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Ricardo Machado Soares,&ast; Catarina Cunha Ferreira,&ast; Joana da Silva Fernandes, Carolina Madeira, Luís MA Silva, Eduardo Saraiva, Lígia Ribeiro, Sofia Fonseca Department of Ophthalmology - Centro Hospitalar Vila Nova de Gaia e Espinho, Porto, Portugal&ast;These authors contributed equally to this workCorrespondence: Ricardo Machado Soares, Department of Ophthalmology, Centro Hospitalar Vila Nova de Gaia e Espinho, EPE, Rua Conceição Fernandes, S/N, 4434-502, Vila Nova de Gaia, Porto, Portugal, Tel +351 915045174, Email ricardo.machado.soares@chvng.min-saude.ptPurpose: To report the long-term functional, anatomical and safety outcomes of 0.2 μg/day fluocinolone acetonide 0.19mg in patients with persistent or recurrent diabetic macular edema (DME).Methods: Retrospective, observational, single-center study of patients with recurrent or persistent DME. All patients received 0.2 μg/day of fluocinolone acetonide 0.19mg, and data were collected at baseline and months 1, 3, 6, 12, 24 and 36 after implantation. Outcomes measured included best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP), and safety outcomes.Results: A total of 28 eyes from 28 patients were included. The mean age was 66.5 years (95% CI 62.8– 70.2) with a mean duration of DME of 8.8 years (95% CI 7.7– 10.0). Only two eyes were phakic. Mean follow-up was 25.4 months (95% CI 21.2– 29.6). Mean BCVA at baseline was 48.6 ETDRS letters (95% CI 41.3– 55.8) and improved as early as month 1 of follow-up with a mean gain in BCVA of 7.8 (95% CI 4.3– 11.3) ETDRS letters (p< 0.001). Statistically significant improvements in BCVA were also observed at months 6, 12 and 24. At baseline, patients had a mean CMT of 530.5μm (95% CI 463.0– 598.0), and a decrease in CMT was observed, starting at the first month of follow-up (mean CMT reduction of − 170.5μm, 95% CI − 223.8– − 117.1; p< 0.001). Statistically significant decreases in CMT were also observed at months 6, 12, 24, and 36, with the maximum decrease observed at month 12 (p< 0.001). Mean IOP at baseline was 16.4mmHg (95% CI 15.3– 17.5) and nine eyes (32.1%) had an IOP ≥ 21mmHg during follow-up.Conclusion: Our results support the effectiveness and safety profile of fluocinolone acetonide. Although additional long-term real-world evidence is required, fluocinolone acetonide may represent a safe strategy for daily, low-dose, sustained and localized release to the posterior segment of the eye, providing both functional and anatomical benefits in DME.Keywords: diabetic macular edema, intravitreal implant, best corrected visual acuity, intravitreal corticosteroid, sub-optimal response

Margarida Vale,1 Francisca Leite,2,3 Catarina Madeira1,2,4 1NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal; 2Associação CoLAB TRIALS, Évora, Portugal; 3Hospital da Luz Learning Health, Lisboa, Portugal; 4CHRC, NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, PortugalCorrespondence: Catarina Madeira, CoLAB TRIALS, Largo do Senhor da Pobreza, Escola Superior de Enfermagem São João de, Deus, Évora, 7000-811, Portugal, Tel +351 91 4006726, Email catarina.madeira@colabtrials.ptPurpose: Over the last years, in response to the increasing complexity and demand of clinical trials, there has been a growing concern with the application of efficient risk management methodologies. The main objective of this work is to assess the current level of implementation of risk management activities by clinical trials sites’ teams and identify points of improvement.Methods: A cross-sectional study was conducted through an original, non-validated questionnaire created to assess the risk management practices at Portuguese clinical trial sites. The web-based survey was sent by e-mail to the clinical trial sites identified, and it was available for one month. Descriptive statistics were used to summarize the findings.Results: In total, 46 clinical trial sites accepted to participate in this study. The surveys’ answers showed that although 57.0% of sites reported the use of a systematic risk management tool, only nine sites (19.6%) described a standard tool or document that captured systematically the analysis of risks at the site level. Most of the sites (87.0%) showed willing to use a risk management tool specifically tailored for their operational needs, with the lack of knowledge about risk management being the main reason against its implementation.Conclusion: This work indicates that the surveyed clinical trial sites generally recognize the importance of risk management methodologies as an opportunity to anticipate difficulties in the trial conduct and optimize the use of sites’ resources. However, mainly due to lack of experience with risk management methodologies, sites are not currently implementing these strategies in the management of their trial-related operations. The development of a risk management tool for sites can be useful in this context.Keywords: clinical research, operational risks, planning, trial feasibility, healthcare, risk assessment tool

Ana Filipa Moleiro,1,2 Gonçalo Godinho,3 Carolina Madeira,4 Ana Faria Pereira,1 Elisete Brandão,1 Fernando Falcão-Reis,1,2 João Nuno Beato,1,2 Susana Penas1,2 1Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Porto, Portugal; 2Department of Surgery and Physiology, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; 3Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal; 4Department of Ophthalmology, Centro Hospitalar Gaia-Espinho, Gaia, PortugalCorrespondence: Ana Filipa Moleiro, Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Alameda Hernani Monteiro, Porto, 4200-426, Portugal, Tel +351 915689259, Email anafomoleiro@gmail.comPurpose: This work aimed to longitudinally assess the peripapillary (PPCT) and subfoveal (SFCT) choroidal thickness (CT), in patients diagnosed with central (CRVO) or branch retinal vein occlusions (BRVO), correlating SFCT with central macular thickness (CMT) and PPCT with peripapillary retinal nerve fiber layer thickness (pRNFL).Patients and Methods: This was a retrospective longitudinal study of 71 eyes from 71 patients with treatment-naïve retinal vein occlusion (24 CRVO and 40 BRVO). Spectral-domain optical coherence tomography (SD-OCT, Spectralis HRA-OCT, Heidelberg) was used to measure PPCT, SFCT, pRNFL and CMT of the affected and fellow eyes at baseline (acute phase) and at 3 and 9 months post anti-VEGF treatment. IBM SPSS Statistics version 27.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. A p-value ≤ 0.05 was considered statistically significant.Results: Affected eyes presented a thicker baseline PPCT and SFCT compared to their fellow eyes both in CRVO and BRVO (p < 0.05). Both groups presented a significant decrease of PPCT in the affected eyes at 3 months compared to baseline (p < 0.05). At 9 months, compared to 3 months, PPCT remained stable (p > 0.05). Similarly, affected eyes’ SFCT significantly decreased at 3 months (p < 0.05) in both groups. At 9 months, compared to 3 months, SFCT decreased in the CRVO patients (p = 0.047) but remained stable in the BRVO patients (p = 0.850). No correIations between SFCT and CMT were seen at any timepoint in both groups (p > 0.05). PPCT correlates with pRNFL in CRVO at 3 months, although no other correlations were found during the follow-up. In BRVO, PPCT did not show any significant correlation with pRNFL.Conclusion: Both in CRVO and BRVO eyes, PPCT and SFCT at diagnosis are significantly thicker compared to the fellow eye, suggesting a possible increase in CT immediately after the occlusion, which is followed by a decrease at an early follow-up stage.Keywords: biomarkers, vascular retinal diseases, retinal vein occlusions, choroidal thickness, optical coherence tomography

Mário Lima-Fontes,1 Gonçalo Godinho,2 Ana Maria Cunha,1 Carolina Madeira,3 Manuel Falcão,1,4 Fernando Falcão-Reis,1,4 Ângela Carneiro1,4 1Department of Ophthalmology, Centro Hospitalar Universitário São João, Porto, Portugal; 2Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal; 3Department of Ophthalmology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal; 4Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, PortugalCorrespondence: Mário Lima-Fontes, Department of Ophthalmology, Centro Hospitalar Universitário São João, Alameda Professor Hernâni Monteiro, Porto, 4200-319, Portugal, Tel +351 918420563, Fax +351 225513669, Email marioruifontes@gmail.comPurpose: To describe a case of hypotony maculopathy following anti-VEGF intravitreal injection (IVI) in a patient with pseudoxanthoma elasticum (PE).Methods: Clinical case report.Results: A 52-year-old male complained of right eye (OD) vision loss 2 days after an uncomplicated anti-VEGF IVI for the treatment of choroidal neovascularization secondary to angioid streaks. Relevant medical history included PE, pathologic myopia, and a previous pars plana vitrectomy (PPV) due to a retinal detachment. OD best-corrected visual acuity (BCVA) dropped from 6/12 to 6/18 after the IVI. Intraocular pressure (IOP) was 3 mmHg and chorioretinal folds were evident in the posterior pole. Topical dexamethasone and atropine were prescribed, and full recovery was noticed after 3 days. Four months later, the patient developed a new episode of vision loss after another IVI. His BCVA was counting fingers, IOP was 2mmHg, and more noticeable chorioretinal folds were found. This time, an open scleral wound at the injection site was evident and a scleral suture was necessary. Once again, the patient recovered well.Conclusion: Hypotony maculopathy following intravitreal injection is a rare condition. However, the described patient presented several conditions which could be related with poor scleral wound closure: intrinsic scleral fragility due to myopia and pseudoxanthoma elasticum; repeated IVI procedures; and absence of vitreous in the posterior segment due to prior vitrectomy. Despite the good outcome, hypotony maculopathy may be a sight-threatening condition, and special attention is necessary for specific patients with risk factors.Keywords: hypotony maculopathy, intravitreal injection, anti-VEGF, pseudoxanthoma elasticum, angioid streaks

Ana Filipa Moleiro,1,2 Gonçalo Godinho,3 Carolina Madeira,4 Ana Faria Pereira,1 Elisete Brandão,1 Fernando Falcão-Reis,1,2 João Nuno Beato,1,2 Susana Penas1,2 1Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Porto, Portugal; 2Department of Surgery and Physiology, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; 3Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal; 4Department of Ophthalmology, Centro Hospitalar Gaia-Espinho, Gaia, PortugalCorrespondence: Ana Filipa Moleiro, Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Alameda Hernani Monteiro, Porto, 4200-426, Portugal, Tel +351 915689259, Email anafomoleiro@gmail.com

Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.

Carolina Madeira,1 Ana Vasques,2 João Beato,1 Gonçalo Godinho,1 Luís Torrão,1 Manuel Falcão,1,3 Fernando Falcão-Reis,1,3 João Pinheiro-Costa1,4 1Department of Ophthalmology, Centro Hospitalar de São João, Porto, Portugal; 2Faculty of Medicine, University of Porto, Porto, Portugal; 3Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal; 4Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal Purpose: To systematically compare the efficacy of transepithelial accelerated corneal collagen crosslinking (TE-ACXL) with conventional corneal collagen crosslinking (C-CXL) in patients with progressive keratoconus. Methods: Eyes of patients with progressive keratoconus who were treated with C-CXL (3 mW/cm2 for 30 minutes) were compared with those who underwent TE-ACXL (6 mW/cm2 for 15 minutes). Best-corrected visual acuity (BCVA), keratometry values, corneal thickness, and topometric indexes were compared before CXL, and at 2 months, 6 months, and 12 months postoperatively. Results: The study enrolled 26 eyes of which 16 had TE-ACXL and 10 had C-CXL. Both groups were comparable at baseline and 12 months in terms of BCVA (P=0.16 and P=0.57), Kmax (maximum keratometry) (P=0.31 and P=0.73), pachymetry (P=0.75 and P=0.37), index of surface variance (ISV) (P=0.45 and P=0.86), index of vertical asymmetry (IVA) (P=0.26 and P=0.61), and index of height decentration (IHD) (P=0.27 and P=0.86, respectively). We did not observe significant differences between preoperative and 12-month postoperative readings in within-group analysis: ΔKmax (TE-ACXL, -2.13±5.41, P=0.25 vs C-CXL, 0.78±1.65, P=0.17), Δpachymetry (TE-ACXL, 4.10±14.83, P=0.41 vs C-CXL, -8.90±22.09, P=0.24), ΔISV (TE-ACXL, -8.50±21.26, P=0.24 vs C-CXL, 3.80±12.43, P=0.36), ΔIVA (TE-ACXL, -0.12±0.31, P=0.26 vs C-CXL, 0.03±0.18, P=0.61), and ΔIHD (TE-ACXL, -0.03±0.07, P=0.18 vs C-CXL, -0.01±0.03, P=0.88). Conclusion: Both TE-ACXL and C-CXL were similarly effective. Further follow-up is required to determine whether these techniques are comparable in the long-term. Keywords: cornea, keratoconus, crosslinking, transepithelial, riboflavin, ultraviolet radiation, keratometry

The trace metal vanadium is important in many physiological effects. VIVO forms highly stable complexes with ligands containing O-donor atoms, although binding to N- or S-donor containing biogenic ligands in solution is weaker. The first VIVO complexes of dipeptides have recently been isolated containing a deprotonated peptide-N-group. The terminal -NH(sub2) group has been replaced by a hard phenolate, to make VIVO binding more favourable.

Stable isotope analysis has been applied to the investigation of movement in several species, including marine animals. However, its application to nekton living in open coastal areas is still very scarce. This study aims to test if stable isotope analysis can be used for this purpose over a much wider spatial scale than previously investigated. Stable isotope analysis was used to 1) investigate isotopic variation in shrimp and fish, in 11 sites, along a 160 km coastal stretch, to 2) determine the site fidelity of the individuals within each species, and to 3) test the relation between the body size of the individuals within each species, at each site and the percentage of isotopic deviants. Site fidelity was the highest for the intertidal fish Gobius paganellus and Coryphoblennius galerita , with 60% and 64% of individuals considered residents, respectively, and lowest for the demersal fish Diplodus vulgaris and Diplodus sargus with 23% and 33% of resident individuals, respectively. The percentage of isotopic deviants was not correlated with length in any species. Site fidelity was considerably higher than that previously found for other open coastal areas and similar to more structured environments, like coastal ponds. It was hypothesized that the complex tri-dimensional structure of the rocky reefs that occur in this area, often encompassing channels and tide pools, offers conditions favourable to high site fidelity. This study shows that stable isotopes can be used to infer nekton movement in wide open coastal areas. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) hold a great promise for application in several therapies due to their unique biological characteristics. In order to harness their full potential in cell-or gene-based therapies it might be advantageous to enhance some of their features through gene delivery strategies. Accordingly, we are interested in developing an efficient and safe methodology to genetically engineer human bone marrow MSC (BM MSC), enhancing their therapeutic efficacy in Regenerative Medicine. The plasmid DNA delivery was optimized using a cationic liposome-based reagent. Transfection efficiencies ranged from ∼2% to ∼35%, resulting from using a Lipid/DNA ratio of 1.25 with a transgene expression of 7 days. Importantly, the number of plasmid copies in different cell passages was quantified for the first time and ∼20,000 plasmid copies/cell were obtained independently of cell passage. As transfected MSC have shown high viabilities (>90%) and recoveries (>52%) whilemaintaining theirmultipotency, this might be an advantageous transfection strategy when the goal is to express a therapeutic gene in a safe and transient way. [ABSTRACT FROM AUTHOR]

Background: The long-term effect of recombinant human erythropoietin (rhEPO) on the blood-lipid profile has not been well documented. The aim of this study was to evaluate whether rhEPO therapy affects the lipid pattern. [ABSTRACT FROM PUBLISHER]

• Seasonal proteome variation in intertidal shrimps was analyzed in situ. • Shrimps were collected during spring and summer low tides. • Cytoskeleton, energy metabolism and transcription were modulated by season. • Inter-individual variation in protein levels was low. • Molecular plasticity is crucial to cope with environmental fluctuations. The ability of intertidal organisms to maintain their performance via molecular and physiological adjustments under low tide, seasonal fluctuations and extreme events ultimately determines population viability. Analyzing this capacity in the wild is extremely relevant since intertidal communities are under increased climate variability owing to global changes. We addressed the seasonal proteome signatures of a key intertidal species, the shrimp Palaemon elegans , in a natural setting. Shrimps were collected during spring and summer seasons at low tides and were euthanized in situ. Environmental variability was also assessed using hand-held devices and data loggers. Muscle samples were taken for 2D gel electrophoresis and protein identification through mass spectrometry. Proteome data revealed that 55 proteins (10.6% of the proteome) significantly changed between spring and summer collected shrimps, 24 of which were identified. These proteins were mostly involved in cytoskeleton remodelling, energy metabolism and transcription regulation. Overall, shrimps modulate gene expression leading to metabolic and structural adjustments related to seasonal differences in the wild (i.e. abiotic variation and possibly intrinsic cycles of reproduction and growth). This potentially promotes performance and fitness as suggested by the higher condition index in summer-collected shrimps. However, inter-individual variation (% coefficient of variation) in protein levels was quite low (min-max ranges were 0.6–8.3% in spring and 1.2–4.8% in summer), possibly suggesting reduced genetic diversity or physiological canalization. Protein plasticity is relevant to cope with present and upcoming environmental variation related to anthropogenic forcing (e.g. global change, pollution) but low inter-individual variation may limit evolutionary potential of shrimp populations. [ABSTRACT FROM AUTHOR]

Human activities are having a massive negative impact on biodiversity and ecological processes worldwide. The rate and magnitude of ecological transformations induced by climate change, habitat destruction, overexploitation and pollution are now so substantial that a sixth mass extinction event is currently underway. The biodiversity crisis of the Anthropocene urges scientists to put forward a transformative vision to promote the conservation of biodiversity, and thus indirectly the preservation of ecosystem functions. Here, we identify pressing issues in global change biology research and propose an integrative framework based on multilayer biological networks as a tool to support conservation actions and marine risk assessments in multi-stressor scenarios. Multilayer networks can integrate different levels of environmental and biotic complexity, enabling us to combine information on molecular, physiological and behaviour responses, species interactions and biotic communities. The ultimate aim of this framework is to link human-induced environmental changes to species physiology, fitness, biogeography and ecosystem impacts across vast seascapes and time frames, to help guide solutions to address biodiversity loss and ecological tipping points. Further, we also define our current ability to adopt a widespread use of multilayer networks within ecology, evolution and conservation by providing examples of case-studies. We also assess which approaches are ready to be transferred and which ones require further development before use. We conclude that multilayer biological networks will be crucial to inform (using reliable multi-levels integrative indicators) stakeholders and support their decision-making concerning the sustainable use of resources and marine conservation., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The recent pandemic ushered in a marked surge in the adoption of digital health technologies (DHTs), necessitating remote approaches aiming to safeguard both patient and healthcare provider well-being. These technologies encompass an array of terms, including e-health, m-health, telemedicine, wearables, sensors, smartphone apps, digital therapeutics, virtual and augmented reality, and artificial intelligence (AI). Notably, some DHTs employed in critical healthcare decisions may transition into the realm of medical devices, subjecting them to more stringent regulatory scrutiny. Consequently, it is imperative to understand the validation processes of these technologies within clinical studies. Our study summarizes an extensive examination of clinical trials focusing on cardiovascular (CV) diseases and digital health (DH) interventions, with particular attention to those incorporating elements of AI. A dataset comprising 107 eligible trials, registered on clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP) databases until 19 June 2023, forms the basis of our investigation. We focused on clinical trials employing DHTs in the European context, revealing a diverse landscape of interventions. Devices constitute the predominant category (45.8%), followed by behavioral interventions (17.8%). Within the CV domain, trials predominantly span pivotal or confirmatory phases, with a notable presence of smaller feasibility and exploratory studies. Notably, a majority of trials exhibit randomized, parallel assignment designs. When analyzing the multifaceted landscape of trial outcomes, we identified various categories such as physiological and functional measures, diagnostic accuracy, CV events and mortality, patient outcomes, quality of life, treatment adherence and effectiveness, quality of hospital processes, and usability/feasibility measures. Furthermore, we delve into a subset of 15 studies employing AI and machine learning, describing various study design features, intended purposes and the validation strategies employed. In summary, we aimed to elucidate the diverse applications, study design features, and objectives of the evolving CV-related DHT clinical trials field., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Purpose: To report clinical findings and prognostic factors for visual and morphological outcomes in patients with Acanthamoeba keratitis (AK)., Methods: Single-center, retrospective, longitudinal study of 51 cases of AK diagnosed by real-time polymerase chain reaction (RT-PCR) between March 2010 and October 2022. The primary outcome was the final best corrected visual acuity (BCVA). Poor visual outcome was defined as a final BCVA ≥ 1 logMAR unit, while good visual outcome was defined as a final BCVA < 1 logMAR unit. Eyes from these two groups were compared, regarding demographic and initial clinical variables, anti-Acanthamoeba treatment used, and complications of the disease. Early diagnosis was defined as ≤ 14 days from symptom onset to diagnostic confirmation and initiation of Acanthamoeba medical treatment. Multivariable logistic regression was used to determine predictors of poor visual outcome., Results: A total of 51 eyes from 46 patients diagnosed with AK, all contact lens (CL) wearers, were included in this study. Average follow-up was 39.0 ± 30.2 [total range 14-120] months. Thirty-one eyes (60.8 %) presented good visual outcome, with a lower baseline age (30.5 ± 9.0 vs. 42.3 ± 15.8; p = 0.020), better initial BCVA (0.8 ± 0.7 logMAR units vs. 1.3 ± 0.9 logMAR units; p = 0.047), higher rate of early diagnosis (45.2 % vs. 5.6 %; p = 0.004), and higher rate of therapeutic epithelial debridement (64.5 % vs. 10 %; p < 0.001). 20 eyes (39.2 %) presented poor visual outcome, with 12 eyes undergoing evisceration/enucleation (23.5 %). These 20 eyes presented a higher rate of complications (90 % vs. 61.3 %; p = 0.031). In multivariable analysis, early diagnosis of AK (OR 19.78; 95 % CI 2.07-189.11; p = 0.010) and therapeutic epithelial debridement (OR 19.02; 95 % CI 3.27-110.57; p = 0.001) were associated with a good visual outcome., Conclusions: In the present study, poor visual outcome was present in 39 % of affected eyes. Early AK diagnosis (≤14 days from symptom onset) and therapeutic epithelial debridement were associated with good final visual outcome., 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 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.)

For the first time, the pharmacokinetic (PK) profile of tryptophanol-derived isoindolinones, previously reported as p53 activators, was investigated. From the metabolites' identification, performed by liquid chromatography coupled to high resolution tandem mass spectrometry (LC-HRMS/MS), followed by their preparation and structural elucidation, it was possible to identify that the indole C2 and C3 are the main target of the cytochrome P450 (CYP)-promoted oxidative metabolism in the tryptophanol-derived isoindolinone scaffold. Based on these findings, to search for novel p53 activators a series of 16 enantiopure tryptophanol-derived isoindolinones substituted with a bromine in indole C2 was prepared, in yields of 62-89%, and their antiproliferative activity evaluated in human colon adenocarcinoma HCT116 cell lines with and without p53. Structural optimization led to the identification of two ( S )-tryptophanol-derived isoindolinones 3.9-fold and 1.9-fold more active than hit SLMP53-1, respectively. Compounds' metabolic stability evaluation revealed that this substitution led to a metabolic switch, with the impact of Phase I oxidative metabolism being minimized. Through differential scanning fluorimetry (DSF) experiments, the most active compound of the series in cell assays led to an increase in the protein melting temperature ( T ) of 10.39 °C, suggesting an effective binding to wild-type p53 core domain.m ) of 10.39 °C, suggesting an effective binding to wild-type p53 core domain.

Background: Single mutations in COL4A3/COL4A4 genes have been described in patients with autosomal dominant Alport syndrome and thin basement membrane nephropathy, without a shared definition of these patients within the medical community. We aimed to better categorize this clinical entity by examining clinical manifestations, family history, pathological features and genetics., Methods: We retrospectively analyzed patients with causative heterozygous COL4A3/COL4A4 mutations referred to us between 1990 and 2019. Index cases were defined as children who were the first to be diagnosed in their families., Results: The study included 24 index cases and 29 affected relatives, belonging to 25 families with a heterozygous mutation in the COL4A3/COL4A4 genes. During the follow-up, nine patients developed proteinuria [median age 15.7 years (range 5.6-33)], six at clinical diagnosis and four with progression toward chronic kidney disease (CKD) (three required kidney replacement therapy at 25, 45 and 53 years and one had CKD Stage 2 at 46 years). Extrarenal involvement was observed in 24.5% of patients. Hematuria was transmitted in consecutive generations, while CKD was reported in nonconsecutive generations of 11 families [median age 53 years (range 16-80)]. Seventeen patients (32%) underwent kidney biopsy: findings were consistent with Alport syndrome in 12 cases and with thin basement membrane nephropathy in 5 cases., Conclusions: Despite the benign course for these patients described in the literature, a significant percentage is at risk for disease progression. Consequently, we suggest that the assessment of these patients must take into account family history, genetic analysis and pathologic findings. After comparison with the literature, our data suggest that a different definition for Alport syndrome must be considered., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Most animal toxins evolved to interact with specific molecular targets, which makes them highly-prized bioactives for drug development. Marine toxins, in particular, due to their wide chemical diversity, offer a new range of possibilities, a few of which have already been translated into approved drugs. Glycera alba and Hediste diversicolor are sympatric Polychaeta with distinct ecology and behavior suspected to secrete toxins that evolved to interact with distinct molecular targets, thus with differential selectivity and potential applications in drug discovery. Comparative transcriptomics revealed that while G. alba 's venom apparatus is localized in the proboscis and neurotoxins are secreted to overtake prey, H. diversicolor secretes fewer and less specific toxins that are seemingly a defense. Human interactome-directed analysis unraveled novel toxins and other bioactives with potential biomedical applications, like proteins from G. alba 's venom that can regulate apoptosis, whereas H. diversicolor yielded proteins that may control inflammation and cell proliferation in humans. Omics and bioinformatics appear to be powerful tools for marine bioprospecting and drug discovery, enabling molecular mining through transcriptomes of non-model organisms and link their ecology and physiology with protein's specificity and bioreactivity. Interactome-directed analysis against the human proteome seems an efficient alternative to the design of synthetic drugs.

Background: The order and orientation of genes encoded by animal mitogenomes are typically conserved, although there is increasing evidence of multiple rearrangements among mollusks. The mitogenome from a Brazilian brown mussel (hereafter named B1) classified as Perna perna Linnaeus, 1758 and assembled from Illumina short-length reads revealed an unusual gene order very different from other congeneric species. Previous mitogenomic analyses based on the Brazilian specimen and other Mytilidae suggested the polyphyly of the genus Perna ., Methods: To confirm the proposed gene rearrangements, we sequenced a second Brazilian P. perna specimen using the "primer-walking" method and performed the assembly using as reference Perna canaliculus . This time-consuming sequencing method is highly effective when assessing gene order because it relies on sequentially-determined, overlapping fragments. We also sequenced the mitogenomes of eastern and southwestern South African P. perna lineages to analyze the existence of putative intraspecific gene order changes as the two lineages show overlapping distributions but do not exhibit a sister relationship., Results: The three P. perna mitogenomes sequenced in this study exhibit the same gene order as the reference. CREx, a software that heuristically determines rearrangement scenarios, identified numerous gene order changes between B1 and our P. perna mitogenomes, rejecting the previously proposed gene order for the species. Our results validate the monophyly of the genus Perna and indicate a misidentification of B1., Competing Interests: Rita Castilho is an Academic Editor for PeerJ., (© 2022 Cunha et al.)

Coronavirus pandemic started in March 2020 and since then has caused millions of deaths worldwide. Wastewater-based epidemiology (WBE) can be used as an epidemiological surveillance tool to track SARS-CoV-2 dissemination and provide warning of COVID-19 outbreaks. Considering that there are public places that could be potential hotspots of infected people that may reflect the local epidemiological situation, the presence of SARS-CoV-2 RNA was analyzed by RT-qPCR for approximately 16 months in sewage samples from five public places located in the metropolitan area of Belo Horizonte, MG, Brazil: the sewage treatment plant of Confins International Airport (AIR), the main interstate bus terminal (BUS), an upscale shopping centre (SHC1), a popular shopping centre (SHC2) and a university institute (UNI). The results were compared to those of the influent sewage of the two main sewage treatment plants of Belo Horizonte (STP1 and STP2). Viral monitoring in the STPs proved to be an useful regional surveillance tool, reflecting the trends of COVID-19 cases. However, the viral concentrations in the samples from the selected public places were generally much lower than those of the municipal STPs, which may be due to the behaviour of the non-infected or asymptomatic people, who are likely to visit these places relatively more than the symptomatic infected ones. Among these places, the AIR samples presented the highest viral concentrations and concentration peaks were observed previously to local outbreaks. Therefore, airport sewage monitoring can provide an indication of the regional epidemiological situation. For the other places, particularly the UNI, the results suggested a greater potential to detect the infection and trace cases especially among employees and regular attendees. Taken together, the results indicate that for a regular and permanent sentinel sewage surveillance the sewage from STPs, AIR and UNI could be monitored., 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 B.V. All rights reserved.)

This article provides five panel datasets for the projections of the mean replacement ratios of pension income relative to the worker's income. The time dimension is from year 2022 until 2055. The panel groups consider the gender, income and education of the workers. Furthermore, the variables consider different scenarios for the social security system: (1) a baseline with the current policies, (2) an increase of retirement age to 67 years, (3) an increase of the retirement age to 67 years and a 6% increase of the contribution rate, with a rate of 0-3% going to solidarity funds., Competing Interests: The author declares that he has no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article. I received no funding from any institution besides my employer which is the Central Bank of Chile. Furthermore, there are no patents or impediments to publication, including the timing of publication, with respect to the intellectual property of the article or the associated dataset., (© 2022 The Author(s). Published by Elsevier Inc.)

The present study about falls among the older adult population essentially explores bio-physiological factors. In light of the complexity of the factors that cause these accidents, it is important to identify the safety and self-care practices of institutionalized older adults and their relationship with falls in order to introduce prevention measures and personalized cognitive-behavioral strategies. The objective of this study was to: (a) determine the frequency of falls and their recurrence among institutionalized older adults, and (b) to associate the occurrence of falls among institutionalized adults with or without cognitive impairment to communication and safety practices. This was a quantitative, correlational, and longitudinal study with 204 institutionalized older adults living in two long-term care facilities in Portugal. The Scale of Practices and Behaviors for Institutionalized Elderly to Prevent Falls was administered to the sample. The prevalence of falls at a 12-month follow-up was 41.6%, of which 38.3% were recurring episodes. Older adults with cognitive decline showed lower mean scores for safety practices. Further research with larger samples should explore the relationships between communication and safety practices and falls, their recurrence, and fear of new falls.

This article provides a pooled cross-sectional sample of Chilean households from 4 survey waves (1997, 2007, 2012, 2017). The data has information on the demographics of the household, labor participation and occupation, savings rates, plus wealth of different sources. The data is available in both Excel and Stata formats. It is an important data for the study of savings, wages, pensions and wealth inequality., Competing Interests: The author declares that he has no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article. I received no funding from any institution besides my employer which is the Central Bank of Chile. Furthermore, there are no patents or impediments to publication, including the timing of publication, with respect to the intellectual property of the article or the associated dataset., (© 2022 The Author(s).)

Using region-industry panel data for Chile over the period 1985 to 2017, we find no effect of precipitation changes on GDP and a negative impact of higher summer temperatures on Agriculture-Silviculture and Fishing. An increase of one Celsius degree in the month of January implies a 3% and 12% GDP reduction in Agriculture and Fishing, respectively. There is also a negative effect of higher temperatures in January on Construction and Electricity, Gas, and Water. Our analysis suggests that climate change did not have a big impact on the Chilean economy during this period. Stress test exercises that select only the negative and statistically significant coefficients imply that the Chilean GDP would fall between -14.8% and -9% in 2050 and between -29.6% and -16.8% in 2100, according to our model., Competing Interests: The authors have declared that no competing interests exist.

Background: Inhibition of human topoisomerase I (TOP1) by camptothecin and topotecan has been shown to reduce excessive transcription of PAMP (Pathogen-Associated Molecular Pattern)-induced genes in prior studies, preventing death from sepsis in animal models of bacterial and SARS-CoV-2 infections. The TOP1 catalytic activity likely resolves the topological constraints on DNA that encodes these genes to facilitate the transcription induction that leads to excess inflammation. The increased accumulation of TOP1-DNA covalent complex (TOP1cc) following DNA cleavage is the basis for the anticancer efficacy of the TOP1 poisons developed for anticancer treatment. The potential cytotoxicity and mutagenicity of TOP1 targeting cancer drugs pose serious concerns for employing them as therapies in sepsis prevention., Methods: In this study we set up a novel yeast-based screening system that employs yeast strains expressing wild-type or a dominant lethal mutant recombinant human TOP1. The effect of test compounds on growth is monitored with and without overexpression of the recombinant human TOP1., Results: This yeast-based screening system can identify human TOP1 poisons for anticancer efficacy as well as TOP1 suppressors that can inhibit TOP1 DNA binding or cleavage activity in steps prior to the formation of the TOP1cc., Conclusions: This yeast-based screening system can distinguish between TOP1 suppressors and TOP1 poisons. The assay can also identify compounds that are likely to be cytotoxic based on their effect on yeast cell growth that is independent of recombinant human TOP1 overexpression., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)