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Skin disorders affect millions of people all over the world. There are limited options to treat dermal illnesses such as vitiligo, psoriasis, and atopic dermatitis (eczema). Central American ferns are a potential source of bioactive metabolites against those diseases. Currently, Polypodium leucotomos Poir. is the only one being commercially utilized for this purpose. In this work, we evaluated the concentration of the skin bioactive compounds: quinic and chlorogenic acid, in the extract of 20 wild ferns from Costa Rica. We also evaluated the antimicrobial capabilities of the crude extracts of wild ferns and the sun protection factor (SPF) of the extracts. We found 19 out of 20 have either an important concentration of the compounds mentioned above or antimicrobial properties. Also, most samples result in higher SPF than P. aureum's rhizome. We also have studied the fern acclimatization, at different shading conditions, finding a significant influence of the culturing conditions on metabolite production. After acclimatization. So far, we demonstrate that various ferns included in this study are a potential source of treatments for skin conditions., (© 2024. The Author(s).)

Improving the role of electron-transport layers (ETLs) in carbon-based perovskite solar cells (CPSCs) is a promising method to increase their photovoltaic efficiency. Herein, we employed rGO sheets decorated with ZrO 2 nanoparticles to increase the electron transport capability of mesoporous TiO 2 ETLs. We found that the rGO/ZrO 2 dopant enhanced the conductivity of the ETL, reducing the charge-transfer resistance at the ETL/perovskite interface and reducing charge recombination in the corresponding CPSCs. Notably, this dopant did not effectively change the transparency of ETLs, while increasing the light-harvesting ability of their own top perovskite layer by improving the crystallinity of the perovskite layer. The rGO/ZrO 2 -containing ETLs produced a champion efficiency of 15.21%, while devices with a net ETL recorded a maximum efficiency of 11.88%. In addition, the modified devices showed a higher stability behavior against ambient air than the net devices, which was linked to the passivated grain boundaries of the modified perovskite layers along with the improved hydrophobicity., Competing Interests: There is no conflict of interest by any author., (This journal is © The Royal Society of Chemistry.)

Background: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer., Methods: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete., Findings: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction)., Interpretation: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests All authors received research support in the form of medical writing assistance from F Hoffmann-La Roche. SAH declares article processing charges paid by F Hoffmann-La Roche; funding for conducting the clinical trial from F Hoffmann-La Roche; contracted research paid to her institution from Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Celcuity, Cytomx, Daiichi Sankyo, Dantari, Dignitana, G1 Therapeutics, Gilead, Greenwich Life Sciences, GSK, Immunomedics, Eli Lilly, MacroGenics, Novartis, OBI Pharma, Orinove, Orum, Pfizer, Phoenix Molecular Designs, Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, and Zymeworks; speaking fees from Daiichi Sankyo; travel funding from Eli Lilly; uncompensated participation in a data safety monitoring board or advisory board for Alliance and Quantum Leap Health; and unpaid scientific committee membership for Translational Research in Oncology (TRIO). AB declares grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, and Eli Lilly; and consulting fees from Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, and Foundation Medicine. VQ declares funding support for attending meetings and/or travel from F Hoffmann-La Roche; participation in a steering committee for F Hoffmann-La Roche; and a research grant and funding, paid to her institution, from Celgene. YHP declares grants or contracts from Pfizer, AstraZeneca, F Hoffmann-La Roche, and MSD; consulting fees from Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Novartis, Menarini, Lilly, and MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Pfizer, Daiichi Sankyo, AstraZeneca, MSD, Novartis, Eisai, and Boryung; patents planned, issued, or pending from Hanmi; and participation in a data safety monitoring board or advisory board for AstraZeneca, Eisai, Pfizer, and Novartis. IB declares grants or contracts from F Hoffmann-La Roche, Lilly, AstraZeneca, and Agendia; consulting fees from AstraZeneca, F Hoffmann-La Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre Fabre, Bristol Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen, and Veracyte; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, F Hoffmann-La Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre Fabre, Bristol Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen, and Veracyte; funding support for attending meetings and/or travel from F Hoffmann-La Roche, Lilly, and Pierre Fabre; and participation in a data safety monitoring board or advisory board for AstraZeneca, F Hoffmann-La Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre Fabre, Bristol Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen, and Veracyte. HA declares grants or contracts from F Hoffmann-La Roche, MSD, and AstraZeneca. DAY declares grants or contracts, paid to her institution, from Ambrx, Amgen, BIOMARIN, Biothera Pharmaceuticals, Clovis Pharma, Dana-Farber Cancer Institute, Lilly, Roche/Genentech, G1 Therapeutics, Gilead Sciences, Incyte, Innocrin Pharmaceuticals, MacroGenics, MedImmune, Medivation, Merck, Merrimack Pharmaceuticals, Nektar Therapeutics, Novartis, National Surgical Adjuvant Breast and Bowel Project (USA), Pfizer, and Polyphor; and consulting fees, paid to their institution, from AstraZeneca, Athenex, Biotheranostics, G1 Therapeutics, Gilead Sciences, Immunomedics, Merck, Novartis, Pfizer, and Sanofi Aventis. OB declares a grant from TRIO for doing a study and for being an investigator, paid to OB directly and to his institution. GS is employed by TRIO. CX is employed by F Hoffmann-La Roche. EF is employed by Roche Products. TBC declares stock or stock options for F Hoffmann-La Roche; is employed by F Hoffmann-La Roche; and is named on a patent for PHESGO (F Hoffmann-La Roche). PDP-M declares stock or stock options for F Hoffmann-La Roche and is employed by Genentech. VL-V and JS declare stock or stock options for, and are employed by, F Hoffmann-La Roche. TMF and HMM declare stock or stock options for F Hoffmann-La Roche and are employed by Genentech. PAF declares fees, paid to his institution, for being on a steering committee for F Hoffmann-La Roche; grants or contracts paid to his institution from BioNTech, Cepheid, and Pfizer; consulting fees from Novartis, Pfizer, F Hoffmann-La Roche, Daiichi Sankyo, AstraZeneca, Lilly, Eisai, MSD, Pierre Fabre, Seagen, Agendia, Sanofi Aventis, Gilead, and Mylan; payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Novartis, Pfizer, F Hoffmann-La Roche, Daiichi Sankyo, AstraZeneca, Lilly, Eisai, MSD, Pierre Fabre, Seagen, Agendia, Sanofi Aventis, Gilead, and Mylan; and participation in a data safety monitoring board or advisory board for Novartis, Pfizer, F Hoffmann-La Roche, Daiichi Sankyo, AstraZeneca, Lilly, Eisai, MSD, Pierre Fabre, Seagen, Agendia, Sanofi Aventis, Gilead, and Mylan., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The need for alternative drugs to treat methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia has led to a focus on ceftaroline, for which clinical data remain scarce. Herein, the efficacy of ceftaroline fosamil for the treatment of experimental MRSA bacteraemia was compared with that of approved therapies. Five MRSA strains were tested in an immunocompetent BALB/c bacteraemia model. Serum pharmacokinetics of ceftaroline fosamil were determined using HPLC/MS Q-TOF. Two hours after infection with the MRSA strains, mice were administered 50 mg/kg of ceftaroline fosamil every 6 h, for 24 h. This regimen yielded a T>MIC of 61.5% for an MIC of 1 mg/L and proved efficacious against all strains, including an hVISA strain with non-susceptibility to daptomycin, as indicated by the reduction (mean ± s.d.) in log 10 CFU/mL in blood of 2.34 ± 0.33 and log 10 CFU/g in kidney of 2.08 ± 0.22. Similarly, treatment with daptomycin yielded a log reduction of 2.30 ± 0.60 in blood and 2.14 ± 0.31 in kidney. The decrease in bacterial density was less accentuated after treatment with vancomycin, which yielded 1.84 ± 0.73 and 1.95 ± 0.32 log reductions in blood and kidney, respectively. The results of the study showed that the efficacy of ceftaroline fosamil against MRSA bacteraemia in mice is not inferior to that of vancomycin and daptomycin, and indicated the potential use of ceftaroline fosamil against difficult-to-treat S. aureus bacteraemia. Considering these promising data, clinical trials should be conducted to ascertain the efficacy of the drug for treating bloodstream infections in humans., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Salmonella enterica serovar Typhimurium (S. Typhimurium) has become an important intestinal pathogen worldwide and is responsible for lethal invasive infections in populations at risk. There is at present an unmet need for preventive vaccines., Methods: IRTA GN-3728 genome was sequenced by Illumina and d-glutamate and d-glutamate/d-alanine knockout-auxotrophs were constructed. They were characterized using electron microscopy, growth/viability curves, reversion analysis, and motility/agglutination assays. Their potential as vaccine candidates were explored using two BALB/c mouse models for Salmonella infections: a systemic and an intestinal inflammation. Clinical signs/body weight and survival were monitored, mucosal lactoferrin and specific/cross-reactive IgA/IgG were quantified by enzyme-linked-immunosorbent assays and bacterial shedding/burden in fecal/tissues were evaluated., Results: The d-glutamate auxotroph, IRTA ΔmurI, is highly attenuated, immunogenic and fully protective against systemic infection. The IRTA ΔmurI Δalr ΔdadX double auxotroph, constructed to reinforce vaccine safety, showed a higher level of attenuation and was 100% effective against systemic disease. In the intestinal model, it proved to be safe, yielding a low-degree of mucosal inflammation, short-term shedding and undetectable invasiveness in the long-term, while eliciting cross-reactive fecal IgA/serum IgG against clinically relevant multidrug-resistant (MDR) S. Typhimurium strains. It also conferred protection against homologous oral challenge, and protected mice from local and extra-intestinal dissemination caused by one MDR strain responsible for an international outbreak of highly severe human infections. Additionally, oral vaccination promoted extended survival after lethal heterologous infection., Conclusion: This study yielded a very safe S. Typhimurium vaccine candidate that could be further refined for mucosal application against disease in humans., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Ber is an antioxidant-rich fruit from Asia and has recently been cultured in Central America. The antioxidant capacity and antimicrobial activity of Z. mauritiana cultured of bers from Guanacaste, Costa Rica, were evaluated. Two farm locations and two cultivars were evaluated. Total polyphenolic compounds (TPC), proanthocyanidin compounds (PAC), and ascorbic acid were spectrophotometrically quantified. Antioxidant activity has been analyzed using the DPPH method. Antimicrobial susceptibility was determined using the Kirby-Bauer disk diffusion method. Ber samples contained 11-44 mg GAE/g TPC. Green fruits and leaves had the highest concentrations. The ascorbic acid concentration in ber fruits was determined between 251 and 466 mg/100 g. Ber vitamin C content is higher than most common fruits. Proanthocyanidin compounds were determined between 1.8 and 9.9 mg 4-MCG/g, and the highest concentration was observed in the leaves. Our samples showed the antioxidant activity of 90-387 μmol TE/g, which was moderate activity. The nutritional quality of ber fruits was related to maturity conditions. The ber fruits, a crop from Asia previously adapted to live in Costa Rica, are rich in vitamin C and TPC, and the concentration of those metabolites was even higher than the concentration reported in bers grown in other countries. The TPC and PACs had an interestingly wide antimicrobial spectrum. Cultivars and farm locations have a significant effect on metabolite production., Competing Interests: The authors declare no competing interests., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Secondary metabolites from Hibiscus sabdariffa have been used to prevent different diseases. Roselle Hibiscus is known for being rich in phenolic bioactive compounds. The extraction conditions are directly related to the chemical composition and then to the overall bioactivity of the extract. In this study, a Box-Behnken experimental design has been used to optimize the antioxidant activity, considering four variables: ethanol:water ratio, temperature, extraction time, and solvent:solid ratio. The experiment comprises 27 experiments and 3 repetitions at the central point. The results are described by surface response analysis and a second-degree polynomial equation. The model explains 87% of the variation in the response. The maximum antioxidant activity is yielded when 1% solids are extracted in 35.5% ethanol at 60 °C for 33 min. Finally, a nutritional functional supplement of 495 µmol Trolox Equivalent (TE) antioxidant capacity was prepared with the optimized extract.

Background: KRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II-III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE., Methods: Patients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive., Results: Biomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups., Conclusions: Although our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer., Trial Registration: ClinicalTrials.gov NCT02131064. Registered 06 May 2014., (© 2023. The Author(s).)

Pseudomonas aeruginosa is an opportunistic nosocomial pathogen that causes serious infections in the respiratory tract of immunocompromised or critically ill patients, and it is also a significant source of bacteremia. Treatment of these infections can be complicated due to the emergence of multidrug-resistant P. aeruginosa strains worldwide. Hence, the development of prophylactic vaccines is a priority for at-risk patients. We have previously developed a vaccine candidate with a single auxotrophy for D-glutamate, PAO1 Δ murI , which protects against sepsis and acute pneumonia caused by P. aeruginosa . Given the paramount importance of safety in the development of live attenuated vaccines, we have improved the safety of the vaccine candidate by reducing the probability of a reversion to virulence by the inclusion of an additional auxotrophy for D-alanine. Single and double auxotrophs behaved in a similar manner in relation to the attenuation level, immunogenicity and protective efficacy, but the double auxotroph has the advantage of being more stable and safer as a candidate vaccine against respiratory infections caused by P. aeruginosa .

Risk management for workers involved in the handling and preparation of cytotoxic drugs is challenging. This study aims to investigate drug contamination of the exterior surfaces of cytotoxic drug vials. Two batches of commercially available cytotoxic drugs in unprotected vials (ifosfamide, etoposide phosphate and cyclophosphamide) and plastic shrink wrap vials (doxorubicin, cytarabine and busulfan) were tested without removing the flip-off cap or the plastic wrap, and without prewashing. The results showed significant trace amounts of cytotoxic drugs on the exterior surfaces in both unprotected (eg, cyclophosphamide, ifosfamide) and protected plastic shrink wrap vials (eg, cytarabine), indicating that the secondary packaging of protected vials does not systematically prevent exposure to the handlers. These results focus on the need for guidelines to prevent cytotoxic vial contamination and safety recommendations for staff in the handling and storage of these vials., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The development of a whole-cell vaccine from bacteria auxotrophic for D-amino acids present in the bacterial cell wall is considered a promising strategy for providing protection against bacterial infections. Here, we constructed a prototype vaccine, consisting of a glutamate racemase-deficient mutant, for preventing Klebsiella pneumoniae infections. The deletion mutant lacks the murI gene and requires exogenous addition of D-glutamate for growth. The results showed that the K. pneumoniae Δ murI strain is attenuated and includes a favourable combination of antigens for inducing a robust immune response and conferring an adequate level of cross-protection against systemic infections caused by K. pneumoniae strains, including some hypervirulent serotypes with elevated production of capsule polysaccharide as well as multiresistant K. pneumoniae strains. The auxotroph also induced specific production of IL-17A and IFN-γ. The rapid elimination of the strain from the blood of mice without causing disease suggests a high level of safety for administration as a vaccine.

Vector-borne diseases, such as those transmitted by Aedes aegypti , are a constant threat to inhabitants of tropical regions of the planet. Synthetic chemicals are commonly used as a strategy to control them; however, these products are known to persist in ecosystems and drive the appearance of resistance genes in arthropod vectors. Thus, the use of natural products has emerged as an environmentally friendly alternative in integrated vector control strategies. The present bioguided study investigated the larvicidal potential of Ipomoea cairica extracts, fractionated using thin-layer and open-column chromatography, because this species has been shown to exert larvicidal effects on the genus Aedes . The objective of this study was to evaluate the nonvolatile components in ethanolic extract of I. cairica stems as a potential natural larvicidal, and coumarins, such as 7-hydroxy-6-methoxychromen-2-one (scopoletin) and 7-hydroxychromen-2-one (umbelliferone), were identified as major compounds; however, they were not shown to be responsible for the larvicidal activity. Based on the results of the larvicidal action tests, these coumarins are not directly responsible for the larvicidal activity, but this activity might be attributed to a synergistic effect of all the compounds present in the most active secondary fraction, called F.DCM, which had an LC 50 value of 30.608 mg/L. This type of study has yet not been conducted in the region; therefore, it is an important contribution to recognizing a natural and easy-to-cultivate source of vector control, such I. cairica .