and intensified intervention can counteract the chronification of mental disorders., (© 2024. Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.)

Background: Over the past decade, long-term use of prescription opioids for chronic non-cancer pain has risen globally despite the associated risks. Most opioid users receive their first prescription in primary care., Aim: To investigate the perspective of patients who are long-term opioid users in primary care regarding the role of healthcare providers (HCPs) in their prolonged opioid use., Design and Setting: Semi-structured interviews in Dutch primary care., Method: We recruited patients who were long-term users of opioids for chronic non-cancer pain from seven community pharmacies in the Netherlands. In-depth, semi-structured interviews focused on patients' experiences with long-term opioid use, access to opioids, and the guidance of their HCPs (primarily their GPs and pharmacists). A directed content analysis was conducted on the transcribed interviews using NVivo., Results: Participants ( n = 25) described ways in which HCPs impacted their long-term use of opioids. These encompassed the initiation of treatment, chronic use of opioids, and discontinuation of treatment. Participants stressed the need for risk counselling during initial prescribing, ongoing medication evaluations including tapering conversations, and more support from their HCP during a tapering attempt., Conclusion: Patients' perspectives illustrate the important role of HCPs across the spectrum of opioid use - from initiation to tapering. The results of this study underscore the importance of clear risk counselling starting at initial prescribing, repeated medication assessments throughout treatment, addressing tapering at regular intervals, and strong support during tapering. These insights carry significant implications for clinical practice, emphasising the importance of informed and patient-centred care when it comes to opioid use for chronic non-cancer pain management., (© The Authors.)

Breast cancer is one of the leading causes of mortality in women globally. The efficacy of breast cancer treatments, notably chemotherapy, is hampered by inadequate localized delivery of anticancer agents to the tumor site, resulting in compromised efficacy and increased systemic toxicity. In this study, we have developed redox-sensitive poly(lactic- co -glycolic acid) (PLGA) nanoparticles for the smart delivery of palbociclib (PLB) to breast cancer. The particle size of formulated PLB@PLGA-NPs (nonredox-sensitive) and RS-PLB@PLGA-NPs (redox-sensitive) NPs were 187.1 ± 1.8 nm and 193.7 ± 1.5 nm, respectively. The zeta potentials of nonredox-sensitive and redox-sensitive NPs were +24.99 ± 2.67 mV and +9.095 ± 1.87 mV, respectively. The developed NPs were characterized for morphological and various physicochemical parameters such as SEM, TEM, XRD, DSC, TGA, XPS, etc. The % entrapment efficiency of PLB@PLGA-NPs and RS-PLB@PLGA-NPs was found to be 85.48 ± 1.29% and 87.72 ± 1.55%, respectively. RS-PLB@PLGA-NPs displayed a rapid drug release at acidic pH and a higher GSH concentration compared to PLB@PLGA-NPs. The cytotoxicity assay in MCF-7 cells suggested that PLB@PLGA-NPs and RS-PLB@PLGA-NPs were 5.24-fold and 14.53-fold higher cytotoxic compared to the free PLB, respectively. Further, the cellular uptake study demonstrated that redox-sensitive NPs had significantly higher cellular uptake compared to nonredox-sensitive NPs and free Coumarin 6 dye. Additionally, AO/EtBr assay and reactive oxygen species analysis confirmed the superior activity of RS-PLB@PLGA-NPs over PLB@PLGA-NPs and free PLB. In vivo anticancer activity in dimethyl-benz(a)anthracene-induced breast cancer rats depicted that RS-PLB@PLGA-NPs was highly effective in reducing the tumor size, hypoxic tumor, and tumor vascularity compared to PLB@PLGA-NPs and free PLB. Further, hemocompatibility study reveals that the developed NPs were nonhemolytic to human blood. Moreover, an in vivo histopathology study confirmed that both nanoparticles were safe and nontoxic to the vital organs.

Microneedle technology offers a minimally invasive treatment strategy to deliver chemotherapeutics to localized tumors. Amalgamating the surface functionalized nanoparticles with microneedle technology can potentially deliver drugs directly to tumors and subsequently target cancer cells via, overexpressed receptors on the cell surface, thereby enhancing the treatment efficacy while reducing side effects. Here, we report cetuximab anchored hyaluronic acid-oleylamine and chitosan-oleic acid-based hybrid nanoparticle (HA-OA/CS-OA NPT)-loaded dissolving microneedles (MN) for targeted delivery of cabazitaxel (CBT) in localized breast cancer tumor. The HA-OA/CS-OA NPT was characterized for their size, surface charge, morphology, physicochemical characteristics, drug release behavior, and in vitro anti-cancer efficacy. The HA-OA/CS-OA NPT were of ~125 nm size, showed enhanced cytotoxicity and cellular uptake, and elicited a superior apoptotic response against MDA-MB-231 cells. Subsequently, the morphology and physicochemical characteristics of HA-OA/CS-OA NPT-loaded MN were also evaluated. The fabricated microneedles were of ~550 μm height and showed loading of nanoparticles equivalent to ~250 μg of CBT. The ex vivo skin permeation study revealed fast dissolution of microneedles upon hydration, while the drug permeation across the skin exhibited ~4-fold improvement in comparison to free drug-loaded MN. In vivo studies performed on DMBA-induced breast cancer in female SD rats showed a marked reduction in tumor volume after administration of drug and nanoparticle-loaded microneedles in comparison to intravenous administration of free drug. However, the HA-OA/CS-OA NPT-MN showed the highest tumor reduction and survival rate, with the lowest body weight reduction in comparison to other treatment groups, indicating its superior efficacy and low systemic toxicity. Overall, the dissolving microneedle-mediated delivery of targeted nanoparticles loaded with chemotherapeutics offers a superior alternative to conventional intravenous chemotherapy., 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 © 2024 Elsevier B.V. All rights reserved.)

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies., 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 © 2024 Elsevier B.V. All rights reserved.)

Whether 30-day modified Rankin Scale (mRS) scores can predict 90-day scores is unclear. This study derived and validated a model to predict ordinal 90-day mRS score in an intracerebral hemorrhage (ICH) population using 30-day mRS values and routinely available baseline variables. Adults enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage-2 (ATACH-2) trial between May 2011 and September 2015 with acute ICH, who were alive at 30 days and had mRS scores reported at both 30 and 90 days were included in this post-hoc analysis. A proportional odds regression model for predicting ordinal 90-day mRS scores was developed and internally validated using bootstrapping. Variables in the model included: mRS score at 30 days, age (years), hematoma volume (cm3), hematoma location (deep [basal ganglia, thalamus], lobar, or infratentorial), presence of intraventricular hemorrhage (IVH), baseline Glasgow Coma Scale (GCS) score, and National Institutes of Health Stroke Scale (NIHSS) score at randomization. We assessed model fit, calibration, discrimination, and agreement (ordinal, dichotomized functional independence), and EuroQol-5D ([EQ-5D] utility weighted) between predicted and observed 90-day mRS. A total of 898/1000 participants were included. Following bootstrap internal validation, our model (calibration slope = 0.967) had an optimism-corrected c-index of 0.884 (95% CI = 0.873-0.896) and R2 = 0.712 for 90-day mRS score. The weighted ĸ for agreement between observed and predicted ordinal 90-day mRS score was 0.811 (95% CI = 0.787-0.834). Agreement between observed and predicted functional independence (mRS score of 0-2) at 90 days was 74.3% (95% CI = 69.9-78.7%). The mean ± SD absolute difference between predicted and observed EQ-5D-weighted mRS score was negligible (0.005 ± 0.145). This tool allows practitioners and researchers to utilize clinically available information along with the mRS score 30 days after ICH to reliably predict the mRS score at 90 days., Competing Interests: WLB and GF have no conflicts of interest to report. MS reports receiving research grants from Bristol Myers Squibb, Bayer, and Javelin Medical; and consulting fees from Janssen, HLS Therapeutics, AstraZeneca, and Bayer. AC has received fees for serving on an adjudication committee from Boehringer Ingelheim and AbbVie; grant support and fees for serving on committees from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, and Pfizer; consulting fees from Janssen, Portola Pharmaceuticals, and Ono Pharmaceuticals; and fees for serving on a steering committee and consulting fees from Bayer. MJC is a previous employee of AstraZeneca. MO and BC are employees of AstraZeneca. TEM has nothing to disclose. CIC has received research funding and/or consulting honoraria from Janssen Pharmaceuticals, Bayer AG, and AstraZeneca., (Copyright: © 2024 Baker 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.)

Objective: Recurrent respiratory papillomatosis is a benign manifestation of human papillomavirus types 6 and 11 in the respiratory tract. Disease is recurrent, and factors predicting these recurrences and severity of disease are incompletely characterised. This retrospective cohort study examined the relationship of immunosuppression with recurrent respiratory papillomatosis morbidity., Methods: A retrospective cohort of 97 adult patients with recurrent respiratory papillomatosis treated at a tertiary referral centre from 2005 to 2020 was conducted. Measures assessed included inter-surgical interval, Voice Handicap Index ('VHI-10') and anatomical Derkay scores., Results: Bivariate analyses comparing average inter-surgical interval, Voice Handicap Index and Derkay scores in immunosuppressed and healthy patients were insignificant. When controlling for diabetes mellitus and comparing immunosuppressed to healthy patients, inter-surgical interval and Voice Handicap Index change were insignificant ( p = 0.458 and p = 0.465, respectively)., Conclusion: Recurrent respiratory papillomatosis morbidity for immunosuppressed patients did not significantly differ from that of immunocompetent patients.

Herein, we have compared the effectivity of light-based photoactivated cancer therapy and ultrasound-based sonodynamic therapy with Re(I)-tricarbonyl complexes ( Re1 - Re3 ) against cancer cells. The observed photophysical and TD-DFT calculations indicated the potential of Re1 - Re3 to act as good anticancer agents under visible light/ultrasound exposure. Re1 did not display any dark- or light- or ultrasound-triggered anticancer activity. However, Re2 and Re3 displayed concentration-dependent anticancer activity upon light and ultrasound exposure. Interestingly, Re3 produced 1 O 2 and OH • on light/ultrasound exposure. Moreover, Re3 induced NADH photo-oxidation in PBS and produced H 2 O 2 . To the best of our knowledge, NADH photo-oxidation has been achieved here with the Re(I) complex for the first time in PBS. Additionally, Re3 released CO upon light/ultrasound exposure. The cell death mechanism revealed that Re3 produced an apoptotic cell death response in HeLa cells via ROS generation. Interestingly, Re3 showed slightly better anticancer activity under light exposure compared to ultrasound exposure.

The relentless increase in drug resistance of platinum-based chemotherapeutics has opened the scope for other new cancer therapies with novel mechanisms of action (MoA). Recently, photocatalytic cancer therapy, an intrusive catalytic treatment, is receiving significant interest due to its multitargeting cell death mechanism with high selectivity. Here, we report the synthesis and characterization of three photoresponsive Ru(II) complexes, viz., [Ru(ph-tpy)(bpy)Cl]PF 6 ( Ru1 ), [Ru(ph-tpy)(phen)Cl]PF 6 ( Ru2 ), and [Ru(ph-tpy)(aip)Cl]PF 6 ( Ru3 ), where, ph-tpy = 4'-phenyl-2,2':6',2″-terpyridine, bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, and aip = 2-(anthracen-9-yl)-1 H -imidazo[4,5- f ][1,10] phenanthroline, showing photocatalytic anticancer activity. The X-ray crystal structures of Ru1 and Ru2 revealed a distorted octahedral geometry with a RuN 5 Cl core. The complexes showed an intense absorption band in the 440-600 nm range corresponding to the metal-to-ligand charge transfer (MLCT) that was further used to achieve the green light-induced photocatalytic anticancer effect. The mitochondria-targeting photostable complex Ru3 induced phototoxicity with IC 50 and PI values of ca. 0.7 μM and 88, respectively, under white light irradiation and ca. 1.9 μM and 35 under green light irradiation against HeLa cells. The complexes ( Ru1 - Ru3 ) showed negligible dark cytotoxicity toward normal splenocytes (IC 50s > 50 μM). The cell death mechanistic study revealed that Ru3 induced ROS-mediated apoptosis in HeLa cells via mitochondrial depolarization under white or green light exposure. Interestingly, Ru3 also acted as a highly potent catalyst for NADH photo-oxidation under green light. This NADH photo-oxidation process also contributed to the photocytotoxicity of the complexes. Overall, Ru3 presented multitargeting synergistic type I and type II photochemotherapeutic effects.

Marburg virus, a member of the Filoviridae, is the causative agent of Marburg virus disease (MVD), a hemorrhagic fever with a case fatality rate of up to 90 %. Acute kidney injury is common in MVD and is associated with increased mortality, but its pathogenesis in MVD remains poorly understood. Interestingly, autopsies show the presence of viral proteins in different parts of the nephron, particularly in proximal tubular cells (PTC). These findings suggest a potential role for the virus in the development of MVD-related kidney injury. To shed light on this effect, we infected primary human PTC with Lake Victoria Marburg virus and conducted transcriptomic analysis at multiple time points. Unexpectedly, infection did not induce marked cytopathic effects in primary tubular cells at 20 and 40 h post infection. However, gene expression analysis revealed robust renal viral replication and dysregulation of genes essential for different cellular functions. The gene sets mainly downregulated in PTC were associated with the targets of the transcription factors MYC and E2F, DNA repair, the G2M checkpoint, as well as oxidative phosphorylation. Importantly, the downregulated factors comprise PGC-1α, a well-known factor in acute and chronic kidney injury. By contrast, the most highly upregulated gene sets were those related to the inflammatory response and cholesterol homeostasis. In conclusion, Marburg virus infects and replicates in human primary PTC and induces downregulation of processes known to be relevant for acute kidney injury as well as a strong inflammatory response., 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 © 2024. Published by Elsevier B.V.)

We used serial block-face scanning electron microscopy (SBF-SEM) to study the host-pathogen interface between Arabidopsis cotyledons and the hemibiotrophic fungus Colletotrichum higginsianum . By combining high-pressure freezing and freeze-substitution with SBF-SEM, followed by segmentation and reconstruction of the imaging volume using the freely accessible software IMOD, we created 3D models of the series of cytological events that occur during the Colletotrichum-Arabidopsis susceptible interaction. We found that the host cell membranes underwent massive expansion to accommodate the rapidly growing intracellular hypha. As the fungal infection proceeded from the biotrophic to the necrotrophic stage, the host cell membranes went through increasing levels of disintegration culminating in host cell death. Intriguingly, we documented autophagosomes in proximity to biotrophic hyphae using transmission electron microscopy (TEM) and a concurrent increase in autophagic flux between early to mid/late biotrophic phase of the infection process. Occasionally, we observed osmiophilic bodies in the vicinity of biotrophic hyphae using TEM only and near necrotrophic hyphae under both TEM and SBF-SEM. Overall, we established a method for obtaining serial SBF-SEM images, each with a lateral ( x-y ) pixel resolution of 10 nm and an axial ( z ) resolution of 40 nm, that can be reconstructed into interactive 3D models using the IMOD. Application of this method to the Colletotrichum-Arabidopsis pathosystem allowed us to more fully understand the spatial arrangement and morphological architecture of the fungal hyphae after they penetrate epidermal cells of Arabidopsis cotyledons and the cytological changes the host cell undergoes as the infection progresses toward necrotrophy. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY 4.0 International license., Competing Interests: The author(s) declare no conflict of interest.

Introduction: Influenza A virus (IAV) infection can cause the often-lethal acute respiratory distress syndrome (ARDS) of the lung. Concomitantly, acute kidney injury (AKI) is frequently noticed during IAV infection, correlating with an increased mortality. The aim of this study was to elucidate the interaction of IAV with human kidney cells and, thereby, to assess the mechanisms underlying IAV-mediated AKI., Methods: To investigate IAV effects on nephron cells we performed infectivity assays with human IAV, as well as with human isolates of either low or highly pathogenic avian IAV. Also, transcriptome and proteome analysis of IAV-infected primary human distal tubular kidney cells (DTC) was performed. Furthermore, the DTC transcriptome was compared to existing transcriptomic data from IAV-infected lung and trachea cells., Results: We demonstrate productive replication of all tested IAV strains on primary and immortalized nephron cells. Comparison of our transcriptome and proteome analysis of H1N1-type IAV-infected human primary distal tubular cells (DTC) with existing data from H1N1-type IAV-infected lung and primary trachea cells revealed enrichment of specific factors responsible for regulated cell death in primary DTC, which could be targeted by specific inhibitors., Discussion: IAV not only infects, but also productively replicates on different human nephron cells. Importantly, multi-omics analysis revealed regulated cell death as potential contributing factor for the clinically observed kidney pathology in influenza., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Koch, Shehata, Müller-Ruttloff, Gouda, Wetzstein, Patyna, Scholz, Schmid, Dietrich, Münch, Ziebuhr, Geiger, Martinez-Sobrido, Baer, Mostafa and Pleschka.)

Importance: There is a lack of trials examining the effect of counseling interventions for child, adolescent, and younger adult (CAYA) cancer survivors., Objective: To assess lifestyle habits and the psychosocial situation of CAYAs to determine the efficacy of needs-based interventions in the CARE for CAYA program (CFC-P)., Design, Setting, and Participants: The CFC-P was conducted as a multicenter program in 14 German outpatient clinics, mainly university cancer centers. Recruitment began January 1, 2018; a randomized clinical trial was conducted until July 15, 2019; and intervention was continued as a longitudinal cohort study until March 31, 2021. Data preparation was conducted from April 1, 2021, and analysis was conducted from August 14, 2021, to May 31, 2022. Herein, predefined confirmatory analyses pertain to the RCT and descriptive results relate to the overall longitudinal study. Data analysis was based on the full analysis set, which is as close as possible to the intention-to-treat principle., Intervention: A comprehensive assessment determined needs in physical activity, nutrition and psychooncology. Those with high needs participated in 1 to 3 modules. In the RCT, the IG received 5 counseling sessions plus newsletters, while the control group CG received 1 counseling session., Main Outcomes and Measures: The primary outcome was the change in the rate of CAYAs with high needs at 52 weeks. Secondary outcomes were feasibility, modular-specific end points, satisfaction, quality of life, and fatigue., Results: Of 1502 approached CAYAs aged 15 to 39 years, 692 declined participation. Another 22 CAYAs were excluded, resulting in 788 participants. In the randomized clinical trial, 359 CAYAs were randomized (intervention group [IG], n = 183; control group [CG], n = 176), and 274 were followed up. In the RCT, the median age was 25.0 (IQR, 19.9-32.2) years; 226 were female (63.0%) and 133 male (37.0%). After 52 weeks, 120 CAYAs (87.0%) in the IG and 115 (86.5%) in the CG still had a high need in at least 1 module (odds ratio, 1.04; 95% CI, 0.51-2.11; P = .91). Both groups reported reduced needs, improved quality of life, reduced fatigue, and high satisfaction with the CFC-P., Conclusions and Relevance: In this randomized clinical trial, the implementation of a lifestyle program in this cohort was deemed necessary, despite not meeting the primary outcome. The interventions did not alter the rate of high needs. The results may provide guidance for the development of multimodal interventions in the follow-up care of CAYAs., Trial Registration: German Clinical Trial Register: DRKS00012504.

The relationship between 30- and 90-day modified Rankin Scale (mRS) scores in intracerebral hemorrhage (ICH) patients was evaluated. This post hoc cohort analysis of the ATACH-2 trial included patients with acute ICH who were alive at 30 days and who had mRS scores reported at 30 and 90 days. The mRS score was then converted to a utility (EuroQol-5 Dimension-3 Level [EQ-5D-3L])-weighted mRS score. After adjustment of 30-day mRS score for key covariates using multivariable ordinal regression, the relationship between 30-day and observed 90-day functional outcome was assessed via absolute difference in the utility-weighted version. Of the 1000 trial subjects, 898 met inclusion criteria. This low-moderate severity ICH cohort had a median baseline GCS score of 15 and median hematoma volume of 9.7 mL. Observed 30-day mRS had the largest association with observed 90-day values (χ 2  = 302.9, p < 0.0001). Patients generally either maintained the same mRS scores between 30 and 90 days (48 %) or experienced a 1-point (32 %) or 2-point (10 %) improvement by 90 days. The mean ± standard deviation (SD) EQ-5D-3L at 90 days was 0.67 ± 0.26. Following adjustment, the mean absolute difference between predicted and observed utility-weighted 90-day mRS scores was 0.006 ± 0.13 points and less than the estimated minimal clinically important difference of 0.13 points. The difference in average utility-weighted mRS scores at 30 and 90 days was not clinically relevant, suggesting 30-day score may be a reasonable proxy for 90-day values in patients with ICH when 90-day values are not available., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CIC received research funding from Alexion, AstraZeneca Rare Disease, Bayer AG, Global Blood Therapeutics, and Janssen; received consulting fees from Alexion, AstraZeneca Rare Disease, and Global Blood Therapeutics; and received honoraria from Medscape. MC received consulting fees from Alexion and AstraZeneca Rare Disease; and received consulting fees from and served on the speakers’ bureau for Portola Pharmaceuticals. WLB has received consulting fees from AstraZeneca Rare Disease and Bayer AG. BK, BL, and MJC are employees of Alexion and AstraZeneca Rare Disease. ATC received research funding, consulting fees, and honoraria from Alexion, AstraZeneca Rare Disease, Bayer AG, and Bristol Myers Squibb/Pfizer., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The current study focuses on the development of gelatin-coated polycaprolactone (PCL) nanofibers co-loaded with luliconazole and naringenin for accelerated healing of infected diabetic wounds. Inherently, PCL nanofibers have excellent biocompatibility and biodegradation profiles but lack bioadhesion characteristics, which limits their use as dressing materials. So, coating them with a biocompatible and hydrophilic material like gelatin can improve bioadhesion. The preparation of nanofibers was done with the electrospinning technique. The solid state characterization and in-vitro performance assessment of nanofibers indicate the formation of uniformly interconnected nanofibers of 200-400 nm in diameter with smooth surface topography, excellent drug entrapment, and a surface pH of 5.6-6.8. The antifungal study showed that the nanofiber matrix exhibits excellent biofilm inhibition activity against several strains of Candida. Further, in-vivo assessment of nanofiber performance on C. albicans infected wounds in diabetic rats indicated accelerated wound healing efficacy in comparison to gauge-treated groups. Additionally, a higher blood flow and rapid re-epithelialization of wound tissue in the treatment group corroborated with the results obtained in the wound closure study. Overall, the developed dual-drug-loaded electrospun nanofiber mats have good compatibility, surface properties, and excellent wound healing potential, which can provide an extra edge in the management of complex diabetic wounds., Competing Interests: Declaration of competing interest All Authors declare not to have any conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Theranostic nanoparticles have gained significant attention in cancer diagnosis and therapy. In this study, estrone (ES) and folic acid (FA) functionalized single and dual receptor targeted theranostic chitosan nanoparticles were developed for breast cancer imaging and therapy. These nanoparticles (NPs) were loaded with palbociclib (PB) and ultra-small magnesium nanoclusters (UMN). The developed nontargeted theranostic NPs (PB-UMN-CS-NPs), estrogen receptor targeted theranostic NPs (PB-UMN-CS-ES-NPs), folate receptor targeted theranostic NPs (PB-UMN-CS-FA-NPs), and dual targeted theranostic NPs (PB-UMN-CS-ES-FA-NPs) have particle sizes of 178.4 ± 1.21 nm, 181.6± 1.35 nm, 185.1± 1.33 nm, and 198.2± 1.43 nm with surface charges of +19.02± 0.382 mV, +13.89±0.410 mV, +16.72±0.527 mV and +15.23±0.377 mV, respectively. Cytotoxicity studies on estrogen receptor (ER) and folate receptor (FR) expressing breast cancer cells revealed that dual-targeted theranostic NPs (PB-UMN-CS-FA-ES-NPs) were more effective, inhibiting cell growth by 54.17 and 42.23 times in MCF-7 and T-47D cells compared to free PB, respectively. Additionally, developed NPs were capable of inhibiting the cell cycle progression of MCF-7 cells from the G1 phase to the S phase more efficiently compared to free PB. Ultrasound and photoacoustic (USG/PA) imaging demonstrated that dual targeted theranostic NPs were capable of effectively reducing hypoxic tumor volume and significantly suppressing tumor vascularity compared to free PB, nontargeted, FR targeted and ER targeted NPs. Moreover, in vivo optical imaging demonstrated tumor specific accumulation of the dual-targeted theranostic NPs. Furthermore, in vitro hemocompatibility and histopathological studies confirmed the biocompatibility of developed nanoformulations., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Chronic wounds are prone to fungal infections, possess a significant challenge, and result in substantial mortality. Diabetic wounds infected with Candida strains are extremely common. It can create biofilm at the wound site, which can lead to antibiotic resistance. As a result, developing innovative dressing materials that combat fungal infections while also providing wound healing is a viable strategy to treat infected wounds and address the issue of antibiotic resistance. Present work proposed anti-infective dressing material for the treatment of fungal strains Candida-infected diabetic foot ulcer (DFU). The nanofiber was fabricated using polyvinyl Alcohol/chitosan as hydrogel base and co-loaded with silver nanoparticles (AgNP) and luliconazole-nanoparticles (LZNP) nanoparticles, prepared using PLGA. Fabricated nanofibers had pH close to target area and exhibited hydrophilic surface suitable for adhesion to wound area. The nanofibers showed strong antifungal and antibiofilm properties against different strains of Candida; mainly C. albicans, C. auris, C. krusei, C. parapsilosis and C. tropicalis. Nanofibers exhibited excellent water retention potential and water vapour transmission rate. The nanofibers had sufficient payload capacity towards AgNP and LZNP, and provided controlled release of payload, which was also confirmed by in-vivo imaging. In-vitro studies confirmed the biocompatibility and enhanced proliferation of Human keratinocytes cells (HaCaT). In-vivo studies showed accelerated wound closure by providing ant-infective action, supporting cellular proliferation and improving blood flow, all collectively contributing in expedited wound healing., Competing Interests: Declaration of competing interest All authors declare not to have any conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The increase in antibacterial drug resistance is threatening global health conditions. Recently, antibacterial photodynamic therapy (aPDT) has emerged as an effective antibacterial treatment with high cure gain. In this work, three Zn(II) complexes viz., [Zn(en)(acac)Cl] (1), [Zn(bpy)(acac)Cl] (2), [Zn(en)(cur)Cl] (3), where en=ethylenediamine (1 and 3), bpy=2,2'-bipyridine (2), acac=acetylacetonate (1 and 2), cur=curcumin monoanionic (3) were developed as aPDT agents. Complexes 1-3 were synthesized and fully characterized using NMR, HRMS, FTIR, UV-Vis. and fluorescence spectroscopy. The HOMO-LUMO energy gap (Eg), and adiabatic splittings (Δ S1-T1 and Δ S0-T1 ) obtained from DFT calculation indicated the photosensivity of the complexes. These complexes have not shown any potent antibacterial activity under dark conditions but the antibacterial activity of these complexes was significantly enhanced upon light exposure (MIC value up to 0.025 μg/mL) due to their light-mediated 1 O 2 generation abilities. The molecular docking study suggested that complexes 1-3 interact efficiently with DNA gyrase B (PDB ID: 4uro). Importantly, 1-3 did not show any toxicity toward normal HEK-293 cells. Overall, in this work, we have demonstrated the promising potential of Zn(II) complexes as effective antibacterial agents under the influence of visible light., (© 2023 Wiley-VCH GmbH.)

Aim: p-Toluenesulfonic acid-(PTSA) and grinding-induced novel synthesis of ethylquinolin-thiazolo-triazole derivatives was performed using green chemistry. Materials & methods: Development of a nanoconjugate drug-delivery system of ethylquinolin-thiazolo-triazole was carried out with D-α-tocopheryl polyethylene glycol succinate (TPGS) and the formulation was further characterized by transmission electron microscopy, atomic force microscopy, dynamic light scattering and in vitro drug release assay. The effect of 3a nanoparticles was assessed against a cervical cancer cell line (HeLa) through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect on apoptosis was determined. Results & discussion: The 3a nanoparticles triggered the apoptotic mode of cell death after increasing the intracellular reactive oxygen level by enhancing cellular uptake of micelles. Furthermore, in silico studies revealed higher absorption, distribution, metabolism, elimination and toxicity properties and bioavailability of the enzyme tyrosine protein kinase. Conclusion: The 3a nanoparticles enhanced the therapeutic potential and have higher potential for targeted drug delivery against cervical cancer.

Photodynamic therapy (PDT) has evolved as a new therapeutic modality for cancer treatment with fewer side effects and drug resistance. Curcumin exhibits PDT activity, but its low bioavailability restricts its clinical application. Here, the bioavailability of curcumin was increased by its complex formation with the Zn(II) center. For a structure-activity relationship study, Zn(II)-based complexes ( 1 - 3 ) comprising N^N-based ligands (2,2'-bipyridine in 1 and 2 or 1,10-phenanthroline in 3 ) and O^O-based ligands (acetylacetone in 1 , monoanionic curcumin in 2 and 3 ) were synthesized and thoroughly characterized. The X-ray structure of the control complex, 1 , indicated a square pyramidal shape of the molecules. Photophysical and TD-DFT studies indicated the potential of 2 and 3 as good visible light type-II photosensitizers for PDT. Guided by the TD-DFT studies, the low-energy visible light-triggered singlet oxygen ( 1 O 2 ) generation efficacy of 2 and 3 was explored in solution and in cancer cells. As predicted by the TD-DFT calculations, these complexes produced 1 O 2 efficiently in the cytosol of MCF-7 cancer cells and ultimately displayed excellent apoptotic anticancer activity in the presence of light. Moreover, the molecular docking investigation showed that complexes 2 and 3 have very good binding affinities with caspase-9 and p-53 proteins and could activate them for cellular apoptosis. Further molecular dynamics simulations confirmed the stability of 3 in the caspase-9 protein binding site.

Background: Injectable opioid agonist treatment (iOAT) has proven to be a safe and effective treatment option for severe opioid use disorder (OUD). Yet, iOAT is often isolated from other health and social services. To align with a person-centered care approach, iOAT can be embedded in sites that combine systems and services that have been historically fragmented and that address multiple comorbidities (integrated care sites). The present study investigates the addition of iOAT at an integrated care in Vancouver, British Columbia. We aimed to capture what it means for service users and service providers to incorporate iOAT in an integrated care site and describe the processes by which the site keeps people engaged., Methods: We conducted 22 interviews with 15 service users and 14 interviews with 13 service providers across two rounds of individual semi-structured interviews (Fall 2021, Summer 2022). The second interview round was precipitated by a service interruption in medication dispensation. Interview audio was recorded, transcribed, and then analysed in NVivo 1.6 following an interpretive description approach., Results: The emergent themes from the analysis are represented in two categories: (1) a holistic approach (client autonomy, de-medicalized care, supportive staff relationships, multiple opportunities for engagement, barriers to iOAT integration) and (2) a sense of place (physical location, social connection and community belonging, food)., Conclusion: Incorporating iOAT at an integrated care site revealed how iOAT delivery can be strengthened through its direct connection to a diverse, comprehensive network of health and social services that are provided in a community atmosphere with high quality therapeutic relationships., (© 2023. The Author(s).)

Objective: This paper assesses the clinical and imaging characteristics, histopathological findings, and treatment outcomes of patients with Rathke's cleft cyst (RCC), as well as identifies potential risk factors for preoperative visual and pituitary dysfunction, intraoperative cerebrospinal fluid (CSF) leak, and recurrence. Through analyzing these factors, the study aims to contribute to the current understanding of the management of RCCs and identify opportunities for improving patient outcomes., Methods: We performed a retrospective analysis of 45 RCC patients between ages 18-80 treated by Endoscopic Endonasal Approach (EEA) and cyst marsupialization between 2010 and 2022 at a single institution., Results: The median patient age was 34, and 73% were female. The mean follow-up was 70 ± 43 months. Preoperative visual impairment correlated with cyst diameter (OR = 1.41, 95% CI = 1.07 to 1.85, p-value = 0.01) and older age (OR = 1.06, 95% CI = 1.01 to 1.11, p-value = 0.02). Intraoperative CSF leaks were 11 times more likely for cysts ≥ 2 cm (OR = 11.3, 95% CI = 1.25 to 97.37, p-value = 0.03), with the odds of leakage doubling for every 0.1 cm increase in cyst size (OR = 1.41, 95% CI = 1.08 to 1.84, p-value = 0.01). Preoperative RCC appearing hypointense on T1 images demonstrated significantly higher CSF leak rates than hyperintense lesions (OR = 122.88, 95% CI = 1.5 to 10077.54, p-value = 0.03). Preoperative pituitary hypofunction was significantly more likely in patients with the presence of inflammation on histopathology (OR = 20.53, 95% CI = 2.20 to 191.45, p-value = 0.008 ) and T2 hyperintensity on magnetic resonance imaging (MRI) sequences (OR = 23.2, 95% CI = 2.56 to 211.02, p-value = 0.005). Notably, except for the hyperprolactinemia, no postoperative improvement was observed in pituitary function., Conclusion: Carefully considering risk factors, surgeons can appropriately counsel patients and deliver expectations for complications and long-term results. In contrast to preoperative visual impairment, preoperative pituitary dysfunction was found to have the least improvement post-surgery. It was the most significant permanent complication, with our data indicating the link to the cyst signal intensity on T2 MR and inflammation on histopathology. Earlier surgical intervention might improve the preservation of pituitary function., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Recurrent respiratory papillomatosis (RRP) is a chronic disease of the upper respiratory tract caused by human papillomavirus types 6 and 11. The disease course is characteristically unpredictable, ranging from spontaneous remission to aggressive, recurrent disease. Thus, management is often challenging and requires unique approaches tailored to each individual patient. While recent literature has described risk factors for more aggressive disease, few sources have investigated the impact of smoking on RRP disease course and risk for malignant transformation., Methods: A retrospective chart review was conducted for adult RRP patients evaluated at an academic tertiary care center between 2005 and 2020. A total of 188 patients were identified. Demographic and clinical data were collected, including smoking and alcohol history, HPV subtype, history of dysplasia and/or carcinoma, voice handicap index scores, Derkay scores, debulkings (in office and operating room), and days to papilloma recurrence., Results: Malignant degeneration in RRP occurred in 16.3% of smokers and 3.6% of nonsmokers. Smokers who developed carcinoma had less debulkings per years of evaluation than those not developing carcinoma (0.21 vs 0.92, P  = .004). Additionally, patients that either presented with or developed carcinoma during their course had a higher pack-year smoking history (18.0 vs 12.21, P  = .0002). No difference in days to recurrence or inter-surgical interval was demonstrated between smokers and nonsmokers., Conclusions: The report demonstrates that smoking can increase the risk of malignant transformation in RRP patients.

Objective: To define and contextualize life-threatening gastrointestinal (GI) bleeding in the setting of factor Xa (FXa) inhibitor therapy and to derive a consensus-based, clinically oriented approach to the administration of FXa inhibitor reversal therapy., Methods: We convened an expert panel of clinicians representing specialties in emergency medicine, gastroenterology, vascular medicine, and trauma surgery. Consensus was reached among the clinician panelists using the Delphi technique, which consisted of 2 survey questionnaires followed by virtual, real-time consensus-building exercises., Results: Hypovolemia and hemodynamic instability were considered the most important clinical signs of FXa inhibitor-related, life-threatening GI bleeds. Clinician panelists agreed that potentially life-threatening GI bleeding should be determined on the basis of hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. Last, the panel agreed that all patients with life-threatening, FXa inhibitor-associated GI bleeding should be considered for FXa inhibitor reversal therapy; the decision to reverse FXa inhibition should be individualized, weighing the risks and benefits of reversal; and when reversal is elected, therapy should be administered within 1 h after initial emergency department evaluation, when possible., Conclusions: Consensus-based definitions of life-threatening GI bleeding and approaches to FXa inhibitor reversal centered on hemodynamic instability, signs of shock, individual patient characteristics, and clinical judgment. The results from this Delphi panel may inform clinical decision-making for the treatment of patients experiencing GI bleeding associated with FXa inhibitor use in the emergency department setting., Competing Interests: Anna Hundt Golden, Jon Russo, and Mark Price are full‐time employees of RTI Health Solutions, an independent nonprofit research organization, which was retained by Alexion, AstraZeneca Rare Disease, to conduct the research that is the subject of this manuscript. Their compensation is unconnected to the studies on which they work. Allen Mangel was a full‐time employee of RTI Health Solutions at the time this research was conducted. Bruce Koch is an employee of AstraZeneca and may hold shares and/or stock options in the company. Mary J. Christoph was an employee of AstraZeneca at the time this research was conducted and may hold shares and/or stock options in the company. Gregory J. Fermann has served on the scientific advisory board for Milestone Pharmaceuticals, as a consultant to Astra Zeneca, and on Speaker's Bureau for Astra Zeneca, and has received research support from Siemens, Abbott, InCarda Therapeutics, and the National Institutes of Health. Brooks D. Cash and Marc Maegele have served as consultants for AstraZeneca. Nayantara Coelho‐Prabhu has served as a consultant for Boston Scientific and Alexion and has received research funding from Cook Endoscopy and Fujifilm. Roland Bingisser has served as a consultant for AstraZeneca, SpinChip, and Phillips point‐of‐care systems; has received fees for presentations from AstraZeneca; and serves as an editor for medStandards. Vinay Sehgal has served as a consultant for Apollo Endosurgery, Pentax, Medtronic, Pharmacosmos, Microtech, and AstraZeneca; has served on advisory boards for Pharmacosmos and Microtech; and has received educational grants from Apollo Endosurgery, Pentax, and Medtronic. Alexander T. Cohen has received grants or contracts from Alexion, AstraZeneca, Bristol‐Myers Squibb, and Pfizer; consulting fees from Alexion, AstraZeneca, Bayer AG, Bristol‐Myers Squibb, and Pfizer; and payments or honoraria from Alexion, AstraZeneca, Bayer AG, Bristol‐Myers Squibb, and Pfizer. Truman J. Milling Jr. has served as a consultant for AstraZeneca, CSL Behring, CellPhire, Acasti Pharma, and Octapharma., (© 2023 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Cancer often causes long-term physical and psychological impairments. Lifestyle modification and nature-based interventions (NBIs) can have a positive impact on patients' quality of life (QOL). This participants-blinded, non-randomized controlled study assessed parameters at weeks 0, 12, and 24, including, as a primary endpoint, QOL in cancer patients on the Functional Assessment of Cancer Therapy-General (FACT-G) at week 12. QOL in breast cancer patients, fatigue, well-being, stress, anxiety/depression, socio-psychological well-being, benefits of nature interaction, insomnia, self-efficacy, mindfulness, and self-compassion were assessed as secondary endpoints. N = 107 cancer patients (96.3% women; 52.5 ± 9.3 years, 80.4% breast cancer) were assigned to either a 12-week nature-based (NDC; n = 56) or conventional (DC; n = 51) oncology day care clinic program, whereby the assignment group was not known to the participants. There was no significant group difference for the primary endpoint. At week 24, QOL, fatigue, mindfulness and self-compassion scores were significantly higher, and at weeks 12 and 24, the insomnia score was significantly lower in NDC compared to DC. In conclusion, this study indicates positive and clinically relevant effects of the program on QOL, fatigue, and psychological parameters. NBIs seem to have a more pronounced effect.