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Cytomegalovirus (CMV) reactivation during chemotherapy or after organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality, and the risk of reactivation increases with patients’ age. Bendamustine, an alkylating agent currently used for treatment of indolent and aggressive non-Hodgkin lymphomas, can augment the risk of secondary infections including CMV reactivation. In this real-world study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapsed/refractory indolent and aggressive diseases treated with bendamustine-containing regimens. In particular, patients who received bendamustine plus rituximab and dexamethasone were at higher risk of CMV reactivation, especially when administered as first-line therapy and after the third course of bendamustine. In addition, patients with CMV reactivation showed a significant depression of circulating CD4+ T cell count and anti-CMV IgG levels during active infection, suggesting an impairment of immune system functions which are not able to properly face viral reactivation. Therefore, a close and early monitoring of clinical and laboratory findings might improve clinical management and outcome of non-Hodgkin lymphoma patients by preventing the development of CMV disease in a subgroup of subjects treated with bendamustine more susceptible to viral reactivation.

Pasquale Pagliano,1 Giuliana Scarpati,2 Carmine Sellitto,3 Valeria Conti,3 Anna Maria Spera,1 Tiziana Ascione,4 Ornella Piazza,2 Amelia Filippelli3 1Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, Unit of Infectious Diseases, University of Salerno, Baronissi, Italy; 2Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, Unit of Anesthesiology, University of Salerno, Baronissi, Italy; 3Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, Unit of Pharmacology, University of Salerno, Baronissi, Italy; 4Department of Medicine, Service of Infectious Diseases, Cardarelli Hospital, Naples, ItalyCorrespondence: Pasquale PaglianoDepartment of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, Unit of Infectious Diseases, University of Salerno, Via S. Allende 1, Baronissi, ItalyTel +393397504168Email ppagliano@unisa.itAbstract: The coronavirus infectious disease-2019 (COVID-19) has overwhelmed like a shock wave in a completely unprepared world. Despite coronavirus infections were involved in previous epidemic outbreaks, no antiviral agent was developed for specific treatment. As a consequence, since the beginning of this pandemic, both repositioned and experimental drugs were used to treat the infected patients without evidence of clinical efficacy. Just based on experience coming from the use of antiviral agents to treat other viruses (eg, lopinavir/ritonavir, remdesivir) and supposed antiviral or immunomodulatory activities of drugs with no approved antiviral indications (eg hydroxychloroquine, tocilizumab), clinicians have faced the ongoing pandemic. Currently, after about 9 months from the COVID-19 spread, there is still no antiviral agent capable of ensuring the cure of this syndrome. Clinical trials are beginning to confirm the benefits of some drugs, while for other compounds, efficacy and safety have not yet been confirmed. Randomized clinical trials (RCT) have denied or downsized the beneficial effects attributed to certain molecules, such as aminoquinolines, largely used in clinical practice at the beginning of COVID-19 spread. Conversely, at the same time, they have provided evidence for unexpected effectiveness of other agents that have been underutilized, such as steroids, which were not used in SARS treatment because of the threatened effect on viral replication. Evidence deriving from pathologic studies have demonstrated that the prothrombotic effects of SARS-CoV-2 can be prevented by heparin prophylaxis, underlining the need for personalized treatment for patients with severe disease. The main aim of this review is to synthesize the available information and evidence on both repositioned and experimental drugs for the treatment of COVID-19, focusing on the need to exercise caution on the use of unproven medical therapies.Keywords: SARS-CoV-2, ARDS, remdesivir, chloroquine, steroids, heparin

Abstract Background Endocrine therapy (ET) has improved the clinical outcomes of Estrogen receptor alpha-positive (ERɑ +) breast cancer (BC) patients, even though resistance to ET remains a clinical issue. Mutations in the hormone-binding domain of ERɑ represent an acquired intrinsic mechanism of ET resistance. However, the latter also depends on the multiple functional interactions between BC cells and the tumor microenvironment (TME). Here, we investigated how the most common Y537S-ERɑ mutation may influence the behavior of fibroblasts, the most prominent component of the TME. Methods We conducted coculture experiments with normal human foreskin fibroblasts BJ1-hTERT (NFs), cancer-associated fibroblasts (CAFs), isolated from human BC specimens, and Y537S CRISPR-expressing MCF-7 BC cells (MCF-7YS). Mass spectrometry (MS) and Metacore analyses were performed to investigate how the functional interactions between BC cells/fibroblasts may affect their proteomic profile. The impact of fibroblasts on BC tumor growth and metastatic potential was evaluated in nude mice. Results Mutant BC conditioned medium (CM) affected the morphology/proliferation/migration of both NFs and CAFs. 198 deregulated proteins signed the proteomic similarity profile of NFs exposed to the YS-CM and CAFs. Among the upregulated proteins, Yes-associated protein 1 (YAP1) was the main central hub in the direct interaction network. Increased YAP1 protein expression and activity were confirmed in NFs treated with MCF-7YS-CM. However, YAP1 activation appears to crosstalk with the insulin growth factor-1 receptor (IGF-1R). Higher amount of IGF-1 were noticed in the MCF-7YS-CM cells compared to the MCF-7P, and IGF-1 immunodepletion reversed the enhanced YAP1 expression and activity. Mutant cells upon exposure to the NF- and CAF-CM exhibited an enhanced proliferation/growth/migration/invasion compared to the MCF-7P. MCF-7YS cells when implanted with CAFs showed an early relative increased tumor volume compared to YS alone. No changes were observed when MCF-7P cells were co-implanted with CAFs. Compared with that in MCF-7P cells, the metastatic burden of MCF-7YS cells was intrinsically greater, and this effect was augmented upon treatment with NF-CM and further increased with CAF-CM. Conclusions YS mutant BC cells induced the conversion of fibroblasts into CAFs, via YAP, which represent a potential therapeutic target which interrupt the functional interactions between mutant cells/TME and to be implemented in the novel therapeutic strategy of a subset of metastatic BC patients carrying the frequent Y537S mutations.

In this contribution, new data concerning algae, bryophytes, fungi and lichens of the Italian flora are presented. It includes new records, confirmations or exclusions for the algal genera Chara and Tolypella, the bryophyte genera Pogonatum, Pseudephemerum, and Riella, the fungal genera Arrhenia, Arthonia, Buchwaldoboletus, Dacampia, Hebeloma, Inocybe, and Trechispora, and the lichen genera Aspicilia, Bellemerea, Cladonia, Hypotrachyna, Maronea, Parvoplaca, Polyozosia, Schismatomma, Solenopsora, Trapelia, and Zwackhia.

Tissue homeostasis, function recovery, and protection mechanisms are boosted by the balanced and timely control of inflammation and oxidative stress. Nowadays, many natural products and bio-derivates exhibit antioxidant and anti-inflammatory activity, supporting medical care and tissue wellness against inflammation, oxidative stress, and inflammaging. Castanea sativa wood distillate (WD) is a bio-derivative used as a corroborant and biofertilizer in agriculture. Based on the safety profile of low concentrations of WD on human cells, the present study aims to assess the anti-inflammatory and antioxidant activity of WD on different cell types in the integumentary system. Human keratinocytes, mucosal epithelium, dermal fibroblasts, and endothelial cells were exposed to WD, and the concentrations devoid of pro-apoptotic potential were profiled. Then, the effect of nontoxic doses of WD revealed an anti-inflammatory effect, observed through the immunodetection of prostanoid cascade markers in experimentally induced inflammation. A reduction in endothelial hyperpermeability was evidenced by the immunofluorescence analysis of cell–cell adhesion proteins, VE-cadherin and ZO-1. In addition, WD buffered the exogenously produced oxidative stress. On the whole, WD showed both anti-inflammatory and antioxidant activities on the various cell types, preserving endothelial barrier integrity. Overall, this study supports the involvement of this bio-derivative in novel exploitable fields, such as therapeutic dermatological applications for human and animal medical care.

Adverse events following immunizations (AEFIs) with recombinant zoster vaccine (RZV) are underexplored in fragile populations. This study aims to assess incidence, duration, and characteristics of AEFIs, focusing on the impact of sex, age, and prior Herpes Zoster (HZ) infection in a frail population, including solid organ transplant recipients. We conducted an observational study on patients receiving RZV, and AEFIs were classified as local or systemic and analyzed for incidence, duration, and patterns across groups. We showed that females had a higher incidence of AEFIs (p = 0.02), both local and systemic symptoms, such as swelling +/− redness at the site of injection and fatigue, after the first and second doses. Younger adults experienced more systemic reactions, while older adults reported more local events (e.g., redness and swelling, p = 0.01). Moreover, patients with previous HZ infection exhibited a higher incidence of AEFIs after the second dose (68% vs. 38%, p = 0.001). In conclusion, sex, age, and clinical history significantly influenced AEFI incidence and manifestations. Therefore, it is important to personalize vaccination strategies in frail populations, by tailored administration and monitoring plans, especially in females and individuals with prior HZ infection, to improve vaccine safety and patient outcomes.

Highly active antiretroviral therapy has led to a significant increase in the life expectancy of people living with HIV. The trade-off is that HIV-infected patients often suffer from comorbidities that require additional treatment, increasing the risk of Drug-Drug Interactions (DDIs), the clinical relevance of which has often not been determined during registration trials of the drugs involved. Therefore, it is important to identify potential clinically relevant DDIs in order to establish the most appropriate therapeutic approaches. This review aims to summarize and analyze data from studies published over the last two decades on DDI-related adverse clinical outcomes involving anti-HIV drugs and those used to treat comorbidities. Several studies have examined the pharmacokinetics and tolerability of different drug combinations. Protease inhibitors, followed by nonnucleoside reverse transcriptase inhibitors and integrase inhibitors have been recognized as the main players in DDIs with antivirals used to control co-infection, such as Hepatitis C virus, or with drugs commonly used to treat HIV comorbidities, such as lipid-lowering agents, proton pump inhibitors and anticancer drugs. However, the studies do not seem to be consistent with regard to sample size and follow-up, the drugs involved, or the results obtained. It should be noted that most of the available studies were conducted in healthy volunteers without being replicated in patients. This hampered the assessment of the clinical burden of DDIs and, consequently, the optimal pharmacological management of people living with HIV.

Background/Objectives: Antibiotic resistance is a growing global threat that significantly impacts public health and healthcare costs. The Italian National Action Plan on Antimicrobial Resistance (PNCAR) was introduced in 2017 to address this issue by improving antibiotic stewardship. This study aimed to evaluate the effectiveness of the PNCAR in enhancing antibiotic management practices in a hospital in southern Italy before and after its implementation. Methods: We conducted an observational monocentric study to analyze antibiotic consumption in a hospital setting before and after the COVID-19 pandemic (2019 and 2023) and to examine prescription appropriateness and the types of used antibiotics. Results: After PNCAR introduction, we recorded a significant increase in antibiotic prescription appropriateness and in Access antibiotic and targeted therapy usage, while Reserve antibiotics were prescribed in ~10% of the cases, with an increasing trend in 2023. Conclusions: Our study supports the importance of targeted stewardship initiatives, including continuous monitoring and education, to sustain antibiotic prescription appropriateness and to reduce antimicrobial resistance.

The COVID-19 pandemic has left behind mental health issues like anxiety, depression, and sleep disorders among survivors. This study assessed the efficacy of spa therapy in enhancing psychological well-being and sleep quality in individuals with chronic arthro-rheumatic, respiratory, and otorhinolaryngological diseases, including COVID-19 recoverees. Our prospective observational study included 144 Caucasian subjects from three Italian spas who underwent a 2-week spa therapy cycle, involving balneotherapy and/or inhalation treatments. Symptoms were assessed with the Visual Analogue Scale (VAS), psychological well-being with Depression Anxiety Stress Scales-21 items (DASS-21), and sleep quality with the Insomnia Severity Index (ISI). Significant reductions in VAS scores for arthro-rheumatic, respiratory, and otorhinolaryngological symptoms were observed after spa therapy, as well as for DASS-21 and ISI scores for sleep quality, transitioning to less severe insomnia categories. Females had more pronounced improvements in DASS-21 scores and sleep quality. Subjects with and without prior SARS-CoV-2 infection experienced significant reductions in anxiety, depression, and stress, with more pronounced improvements in those without prior infection. COVID-19 survivors also showed significant ISI score improvements. Spa therapy is a promising complementary treatment for improving mental health and sleep quality in chronic disease patients, including COVID-19 survivors.

Abstract The evolution and expansion of land plants brought about one of the most dramatic shifts in the history of the Earth system — the birth of modern soils — and likely stimulated massive changes in marine biogeochemistry and climate. Multiple marine extinctions characterized by widespread anoxia, including the Late Devonian mass extinction around 372 million years ago, may have been linked to terrestrial release of the nutrient phosphorus driven by newly-rooted landscapes. Here we use recently published Devonian lake records as variable inputs in an Earth system model of the coupled carbon-nitrogen-phosphorus-oxygen-sulfur biogeochemical cycles to evaluate whether recorded changes to phosphorus fluxes could sustain Devonian marine anoxia sufficient to drive mass extinction. Results show that globally scaled increases in riverine phosphorus export during the Late Devonian mass extinction could have generated widespread marine anoxia, as modeled perturbations in carbon isotope, temperature, oxygen, and carbon dioxide data are generally consistent with the geologic record. Similar results for large scale volcanism suggest the Late Devonian mass extinction was likely multifaceted with both land plants and volcanism as contributing factors.

Abstract Lead exposure has blighted communities across the United States (and the globe), with much of the burden resting on lower income communities, and communities of color. On 17 January 2024, the US Environmental Protection Agency (USEPA) lowered the recommended screening level of lead in residential soils from 400 to 200 parts per million. Our analysis of tens of thousands of citizen‐science collected soil samples from cities and communities around the US indicates that nearly one quarter of households may contain soil lead that exceed the new screening level. Extrapolating across the nation, that equates to nearly 30 million households needing to mitigate potential soil lead hazards, at a potential total cost of 290 billion to $1.2 trillion. We do not think this type of mitigation is feasible at the massive scale required and we have instead focused on a more immediate, far cheaper strategy: capping current soils with clean soils and/or mulch. At a fraction of the cost and labor of disruptive conventional soil mitigation, it yields immediate and potentially life‐changing benefits for those living in these environments.

Abstract Peer‐review is the foundation and the safeguard of scientific research. Without the dedication of our reviewers, the journal would not have been successful. In 2023, 269 reviewers completed 434 reviews for the 174 manuscripts submitted to GeoHealth. Our reviewers are from all continents except Antarctica. Besides reviewers from North America, China, Europe, and China, we started to have reviewers from India, Latin America, and Africa. GeoHealth editorial board is committed to expanding the readership, authorship, and reviewership to other countries. If you have already reviewed for us, no matter where or who you are, we hope you and your colleagues will consider GeoHealth a home for your work. Below is the list of reviewers who completed more than two reviews or have outstanding quality reviews. Two of our reviewers are being nominated for AGU best reviewers awards.

Abstract The G protein-coupled estrogen receptor (GPER) mediates estrogen action in different pathophysiological conditions, including cancer. GPER expression and signaling have been found to join in the progression of triple-negative breast cancer (TNBC), even though controversial data have been reported. In present study, we aimed at providing new mechanistic and biological discoveries knocking out (KO) GPER expression by CRISPR/Cas9 technology in MDA-MB-231 TNBC cells. GPER KO whole transcriptome respect to wild type (WT) MDA-MB-231 cells was determined through total RNA sequencing (RNA-Seq) and gene ontology (GO) enrichment analysis. We ascertained that anti-proliferative and pro-apoptotic gene signatures characterize GPER KO MDA-MB-231 cells. Thereafter, we determined that these cells exhibit a reduced proliferative, clonogenic and self-renewal potential along with an increased mitochondria-dependent apoptosis phenotype. In addition, we recognized that decreased cAMP levels trigger the JNK/c-Jun/p53/Noxa axis, which in turn orchestrates the pro-apoptotic effects observed in GPER KO cells. In accordance with these data, survival analyses in TNBC patients of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset indicated that high Noxa expression correlates with improved outcomes in TNBC patients. Furthermore, we demonstrated that GPER KO in TNBC cells impairs the expression and secretion of the well-acknowledged GPER target gene named CTGF, thus resulting in the inhibition of migratory effects in cancer-associated fibroblasts (CAFs). Overall, the present study provides novel mechanistic and biological insights on GPER KO in TNBC cells suggesting that GPER may be considered as a valuable target in comprehensive therapeutic approaches halting TNBC progression.

The population of Africa is expected to rise to 2.5 billion by 2050, with more than 80% of this increase concentrated in cities. Africa’s anticipated population growth has serious implications for urban resource utilization and management, necessitating multi-level monitoring efforts that can inform planning and decision-making. Commonly, broad extent (e.g., country level) urban change analyses only examine a homogenous “developed” or “built-up” area, which may not capture patterns influenced by the heterogeneity of landscape features within urban areas. Contrarily, studies examining landscape heterogeneity at a finer resolution are typically limited in spatial extent (e.g., single city level). The goal of this study was to develop and test a hierarchical integrated mapping framework using globally available Earth Observation data (e.g., Landsat, Sentinel-2, Sentinel-1, and nightlight imagery) and accessible methodologies to produce national-level land use (LU) and urban-level land cover (LC) map products which may support a range of global and local monitoring and planning initiatives. We test our multi-tier methodology across three rapidly urbanizing African countries for the 2016–2020 period: Ethiopia, Nigeria, and South Africa. The initial output of our methodology includes annual national land use maps (Tier 1) for the purpose of delineating the dynamic boundaries of individual urban areas and monitoring national LU change. To complement Tier 1 LU maps, we detailed urban heterogeneity through LC classifications within urban areas (Tier 2) delineated using Tier 1 LU maps. Based on country-optimized sets of selected features that leverage spatial/texture and temporal dimensions of available data, we obtained an overall map accuracy of between 65 and 80% for Tier 1 maps and between 60 and 80% for Tier 2 maps, dependent on the evaluation country, although with consistent performance across study years providing a solid foundation for monitoring changes. We demonstrate the potential applications for our products through various analyses, including urbanization-driven LU change, and examine LC urban patterns across the three African study countries. While our findings allude to general differences in urban patterns across national scales, further analyses are needed to better understand the complex drivers behind urban LC configurations and their change patterns across different countries, city sizes, and rates of urbanization. Our multi-tier mapping framework is a viable strategy for producing harmonious, multi-level LULC products in developing countries using publicly available data and methodologies, which can serve as a basis for a wide range of informative and insightful monitoring analyses.