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Background: Controversial findings regarding the association between pro-inflammatory cytokines and depression have been reported in pregnant subjects. Scarce data about anxiety and its relationships with cytokines are available in pregnant women. To understand the association between anxiety and cytokines during pregnancy, we conducted the present study in women with or without depression. Methods: Women exhibiting severe depression (SD) and severe anxiety (SA) during the 3rd trimester of pregnancy (n = 139) and control subjects exhibiting neither depression nor anxiety (n = 40) were assessed through the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Serum cytokines were measured by a multiplex bead-based assay. Correlation tests were used to analyze the data and comparisons between groups were performed. A general linear model of analysis of variance was constructed using the group as a dependent variable, interleukin concentrations as independent variables, and HDRS/HARS scores and gestational weeks as covariables. Results: The highest levels of Th1- (IL-6, TNF-α, IL-2, IFN-γ), Th17- (IL-17A, IL-22), and Th2- (IL-9, IL-10, and IL-13) related cytokines were observed in women with SD + SA. The SA group showed higher concentrations of Th1- (IL-6, TNF-α, IL-2, IFN-γ) and Th2- (IL-4, and IL-10) related cytokines than the controls. Positive correlations were found between HDRS and IL-2, IL-6, and TNF-α in the SA group (p < 0.03), and between HDRS and Th1- (IL-2, IL-6, TNF-α), Th2- (IL-9, IL-10, IL-13) and Th17- (IL-17A) cytokines (p < 0.05) in the SD + SA group. After controlling the correlation analysis by gestational weeks, the correlations that remained significant were: HDRS and IL-2, IL-6, IL-9, and IL-17A in the SD + SA group (p < 0.03). HARS scores correlated with IL-17A in the SA group and with IL-17A, IL-17F, and IL-2 in the SD + SA group (p < 0.02). The linear model of analysis of variance showed that HDRS and HARS scores influenced cytokine concentrations; only IL-6 and TNF-α could be explained by the group. Conclusions: We found that the cytokine profiles differ when comparing pregnant subjects exhibiting SA with comorbid SD against those showing only SA without depression. [ABSTRACT FROM AUTHOR]

Introduction: Robot-assisted (RA) surgery has many advantages for urinary tract and pelvic floor reconstruction (UTPFR) but its application is only slowly increasing. Studies are limited in number, patients and follow-up duration. The low-volume high-complexity nature of UTPFR warrants specific research to evaluate the potential role of the RA approach., Methods: During its 2024 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the current literature on RA UTPFR. Priority research questions and strategies were explored in a proposal., Results: Four different topics were discussed. (1) Large multicentre prospective studies on RA UTPFR are needed to evaluate clinical effectiveness and safety. The RA approach needs to be prioritized in specific procedures and patients, to first improve patient care where gains are highest. (2) Models for cost-utility analysis for RA UTPFR are needed to (re)direct limited resources as efficiently as possible in a quickly changing technological field. (3) A modular curriculum for training UTPFR surgeons to become RA certified needs to be developed, to allow valid interpretation and comparison of outcomes. (4) Technological improvements to address tissue handling, accessibility, efficiency and sustainability are needed. Digitalization can be a gamechanger for RA UTPFR through telesurgery (training and expertize coverage), augmented reality and artificial intelligence providing intra-operative assistance, assessment and feedback., Conclusions: The proposal discussed the need for studies on clinical and cost effectiveness, safety, and training curriculum development for RA UTPFR. Recent technological developments hold great promise for RA UTPFR. High-priority research questions were identified., (© 2024 The Author(s). Neurourology and Urodynamics published by Wiley Periodicals LLC.)

The effective measurement of temperature in living systems at the nano and microscopic scales continues to be a challenge to this day. Here, we study the use of 2-(anthracen-2-yl)-1,3-diisopropylguanidine, 1, as a nanothermometer based on fluorescence lifetime measurements and its bioimaging applications. In aqueous solution, 1 is shown in aggregated form and the equilibrium between the two main aggregate types (T-shaped and π-π) is highly sensitive to the temperature. The heating of the medium shifts the equilibrium toward the formation of highly emissive T-shaped aggregates. This species shows a high fluorescence emission and a long lifetime in comparison with the π-π aggregates and the freé monomer. A linear relationship between the fluorescence lifetime and the temperature both in aqueous solution and in a synthetic intracellular buffer was found. Fluorescence lifetime imaging microscopy (FLIM) also showed a linear relationship between lifetime and temperature with an excellent sensitivity in MCF7 breast cancer cells, which opens the door for its potential use as FLIM nanothermometer in the biomedical field., 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.)

Introduction: Ketamine, a versatile anesthetic, has seen increased recreational use, leading to significant health issues, including ketamine-induced uropathy (KIU). KIU manifests with lower urinary tract symptoms (LUTS) and can involve the upper urinary tract. This study aims to provide a comprehensive overview of KIU, addressing its pathophysiology, diagnostic strategies, and treatment options; and to define/identify future research priorities., Methods: During the 2024 meeting of the International Consultation on Incontinence Research Society (ICI-RS) in Bristol, a dedicated Proposal (P) convened to explore KIU. This initiative involved a thorough review of existing literature, expert presentations, and consensus-driven discussions. The methodology ensured a comprehensive exploration of KIU from both clinical and pre-clinical perspectives, leading to actionable research recommendations., Results: Understanding the mechanisms of KIU is crucial for developing effective treatment options targeting specific pathophysiological pathways. Key findings include bladder fibrosis driven by transforming growth factor-β1 (TGF-β1), elevated purinergic responses and upregulated P2X1 purinoceptor expression, decreased barrier function due to increased expression of antiproliferative factor (APF), and functional loss of the bladder through Cav1.2 channel blockade. Research indicates that fibrosis, typically considered irreversible, may be mitigated. However, the exact timing and extent of fibrosis initiation and its impact on long-term outcomes require further research. LUTS typically improve after ketamine cessation but relapse upon resumption, indicating a hypersensitivity mechanism involving elevated serum IgE levels. Advanced stages of KIU do not always correlate with LUTS severity, shedding light on potential systemic effects and the need for evaluating liver enzymes. Furthermore, psychological dependency on ketamine, due to its positive perceptive and mood-altering effects, complicates cessation efforts. Long-term management requires a holistic approach, integrating medical treatments and supportive measures to help patients navigate life with potentially irreversible complications., Conclusion: This comprehensive review spans from fundamental pathology to practical clinical management, addressing both urological and systemic complications, and bridging insights from animal models to human applications. Developing effective treatment strategies necessitates addressing both the physical and psychological aspects of ketamine dependency., (© 2024 Wiley Periodicals LLC.)

Introduction: Ezetimibe inhibits cholesterol uptake by modulation of intestinal sterol absorption. Currently, although some studies have shown alterations in ezetimibe levels caused by alterations in the ABCG5 , ABCG8 , NPC1L1 or UGT1A1 genes, there are no pharmacogenetic guidelines to confirm these biomarkers. The aim of this work was to evaluate the effect of 49 variants in 22 pharmacogenes related to metabolism and transport., Methods: A total of 96 healthy volunteers from four bioequivalence clinical trials of ezetimibe as monotherapy or in combination with simvastatin were studied. Blood samples were extracted for unconjugated ezetimibe plasma quantification and genotyping., Results and Discussion: No association of metabolizing enzyme variants with ezetimibe pharmacokinetic parameters was found. The results show some trends in the univariate analysis for ABCB1 rs2032582 or ABCC2 rs2273697 and C max ( p univariate ( p uv ) = 0.056 and 0.087, respectively), which finally reach significance in the multivariate analysis ( p multivariate ( p mv ) = 0.049 and 0.048, respectively). Nevertheless, these results need to be validated in future studies., Competing Interests: FA-S and DO have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Aptatargets, Chemo, Cinfa, FAES, Farmal' der, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Moderna, MSD, Normon, Novartis, Servier, Silver Pharma, Teva and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 González-Iglesias, Ochoa, Navares-Gómez, Zubiaur, Aldama, Torre, Ríos-Rodríguez, Soria-Chacartegui, Rodríguez-Lopez, Abad-Santos and Novalbos.)

Anticancer therapies with cisplatin and volasertib (BI-6727) were monitored by fluorescence lifetime imaging microscopy (FLIM) in live SK-Mel-2 melanoma cells. A CdSe/ZnS quantum dot functionalized with a peptide containing D-penicillamine and histidine (CdSe/ZnS-PH) was used as intracellular pH fluorescent probe. A faster cytosol acidification was observed for cells treated with cisplatin when compared to volasertib. The first changes in the intracellular pH were found after 2 hours of treatment with cisplatin and 8 hours with volasertib. Additionally, the relationship between cytosol acidification and apoptosis was investigated using an innovative methodology based on time-resolved fluorescence measurements. Similar low percentages of apoptotic cells were observed after short incubation periods (2 - 8 hours) with both drugs. In contrast, late apoptosis and death were found for a large fraction of cells during 24-hour incubation with cisplatin but not volasertib. Thus, the early acidification observed in cisplatin treatment could accelerate apoptosis and cell death. Despite volasertib treatment shows slower mechanism of action than cisplatin, similar inhibitory effects were found for both drugs at longer incubation periods (72 hours). This study proves the potential of CdSe/ZnS-PH nanoparticle as a fluorescence lifetime probe in the study of the mechanism of action of antitumor drugs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ivan Bravo reports financial support was provided by Junta de Comunidades de Castilla-La Mancha. Andres Garzon-Ruiz reports financial support was provided by Spain Ministry of Science and Innovation. If there are other authors, they 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.)

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (C max /DW)), elimination (terminal half-life (T 1/2 ) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and C max /DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and C max /DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T 1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, C max , and CL/F of 5-HMT, which should be confirmed in other studies.

Background and Objective: Orodispersible tablets (ODT) rapidly dissolve in the oral cavity and can improve patient's convenience. This pharmacokinetic study assessed the bioequivalence of a novel 20 mg ODT formulation of bilastine compared with bilastine 20 mg tablets in healthy volunteers under fasting conditions., Methods: A phase I, single-center, open-label, two-period, two-sequence crossover randomized clinical trial was conducted. The study comprised two periods, in which participants were administered a single oral dose of bilastine 20 mg in the form of ODT as the test product, or conventional tablets as the reference product, and a washout of 7 days between each period. Blood samples were collected for up to 72 h. Bioequivalence was established if the 90% confidence intervals of the C max and AUC 0-t were within the acceptance range (80-125%). Safety was evaluated at the follow-up visit (days 4-7 after the second dose) and throughout the study., Results: A total of 42 healthy volunteers were randomized, and 41 completed the study. Pharmacokinetic parameters were comparable for both formulations after a single dose of 20 mg. Bilastine ODT and conventional tablets were bioequivalent as the 90% confidence intervals of the test over reference ratios were within the predefined range (80-125%). Both formulations were well tolerated and showed a similar safety profile., Conclusions: Bilastine ODT was bioequivalent to the reference treatment formulated as conventional tablets when administered as a single oral dose of 20 mg under fasting conditions. Both formulations showed a similar tolerability and safety profile, with no serious adverse events or significant analytical alterations reported., Trial Registration: 2019-004071-39. Date of authorization: 10 December 2019., (© 2024. The Author(s).)

Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the free-text reasons for 28,561 clinical trials that stopped before their endpoints were met. We then evaluated these classes in light of the underlying evidence for the therapeutic hypothesis and target properties. We found that trials are more likely to stop because of a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models. Furthermore, certain trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is broadly expressed across tissues. These results support the growing use of human genetics to evaluate targets for drug discovery programs., (© 2024. The Author(s).)

Ramipril is an angiotensin-converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty-nine healthy volunteers who had participated in a single-dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype-informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7-fold higher dose/weight-corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p-value [p uv ] < 0.001, multivariate p-value [p mv ] < 0.001, β = 0.533, R 2  = 0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6-fold higher AUC/DW than those with the NF phenotype (p uv  = 0.011, p mv  < 0.001, β = 0.259, R 2  = 0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: The predictive ability of the early determination of sex steroids and the total testosterone:estradiol ratio for the risk of severe coronavirus disease 2019 or the potential existence of a biological gradient in this relationship has not been evaluated., Objectives: To assess the relationship of sex steroid levels and the total testosterone:estradiol ratio with the risk of severe acute respiratory syndrome coronavirus 2 infection in men, defined as the need for intensive care unit admission or death, and the predictive ability of each biomarker., Materials and Methods: This was a prospective observational study. We included all consecutive adult men with severe acute respiratory syndrome coronavirus 2 infections in a single center admitted to a general hospital ward or to the intensive care unit. Sex steroids were evaluated at the centralized laboratory of our hospital., Results: We recruited 98 patients, 54 (55.1%) of whom developed severe coronavirus disease in 2019. Compared to patients with nonsevere coronavirus disease 2019, patients with severe coronavirus disease 2019 had significantly lower serum levels of total testosterone (111 ± 89 vs. 191 ± 143 ng/dL; p < 0.001), dehydroepiandrosterone (1.69 ± 1.26 vs. 2.96 ± 2.64 ng/mL; p < 0.001), and dehydroepiandrosterone sulfate (91.72 ± 76.20 vs. 134.28 ± 98.261 μg/dL; p = 0.009), significantly higher levels of estradiol (64.61 ± 59.35 vs. 33.78 ± 13.78 pg/mL; p = 0.001), and significantly lower total testosterone:estradiol ratio (0.28 ± 0.31 vs. 0.70 ± 0.75; p < 0.001). The lower the serum level of androgen and the lower the total testosterone:estradiol ratio values, the higher the likelihood of developing severe coronavirus disease 2019, with the linear trend in the adjusted analyses being statistically significant for all parameters except for androstenedione (p = 0.064). In the receiver operating characteristic analysis, better predictive performance was shown by the total testosterone:estradiol ratio, with an area under the curve of 0.77 (95% confidence interval 0.68-0.87; p < 0.001)., Discussion and Conclusion: Our results suggest that men with severe acute respiratory syndrome coronavirus 2 infection, decreased androgen levels and increased estradiol levels have a higher likelihood of developing an unfavorable outcome. The total testosterone:estradiol ratio showed the best predictive ability., (© 2024 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

In the present work, we study different physicochemical properties related to LADME processes of volasertib, a Polo-like kinase 1 inhibitor in advanced clinical trials. Firstly, the protonation equilibria, the extent of ionization at the physiological pH and pK a values of this drug are studied combining spectroscopic techniques and computational calculations. Secondly, the binding process of volasertib to the human serum albumin (HSA) protein is analyzed by fluorescence spectroscopy. We report a high binding constant to HSA (K a  = 4.10 × 10 6 M -1 ) and their pharmacokinetic implications are discussed accordingly. The negative enthalpy and entropy (ΔH 0  = -54.49 kJ/mol; ΔS 0  = -58.90 J K -1 mol -1 ) determined for the binding process suggests the implication of hydrogen bonds and van der Waals interactions in the formation of the HSA-volasertib complex. Additionally, volasertib is encapsulated in an alginate/montmorillonite bionanocomposite as a proof of concept for an oral delivery nanocarrier. The physical properties of that nanocomposite as well as volasertib delivery kinetics are analyzed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Andres Garzon Ruiz reports financial support was provided by Universidad de Castilla-La Mancha. Ivan Bravo reports financial support was provided by Junta de Comunidades de Castilla-La Mancha. Andres Garzon Ruiz reports financial support was provided by Spain Ministry of Science and Innovation. Margarita Darder reports financial support was provided by Spain Ministry of Science and Innovation. Pedro J. Pacheco Linan reports financial support was provided by Junta de Comunidades de Castilla-La Mancha. Diego Herrera reports financial support was provided by University of Castilla-La Mancha. If there are other authors, they 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recurrent urinary tract infections (rUTIs) are common and can significantly impact a patient's quality of life. The mainstay of treatment is antibiotic-based, which contributes to the global problem of antibiotic resistance among urinary pathogens, so many alternative therapies have been explored. In this mini-review we evaluate evidence for intravesical agents that prevent rUTI, including antibiotic and nonantibiotic options. The current evidence supports the use of intravesical agents that replenish the glycosaminoglycan layer and of aminoglycoside antibiotics as safe and effective therapies to prevent rUTI. PATIENT SUMMARY: We reviewed evidence on the use of bladder instillations to treat repeated urinary infections. Studies have shown that agents that improve the bladder surface and one specific antibiotic class are effective and safe treatments for prevention of recurrent infections., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t 1/2 ) (univariate p -value ( p uv ) = 0.018) and incidence of adverse reactions (ADRs) ( p uv = 0.008, multivariate p ( p mv ) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t 1/2 than the T/T genotype ( p uv = 0.002, p mv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype ( p uv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased ( p uv = 0.007, p mv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics.

The development of new fluorescent probes as molecular sensors is a critical step for the understanding of molecular mechanisms. BODIPY-based probes offer versatility due to their high fluorescence quantum yields, photostability, and tunable absorption/emission wavelengths. Here, we report the synthesis and evaluation of a novel 7-azaindole-BODIPY derivative to probe hydrophobic proteins as well as protein misfolding and aggregation. In organic solvents, this compound shows two efficiently interconverting emissive excited states. In aqueous environments, it forms molecular aggregates with unique photophysical properties. The complex photophysics of the 7-azaindole-BODIPY derivative was explored for sensing applications. In the presence of albumin, the compound is stabilized in hydrophobic protein regions, significantly increasing its fluorescence emission intensity and lifetime. Similar effects occur in the presence of protein aggregates but not with other macromolecules like pepsin, DNA, Ficoll 40, and coconut oil. Fluorescence lifetime imaging microscopy (FLIM) and two-photon fluorescence microscopy on breast (MCF-7) and lung (A549) cancer cells incubated with this compound display longer fluorescence lifetimes and higher emission intensity under oxidative stress. Synchrotron FTIR micro spectroscopy confirmed that the photophysical changes observed were due to protein misfolding and aggregation caused by the oxidative stress. These findings demonstrate that this compound can serve as a fluorescent probe to monitor protein misfolding and aggregation triggered by oxidative stress.

Introduction: The evidence basis for therapy selection in women who have failed primary stress urinary incontinence (SUI) surgery is limited. The ICI-RS group discussed the available data at its meeting in June 2023, particularly the anatomical characteristics as assessed using magnetic resonance imaging (MRI) and ultrasound (US) modalities, functional characteristics associated with storage and voiding urodynamic assessment, as well as the patient characteristics that might influence outcomes. This paper summarizes the evidence base that supported these discussions and offers the basis for research proposals for future groups., Methods: A literature search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was performed, and the data is presented. Research questions are based on the knowledge gaps highlighted., Results: Possible MRI parameters that may influence outcomes were striated urethral sphincter volume, bladder and proximal urethral funneling, pubo-urethral ligament integrity, distance of the bladder neck below the pubococcygeal line, posterior urethra-vesical angle, and bladder neck to levator ani distance. US parameters included sling distance to the urethral lumen and pubis, sling position, bladder neck mobility, and lateral arm asymmetry, twisting, or curling. Urodynamic parameters included detrusor overactivity, Valsalva leak point pressure, maximum urethral closure pressure, and bladder outlet obstruction. Important patient parameters included body mass index, age, and previous interventions., Conclusions: Identifying and quantifying causative factors in patients with recurrent SUI, that allow clinicians to modify subsequent treatment choices and techniques may help reduce treatment failure and complications. Formulating algorithms is the next step in optimizing patient counseling, surgical selection, and healthcare allocation., (© 2023 Wiley Periodicals LLC.)

Introduction: A "Think Tank" at the International Consultation on Incontinence-Research Society meeting held in Bristol, United Kingdom in June 2023 considered the progress and promise of machine learning (ML) applied to urodynamic data., Methods: Examples of the use of ML applied to data from uroflowmetry, pressure flow studies and imaging were presented. The advantages and limitations of ML were considered. Recommendations made during the subsequent debate for research studies were recorded., Results: ML analysis holds great promise for the kind of data generated in urodynamic studies. To date, ML techniques have not yet achieved sufficient accuracy for routine diagnostic application. Potential approaches that can improve the use of ML were agreed and research questions were proposed., Conclusions: ML is well suited to the analysis of urodynamic data, but results to date have not achieved clinical utility. It is considered likely that further research can improve the analysis of the large, multifactorial data sets generated by urodynamic clinics, and improve to some extent data pattern recognition that is currently subject to observer error and artefactual noise., (© 2023 Wiley Periodicals LLC.)

The Peruvian Province, from 6° S in Peru to 42° S in Chile, is a highly productive coastal marine region whose biology and fossil record have long been studied separately but never integrated. To understand how past events and conditions affected today's species composition and interactions, we examined the role of extinction, colonization, geologic changes to explain previously unrecognized peculiar features of the biota and to compare the Peruvian Province's history to that of other climatically similar temperate coasts. We synthesized all available data on the benthic (or benthically feeding) biota, with emphasis on fossilizable taxa, for the interval from the Miocene (23-5.4 Ma) and Pliocene (5.4-2.5 Ma) to the present. We outline the history of ecological guilds including primary producers, herbivores, predators, and suspension-feeders and document patterns of extinction, colonization, and geographic restriction. We identify twelve unusual attributes of the biota, most of which are the result of repeated episodes of extinction. Several guilds present during the Miocene and Pliocene are not represented in the province today, while groups such as kelps and perhaps intertidal predatory sea stars are relative newcomers. Guilds on soft bottoms and in sheltered habitats were severely affected by extinction, whereas those on hard bottoms were most affected by colonists and held their own in diversity. The Peruvian Province has not served as a biogeographic refuge, in contrast to the coasts of Australasia and Argentina, where lineages no longer present in the Peruvian Province survive. The loss of sheltered habitats since the Pliocene explains many of the present-day peculiarities of the biota. The history of the province's biota explains its unique attributes. High productivity, a rich Southern Hemisphere heritage, and colonization from the north account for the present-day composition and unusual characteristics of the biota., Competing Interests: None of the authors have competing interests., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

One of the four cutinases encoded in the Aspergillus nidulans genome, ANCUT1, is described here. Culture conditions were evaluated, and it was found that this enzyme is produced only when cutin is present in the culture medium, unlike the previously described ANCUT2, with which it shares 62% amino acid identity. The differences between them include the fact that ANCUT1 is a smaller enzyme, with experimental molecular weight and pI values of 22 kDa and 6, respectively. It shows maximum activity at pH 9 and 60 °C under assayed conditions and retains more than 60% of activity after incubation for 1 h at 60 °C in a wide range of pH values (6-10) after incubations of 1 or 3 h. It has a higher activity towards medium-chain esters and can modify long-chain length hydroxylated fatty acids constituting cutin. Its substrate specificity properties allow the lipophilization of alkyl coumarates, valuable antioxidants and its thermoalkaline behavior, which competes favorably with other fungal cutinases, suggests it may be useful in many more applications., (© 2024. The Author(s).)

Introduction: Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant. GS is a benign genetic disorder characterized by elevated bilirubin levels, the primary cause of which is the presence of polymorphisms in UGT1A1 gene. In this work, subjects with UGT1A1 intermediate (IM) or poor (PM) metabolizer genotype-informed phenotypes were investigated to determine whether they have a higher incidence of liver disease or other biochemical parameters. Methods: The study population comprised 773 healthy volunteers who underwent biochemical analysis at baseline and at the end of the study which were genotyped for UGT1A1*80 (rs887829), as an indicator of UGT1A1*80+*28 (rs887829 and rs3064744), and UGT1A1*6 (rs4148323). Results: Bilirubin levels were higher in subjects IMs and PMs compared to normal metabolizers (NMs). Decreased uric acid levels was observed in PMs compared to NMs. No associations were observed in liver enzyme levels according to UGT1A1 phenotype. Discussion: Considering that there is no hepatic toxicity in subjects with UGT1A1 IM or PM phenotype, who are more likely to develop GS, this study suggests that they could be included in bioequivalence clinical trials as their biochemical parameters are not affected outside normal ranges., Competing Interests: FA-S and DO have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Aptatargets, Chemo, Cinfa, FAES, Farmal’ der, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Moderna, MSD, Normon, Novartis, Servier, Silver Pharma, Teva, and Zambon. The remaining 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 handling editor JA declared a past co-authorship with the author FA-S., (Copyright © 2024 González-Iglesias, Ochoa, Román, Soria-Chacartegui, Martín-Vilchez, Navares-Gómez, De Miguel, Zubiaur, Rodríguez-Lopez, Abad-Santos and Novalbos.)

Cancer survival is becoming more common which means that there is now a growing population of cancer survivors, in whom pain may be common. However, its prevalence has hardly been addressed systematically. We aimed to assess the prevalence and explore the pathophysiology and impact of pain on health outcomes in cancer survivors. We conducted a retrospective-prospective cohort study in cancer-free patients diagnosed with cancer at least five years before the study start date. We used multivariable regression to establish the association of patients' cancer characteristics with pain, and then the association of patients' pain features with health outcomes and related symptoms. Between March and July 2021, 278 long-term cancer survivors were evaluated. Almost half of them (130/278, 46.8%) had pain, of whom 58.9% had a probable neuropathic component, but only 18 (13.8%) were taking specific drugs for neuropathic pain. A history of surgery-related pain syndrome in breast cancer patients was more than twice as frequent in the pain cohort. Post-chemotherapy and post-radiotherapy pain syndromes were uncommon. Pain was associated with lower QoL, emotional functioning, professional performance, and disability scores. Pain is a frequent health determinant in cancer survivors. Referral to specialised pain services may be a reasonable move in some cases.

Several dolphin lineages have independently invaded freshwater systems. Among these, the evolution of the South Asian river dolphin Platanista and its relatives (Platanistidae) remains virtually unknown as fossils are scarce. Here, we describe Pebanista yacuruna gen. et sp. nov., a dolphin from the Miocene proto-Amazonia of Peru, recovered in phylogenies as the closest relative of Platanista . Morphological characters such as an elongated rostrum and large supraorbital crests, along with ecological interpretations, indicate that this odontocete was fully adapted to fresh waters. Pebanista constitutes the largest freshwater odontocete known, with an estimated body length of 3 meters, highlighting the ample resource availability and biotic diversity in the region, during the Early to Middle Miocene. The finding of Pebanista in proto-Amazonian layers attests that platanistids ventured into freshwater ecosystems not only in South Asia but also in South America, before the modern Amazon River dolphin, during a crucial moment for the Amazonian evolution.

Objective: The objective of this study is to describe a standardised technique of full TOT removal with groin dissection and to report clinical improvement, satisfaction, safety and long-term functional, quality of life (QoL) and sexual QoL outcomes., Materials and Methods: A retrospective review enrolling all women who had full TOT removal, in a tertiary referral centre from May 2017 to November 2020. Functional outcomes, satisfaction and QoL were assessed using a bespoke composite questionnaire (UDI-6, EQ-5D-5L and ICIQ-S) with additional questions on sexual QoL. Secondary outcomes were post-operative recurrent stress urinary incontinence (SUI) and complication rate according to the Clavien-Dindo classification., Results: Full TOT removal using a vaginal approach and bilateral groin/para-labial incisions was performed in 67 patients. Chronic pelvic pain was the main indication for mesh removal (51% of cases, n  = 34). QoL questionnaires were answered by 43 patients. The satisfaction rate was high 86% ( n  = 37), and 81% ( n  = 35) of the patients considered the surgery successful. Seventy per cent ( n  = 30) of patients returned to having a sexual life after surgery. Recurrent SUI was reported in 32% ( n  = 14) of cases. The complication rate was 10% (7/67), all of them Clavien-Dindo ≤2., Conclusion: Despite a high rate of postoperative bothersome SUI, full TOT removal with bilateral groin dissection improves pain and QoL. It is associated with a high overall satisfaction rate and an acceptable rate of complications., Competing Interests: The authors declare that they have NO affiliations with or involvement in any organisation or entity with any financial interest in the subject matter or materials discussed in this manuscript., (© 2024 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

The European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI) is one of the world's leading sources of public biomolecular data. Based at the Wellcome Genome Campus in Hinxton, UK, EMBL-EBI is one of six sites of the European Molecular Biology Laboratory (EMBL), Europe's only intergovernmental life sciences organisation. This overview summarises the latest developments in the services provided by EMBL-EBI data resources to scientific communities globally. These developments aim to ensure EMBL-EBI resources meet the current and future needs of these scientific communities, accelerating the impact of open biological data for all., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Causality algorithms help establish relationships between drug use and adverse event (AE) occurrence. High drug exposure leads to a higher likelihood of an AE being classified as an adverse drug reaction (ADR). However, there is a knowledge gap regarding what concentrations are predictive of ADRs, as this has not been systematically studied. In this work, the Spanish Pharmacovigilance System (SEFV) algorithm was used to define the relationship between the AE occurrence and drug administration in 178 healthy volunteers participating in five desvenlafaxine single-dose clinical trials, a selective serotonin and norepinephrine reuptake inhibitor that may cause dizziness, headache, nausea, dry mouth, constipation and hyperhidrosis. Eighty-three subjects presented 172 AEs that were classified as possible (101), conditional (31), unrelated (24) and probable (16). AUC ∞ and C max were significantly higher in volunteers with vs. without ADRs (5981.24 ng·h/mL and 239.06 ng/mL and 4770.84 ng·h/mL and 200.69 ng/mL, respectively). Six of 19 subjects with conditional AEs with an SEFV score of 3 points presented an AUC ∞ ≥ 6500 ng·h/mL or a C max ≥ 300 ng/mL (i.e., above percentile 75) and were summed one point on their SEFV score and classified as "possible" (4 points), improving the capacity of ADR detection.

Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized β coefficients = 0.386 and 0.346, R 2  = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized β coefficient = 0.224, R 2  = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Flexible and wearable biosensors are the next-generation healthcare devices that can efficiently monitor human health conditions in day-to-day life. Moreover, the rapid growth and technological advancements in wearable optoelectronics have promoted the development of flexible organic photoplethysmography (PPG) biosensor systems that can be implanted directly onto the human body without any additional interface for efficient bio-signal monitoring. As an example, the pulse oximeter utilizes PPG signals to monitor the oxygen saturation (SpO 2 ) in the blood volume using two distinct wavelengths with organic light emitting diode (OLED) as light source and an organic photodiode (OPD) as light sensor. Utilizing the flexible and soft properties of organic semiconductors, pulse oximeter can be both flexible and conformal when fabricated on thin polymeric substrates. It can also provide highly efficient human-machine interface systems that can allow for long-time biological integration and flawless measurement of signal data. In this work, a clear and systematic overview of the latest progress and updates in flexible and wearable all-organic pulse oximetry sensors for SpO 2 monitoring, including design and geometry, processing techniques and materials, encapsulation and various factors affecting the device performance, and limitations are provided. Finally, some of the research challenges and future opportunities in the field are mentioned., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and transport of tadalafil or finasteride (i.e., pharmacogenes) could affect their pharmacokinetic processes altering their drug exposure, efficacy, and toxicity. The main objective of this study was to investigate the effects of variants in pharmacogenes on the pharmacokinetics of tadalafil and finasteride. An exploratory candidate gene study involving 120 variants in 33 genes was performed with 66 male healthy volunteers from two bioequivalence clinical trials after administration of tadalafil/finasteride 5 mg/5 mg under fed or fasting conditions. Afterwards, a confirmatory study was conducted with 189 male and female volunteers receiving tadalafil 20 mg formulations in seven additional bioequivalence clinical trials. Regarding tadalafil, fed volunteers showed higher area in the time-concentration curve (AUC ∞ ), maximum plasma concentration (C max ), and time to reach C max (t max ) compared to fasting volunteers; male volunteers also showed higher AUC ∞ and C max compared to female volunteers. Furthermore, fed volunteers presented higher finasteride AUC ∞ , C max and t max compared to fasting individuals. Variants in ABCC3 , CYP1A2 , CES1 , NUDT15 , SLC22A1/A2 and UGT2B10 were nominally associated with pharmacokinetic variation in tadalafil and/or finasteride but did not remain significant after correction for multiple comparisons. Genetic variation did not demonstrate to clinically impact on the pharmacokinetics of finasteride and tadalafil; however, additional studies with larger sample sizes are needed to assess the effect of rare variants, such as CYP3A4*20 or *22 , on tadalafil and finasteride pharmacokinetics.

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters' genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (C max ) and time to reach it (t max ), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan t max compared to those with T/G and G/G genotypes ( p < 0.001, β = 0.821, R 2 = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC ∞ /DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers ( p = 0.050, β = 1047.35, R 2 = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

AIEgens have emerged as a promising alternative to molecular rotors in bioimaging applications. However, transferring the concept of aggregation-induced emission (AIE) from solution to living systems remains a challenge. Given the highly heterogeneous nature and the compartmentalization of the cell, different approaches are needed to control the self-assembly within the crowded intricate cellular environment. Herein, we report for the first time the self-assembly mechanism of an anthracene-guanidine derivative (AG) forming the rare and highly emissive T-shaped dimer in breast cancer cell lines as a proof of concept. This process is highly sensitive to the local environment in terms of polarity, viscosity, and/or water quantity that should enable the use of the AG as a fluorescence lifetime imaging biosensor for intracellular imaging of cellular structures and the monitoring of intracellular state parameters. Different populations of the monomer and T-shaped and π-π dimers were observed in the cell membrane, cytoplasm, and nucleoplasm, related to the local viscosity and presence of water. The T-shaped dimer is formed preferentially in the nucleus because of the higher density and viscosity compared to the cytoplasm. The present results should serve as a precursor for the development of new design strategies for molecular systems for a wide range of applications such as cell viscosity, density, or temperature sensing and imaging.

Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application., (© 2023. Springer Nature Limited.)

Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised 60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2) and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under fasting conditions presented lower t max (2.21 h vs 2.88 h, β = 1.19, R 2 =0.342, p = 0.012) compared to fed volunteers. NAT2 slow acetylators presented higher AUC ∞ corrected by dose/weight (AUC ∞ /DW; 8243.90 vs 7698.20 and 7161.25 h*ng*mg /ml*kg, β = 0.154, R 2 =0.250, p = 0.044), higher C max /DW (1070.99 vs 834.81 and 803.36 ng*mg /ml*kg, β = 0.245, R 2 =0.320, p = 0.002), and lower t max (2.63 vs 3.19 and 4.15 h, β = -0.346, R 2 =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC ∞ and C max . Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban pharmacokinetics and to determine its clinical significance., Competing Interests: Declaration of Competing Interest Francisco Abad-Santos and Dolores Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmal’der, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To evaluate levels of burnout and correlates of burnout among US rheumatology fellows., Methods: US rheumatology fellows were invited to complete an electronic survey in 2019. Burnout was assessed using the Maslach Burnout Inventory. Measures of depression, fatigue, quality of life, and training year were also collected. Open-ended questions about perceived factors to promote resiliency and factors leading to increased burnout were included. Bivariate and multivariate regression analyses were used to examine correlates of burnout. Open-ended responses were analyzed using thematic analysis., Results: The response rate was 18% (105/582 pediatric and adult rheumatology fellows). Over one-third (38.5%) of postgraduate year (PGY) 4 and 16.7% of PGY5/6 fellows reported at least 1 symptom of burnout. Of PGY4 fellows, 12.8% met criteria for depression compared with 2.4% of PGY5/6 fellows. PGY4 fellows reported worse fatigue and poorer quality of life compared with PGY5/6. In multivariable models controlling for training year and gender, older age (> 31 years) was associated with lower odds of burnout. Thematic analysis of open-ended responses identified factors that help reduce burnout: exercise, family/friends, sleep, support at work, and hobbies. Factors contributing to burnout: pager, documentation, long hours, demands of patient care, and presentations and expectations., Conclusion: This national survey of US rheumatology fellows reveals that early trainee level and younger age are associated with worse levels of fatigue, quality of life, and burnout. Although awareness of and strategies to reduce burnout are needed for all fellows, targeted interventions for younger fellows and those in their first year of training may be of highest yield., (Copyright © 2023 by the Journal of Rheumatology.)

Adeno-associated virus (AAV)-mediated gene therapy has great potential for treating a wide range of retinal degenerative diseases. However, some initial enthusiasm for gene therapy has been tempered by emerging evidence of AAV-associated inflammation, which in several instances has contributed to clinical trial discontinuation. Currently, there is a paucity of data describing the variable immune responses to different AAV serotypes, and similarly, little is known regarding how these responses differ depending on route of ocular delivery, including in animal models of disease. In this study, we characterize the severity and retinal distribution of AAV-associated inflammation in rats triggered by delivery of five different AAV vectors (AAV1, AAV2, AAV6, AAV8, and AAV9), each of which contained enhanced green fluorescent protein (eGFP) driven under control of the constitutively active cytomegalovirus promoter. We further compare the inflammation across three different potential routes (intravitreal, subretinal, and suprachoroidal) of ocular delivery. Compared to buffer-injected controls for each route of delivery, AAV2 and AAV6 induced the most inflammation across all routes of delivery of vectors tested, with AAV6 inducing the highest levels of inflammation when delivered suprachoroidally. AAV1-induced inflammation was highest when delivered suprachoroidally, whereas minimal inflammation was seen with intravitreal delivery. In addition, AAV1, AAV2, and AAV6 each induce infiltration of adaptive immune cells like T cells and B cells into the neural retina, suggesting an innate adaptive response to a single dose of virus. AAV8 and AAV9 induced minimal inflammation across all routes of delivery. Importantly, the degree of inflammation was not correlated with vector-mediated transduction and expression of eGFP. These data emphasize the importance of considering ocular inflammation when selecting AAV serotypes and ocular delivery routes for the development of gene therapy strategies.

In humans, mutations in the beta subunit of cGMP-phosphodiesterase type 6 (PDE6B) cause autosomal recessive retinitis pigmentosa (RP), which typically has an aggressive clinical course of early-onset severe vision loss due to rapid photoreceptor degeneration. In this study, we describe the generation of a novel Pde6b-deficient rat model using CRISPR-Cas9 genome editing. We characterize the model at multiple time points using clinical imaging modalities as well as histology with immunohistochemistry to show rapid photoreceptor degeneration compared to wild-type and heterozygous animals. We describe the manufacture of two different adeno-associated viral (AAV) vectors (AAV2/1, AAV2/5) under current Good Manufacturing Practices (cGMP) and demonstrate their ability to drive human PDE6B expression in vivo. We further demonstrate the ability of AAV-mediated subretinal gene therapy to delay photoreceptor loss in Pde6b-deficient rats compared to untreated controls. However, severe progressive photoreceptor loss was noted even in treated eyes, likely due to the aggressive nature of the disease. These data provide useful preclinical data to guide the development of potential human gene therapy for PDE6B-associated RP. In addition, the rapid photoreceptor degeneration of the Pde6b-deficient rat with intact inner retina may provide a useful model for the study of cell replacement strategies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4 , influenced AUC. The maximum concentration was affected by age and SLC22A1 , but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2 , and SLC22A4 . The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3 . The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3 . Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1 , SLC2A2 , SLC22A2 , or SLC47A1 . Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization.

Interacting proteins tend to have similar functions, influencing the same organismal traits. Interaction networks can be used to expand the list of candidate trait-associated genes from genome-wide association studies. Here, we performed network-based expansion of trait-associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share an underlying genetic and biological process. We identified 73 pleiotropic gene modules linked to multiple traits, enriched in genes involved in processes such as protein ubiquitination and RNA processing. In contrast to gene deletion studies, pleiotropy as defined here captures specifically multicellular-related processes. We show examples of modules linked to human diseases enriched in genes with known pathogenic variants that can be used to map targets of approved drugs for repurposing. Finally, we illustrate the use of network expansion scores to study genes at inflammatory bowel disease genome-wide association study loci, and implicate inflammatory bowel disease-relevant genes with strong functional and genetic support., (© 2023. The Author(s).)

Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6 , CYP3A4 , or CYP2C19 ; ABC transporters like ABCB1 ; SLCO1B1 ; and UGT enzymes like UGT1A1 ) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials ( n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent., Competing Interests: FA-S, DO , and MR have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Aptatargets, Chemo, FAES, Farmalider, Ferrer, Galenicum, GlaxoSmithKline, Gilead, Italfarmaco, Janssen-Cilag, Kern, Normon, Novartis, Servier, Teva, and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Calleja, Zubiaur, Ochoa, Villapalos-García, Mejia-Abril, Soria-Chacartegui, Navares-Gómez, de Miguel, Román, Martín-Vílchez and Abad-Santos.)

Objectives: The use of off-label pharmacotherapies for neuropathic pain (NP) is growing relating to the many unmet needs of patients. However, clinical guidelines fail to address it, and the available evidence is sparse and fragmented. We arranged a formal expert consensus to address this controversial issue and provide some guidance on judicious use., Methods: A two-round standard Delphi survey that involved pain clinic specialists with experience in the research and management of NP was done over an ad hoc 40-item questionnaire prepared by the authors. Consensus on each statement was defined as at least either 80% endorsement or rejection after the second round., Results: Forty-three and thirty-seven panelists participated in the first and second round, respectively. Consensus was reached in 34 out of 40 statements. Endorsed alternatives for unresponsive patients include non-gabapentinoid antiepileptics (oxcarbazepine and eslicarbazepine), venlafaxine, intravenous lidocaine (when doses can be optimized), and some vaporized cannabinoids (under appropriate surveillance). In addition, lacosamide, low-dose naltrexone, propofol, or ketamine could prove beneficial if subjected to more research. Other options were rejected, and there was controversy about the usefulness of topical preparations., Discussion: For patients who do not respond to standard NP treatments, some other viable pharmacological options can be attempted before advancing to other therapeutic stages. This may help patients who are reluctant to or have some contraindication for interventional therapies., (© 2022 World Institute of Pain.)

(1) Background: this article investigates which PK metrics in a single-dose study (concentration at the end of posology interval, C τ , partial areas under the curve, pAUCs, or half-value duration, HVD) are more sensitive and less variable for predicting the failure of a prolonged-release product at steady-state that was the bioequivalent for C max , AUC 0-t and AUC 0-inf , in the single-dose study; (2) Methods: a cross-over study was performed in 36 subjects receiving desvenlafaxine 100 mg prolonged-release tablets. Conventional (C max , AUC 0-t and AUC 0-inf ) and additional (C τ , pAUCs and HVD) PK metrics were considered after single-dose conditions. Predicted PK metrics at steady state (AUC 0-τ , C max,ss , and C τ,ss ) were derived using a population PK model approach; (3) Results: the existing differences in the shape of the concentration-time curves precluded to show equivalence for C τ,ss in the simulated study at steady state. This failure to show equivalence at steady state was predicted by C τ , pAUCs and HVD in the single-dose study. C τ was the most sensitive metric for detecting the different shape, with a lower intra-subject variability than HVD; (4) Conclusions: conventional PK metrics for single-dose studies (C max , AUC 0-t and AUC 0-inf ) are not enough to guarantee bioequivalence at steady state for prolonged-release products.

Amlodipine is an antihypertensive drug with unknown pharmacogenetic biomarkers. This research is a candidate gene study that looked for associations between amlodipine pharmacokinetics and safety and pharmacogenes. Pharmacokinetic and safety data were taken from 160 volunteers from eight bioequivalence trials. In the exploratory step, 70 volunteers were genotyped for 44 polymorphisms in different pharmacogenes. CYP2D6 poor metabolizers (PMs) showed higher half-life (t 1/2 ) (univariate p -value ( p uv ) = 0.039, multivariate p -value ( p mv ) = 0.013, β = -5.31, R 2 = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). SLC22A1 rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC 72 /DW) ( p uv = 0.025; p mv = 0.026, β = 578.90, R 2 = 0.060) compared to the G/G genotype. In the confirmatory step, the cohort was increased to 160 volunteers, who were genotyped for CYP2D6 , SLC22A1 and CYP3A4 . In addition to the previous associations, CYP2D6 UMs showed a lower AUC 72 /DW ( p uv = 0.046, p mv = 0.049, β = -68.80, R 2 = 0.073) compared to NMs, IMs and PMs and the SLC22A1 rs34059508 G/A genotype was associated with thoracic pain ( p uv = 0.038) and dizziness ( p uv = 0.038, p mv = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and CYP2D6 and SLC22A1 . Further research is needed to gather more evidence before its application in clinical practice.

The Open Targets Platform (https://platform.opentargets.org/) is an open source resource to systematically assist drug target identification and prioritisation using publicly available data. Since our last update, we have reimagined, redesigned, and rebuilt the Platform in order to streamline data integration and harmonisation, expand the ways in which users can explore the data, and improve the user experience. The gene-disease causal evidence has been enhanced and expanded to better capture disease causality across rare, common, and somatic diseases. For target and drug annotations, we have incorporated new features that help assess target safety and tractability, including genetic constraint, PROTACtability assessments, and AlphaFold structure predictions. We have also introduced new machine learning applications for knowledge extraction from the published literature, clinical trial information, and drug labels. The new technologies and frameworks introduced since the last update will ease the introduction of new features and the creation of separate instances of the Platform adapted to user requirements. Our new Community forum, expanded training materials, and outreach programme support our users in a range of use cases., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Developmental defects of enamel (DDEs) are widely observed in children and are related to the appearance of dental caries, malocclusion, tooth sensitivity, and unfavorable esthetic conditions. The objective of this cross-sectional study was to determine the prevalence and distribution of enamel defects present in children aged 6 to 12 years in the provinces located in southern Ecuador. A total of 1606 schoolchildren were examined under the World Health Organization criteria for diagnosis of DDEs. The results are presented using percentage frequency measures and chi-square associations. Some types of DDEs were presented by 50% of the schoolchildren, mainly diffuse opacity, with no statistical differences according to place of residence and/or environment, sex, and age (p > 0.05). In Ecuador, it is necessary to carry out studies on the factors that trigger enamel defects, since they may be associated with the high prevalence of caries already reported in other studies in the country.

A theoretical study of cell evolution is presented here. By using a toolbox containing an intracellular catalytic reaction network model and a mutation-selection process, four distinct phases of self-organization were unveiled. First, the nutrients prevail as the central substrate of the chemical reactions. Second, the cell becomes a small-world. Third, a highly connected core component emerges, concurrently with the nutrient carriers becoming the central product of reactions. Finally, the cell reaches a steady configuration where the concentrations of the core chemical species are described by Zipf's law., 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 © 2022 Elsevier Ltd. All rights reserved.)

Cinitapride is a gastrointestinal prokinetic drug, prescribed for the treatment of functional dyspepsia, and as an adjuvant therapy for gastroesophageal reflux disease. In this study, we aimed to explore the impact of relevant variants in CYP3A4 and CYP2C8 and other pharmacogenes, along with demographic characteristics, on cinitapride pharmacokinetics and safety; and to evaluate the impact of CYP2C8 alleles on the enzyme's function. Twenty-five healthy volunteers participating in a bioequivalence clinical trial consented to participate in the study. Participants were genotyped for 56 variants in 19 genes, including cytochrome P450 (CYP) enzymes (e.g., CYP2C8 or CYP3A4) or transporters (e.g., SLC or ABC), among others. CYP2C8*3 carriers showed a reduction in AUC of 42% and C max of 35% compared to *1/*1 subjects (p = 0.003 and p = 0.011, respectively). *4 allele carriers showed a 45% increase in AUC and 63% in C max compared to *1/*1 subjects, although these differences did not reach statistical significance. CYP2C8*3 and *4 alleles may be used to infer the following pharmacogenetic phenotypes: ultrarapid (UM) (*3/*3), rapid (RM) (*1/*3), normal (NM) (*1/*1), intermediate (IM) (*1/*4), and poor (PM) metabolizers (*4/*4). In this study, we properly characterized RMs, NMs, and IMs; however, additional studies are required to properly characterize UMs and PMs. These findings should be relevant with respect to cinitapride, but also to numerous CYP2C8 substrates such as imatinib, loperamide, montelukast, ibuprofen, paclitaxel, pioglitazone, repaglinide, or rosiglitazone., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)