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Margarida Ribeiro,1,2,&ast; João Nogueira Freitas,3,&ast; Mário Lima-Fontes,1 Mariana Leuzinger-Dias,1 Marta Inês Silva,1 Joana Araújo,1,4 Sérgio Estrela-Silva,1,4 António Benevides Melo,1,4 João Tavares-Ferreira,1 Flávio Alves,1 João Barbosa-Breda1,4– 6 1Department of Ophthalmology, Unidade Local de Saúde de São João, Porto, Portugal; 2Department of Biomedicine – Unit of Pharmacology and Therapeutics, Faculty of Medicine of the University of Porto, Porto, Portugal; 3Faculty of Medicine of the University of Porto, Porto, Portugal; 4Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; 5UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; 6KULeuven, Research Group Ophthalmology, Department of Neurosciences, Leuven, Belgium&ast;These authors contributed equally to this workCorrespondence: Margarida Ribeiro, Department of Ophthalmology – Unidade Local de Saúde de São João, Alameda Prof. Hernâni Monteiro, Porto, 4200-319, Portugal, Email margarida.ribeiro.guimaraes@gmail.comPurpose: To evaluate the efficacy and safety of transscleral diode cyclophotocoagulation (TSCPC) at 2 years of follow up.Methods: This is a retrospective review of the records of all adult patients who underwent their first TSCPC treatment between 2014 and 2019 at Unidade Local de Saúde de São João, Porto, Portugal. Data regarding intraocular pressure (IOP), best corrected visual acuity, number of IOP-lowering medications, use of oral acetazolamide, retreatments and complications during a 2-year period following TSCPC were registered. The primary outcome was overall success at 2 years, defined as IOP≥ 6 and ≤ 21 mmHg, with at least 20% IOP reduction from baseline, with or without IOP-lowering medications (qualified and complete success, respectively), without the development of phthisis bulbi or loss of light perception due to glaucoma and no further glaucoma procedures except TSCPC retreatment.Results: Ninety-six eyes from 96 patients were included, mean age was 63 (± 14) years. Mean IOP at baseline was 39.1 (± 13.3) mmHg. Mean IOP reduction at 2 years was 18.5 (42.9%) mmHg (± 16.0, min − 16.0, max 56.0) (p < 0.001) and a significant reduction in the number of IOP-lowering medications and use of oral acetazolamide was observed. IOP reduction at 2 years was positively correlated with baseline IOP (r=0.682; p < 0.001). Overall success (including complete and qualified) was achieved in 42 patients (43.8%), with 34 (35.4%) presenting qualified success. Neovascular glaucoma (NVG) was the predominant diagnosis (n = 30, 31.3%), with a higher mean baseline IOP of 46.3 mmHg (± 11.8, min 21.0, max 70.0) and a larger mean IOP reduction at 2 years of 24.7 (51.0%) mmHg (± 16.4, min − 2.0, max 55.0). Thirteen patients (13.5%) developed persistent hypotony, eight of which converted to phthisis bulbi, of which half had NVG.Conclusion: TSCPC can be an effective IOP-lowering procedure, demonstrating a stronger effect when the preoperative IOP is highest. However, there is a wide variability in the effect (specially in eyes with NVG) and some relevant complications, including 8.3% of patients developing phthisis bulbi after 2 years of follow up.Keywords: intraocular pressure, glaucoma, ocular hypotension, transscleral cyclophotocoagulation, neovascular glaucoma, phthisis bulbi

Rodrigo Vilares-Morgado,1,2 Vera Correia,3 Ana Margarida Ferreira,1 Flávio Alves,1 António Benevides Melo,1,3 Sérgio Estrela-Silva,1,3 Joana Araújo,1,3 João Tavares-Ferreira,1,3 Marta Silva,1 Amândio Rocha-Sousa,1,2 Angela Carneiro,1,2 João Barbosa-Breda1,2,4 1Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Porto, Portugal; 2UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; 3Faculty of Medicine, University of Porto, Porto, Portugal; 4KULeuven, Research Group Ophthalmology, Department of Neurosciences, Leuven, BelgiumCorrespondence: Rodrigo Vilares-Morgado, Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Alameda Professor Hernâni Monteiro, 4202 – 451, Porto, Portugal, Tel +351 914 471 067, Fax +351 225 512 100, Email vilaresmorgador@gmail.comPurpose: To evaluate whether repeated intravitreal injections (IVI) with an anti-vascular endothelial growth factor (anti-VEGF) agent are associated with glaucomatous progression in eyes with glaucoma spectrum diseases (GSD).Methods: Single-center, retrospective, longitudinal study of patients with bilateral and similar GSD who: (1) received ≥ 8 IVI in only one eye during the study period; (2) had ≥ 2 retinal nerve fiber layer thickness (RNFL) measurements obtained by spectral-domain optical coherence tomography (SD-OCT) at least 12 months apart. The primary outcome was the absolute RNFL thickness change, comparing injected and fellow uninjected eyes. Linear mixed effects models were constructed, including a multivariable model.Results: Sixty-eight eyes from 34 patients were included, 34 injected and 34 fellow uninjected eyes. Average baseline age was 67.68± 21.77 years with a follow-up of 3.66± 1.89 years and 25.12± 14.49 IVI. RNFL thickness decreased significantly from 80.92± 15.78 to 77.20± 17.35 μm (p< 0.001; − 1.18± 1.93 μm/year) in injected eyes and from 79.95± 17.91 to 76.61± 17.97 μm (p< 0.001; − 1.07± 0.98 μm/year) in uninjected eyes. In a multivariable linear mixed model of injected eyes, only higher baseline RNFL thickness (p < 0.001) significantly predicted higher absolute RNFL thickness loss. Neither absolute RNFL thickness variation (p=0.716) nor RNFL rate (p=0.779) was significantly different between paired injected and uninjected eyes. Absolute IOP variation was not significantly different between groups (16.62± 4.77 to 15.09± 4.34 mmHg in injected eyes and 17.68± 5.01 to 14.50± 3.39 mmHg in fellow uninjected eyes; p=0.248). The proportion of eyes receiving glaucoma medical treatment increased significantly in both groups (55.9% to 76.5% in injected eyes; p=0.039; 58.8% to 76.5% in uninjected eyes; p = 0.031). The number of glaucoma medications also increased significantly in both groups (1.03± 1.11 to 1.59± 1.18 glaucoma medications in injected eyes; p=0.003; 1.09± 1.11 to 1.56± 1.19 glaucoma medications in uninjected eyes; p=0.003).Conclusion: Repeated IVI do not seem to accelerate glaucomatous progression. Future studies with a longer follow-up are needed.Keywords: glaucoma, intravitreal injections, progression, optical coherence tomography, retinal nerve fiber layer thickness

The active participation of citizens in scientific research, through citizen science, has been proven successful. However, knowledge on the potential of citizen science within formal chemistry learning, at the conceptual and procedural levels, remains insufficiently explored. We developed a citizen science project -- PVC: Perceiving the Value of Chemistry behind water and microplastics -- which sought to involve students in monitoring the physicochemical parameters of coastal water quality, through the detection of microplastics in these waters, in addition to the qualitative identification of plastic contaminants on beaches. The project was conducted throughout the 2018/2019 school year and involved 442 middle school students (Key Stage 3 (KS3) aged 12-14, in Portuguese schools) and 9 chemistry teachers, in the northern coastal region of Portugal. The data on learning outcomes was collected through knowledge tests, applied after project conclusion, and was then compared to data collected up to six months later (retention test). In addition, interviews were conducted with participants, and researchers' field notes were recorded and analyzed. Data analysis suggests the PVC project promoted conceptual chemistry learning related to the analysis of physicochemical water parameters (pH, temperature, turbidity, salinity, nitrate and nitrite concentrations and dissolved oxygen), as well as polymers (polymer types, formation and structure). A positive knowledge retention was registered a few months after the project conclusion. At a process level, participants learned laboratory techniques (sieving, gravity and reduced pressure filtrations and crystallization) and the handling of laboratory materials. Furthermore, teachers recognized that their students' participation in the PVC project fostered the development of their argumentation skills, as well as their reflexive and critical thinking skills. The ability to communicate ideas and results, along with the development of students' digital skills, was also mentioned.

The use of open-pollinated seeds from seed orchards is a common strategy for the deployment of genetically improved eucalypts, including Eucalyptus globulus, an important pulpwood tree in many temperate climate areas. However, seed quality can be affected by the rate of selfing and to a lesser extent by contamination from pollen outside the orchard. Inbreeding between related parents and especially from self-crosses is known to cause diminished growth and developmental abnormalities in the resulting progeny. This study looks at the magnitude and variation in selfing and the impact in inbreeding depression across several E. globulus families collected over the years in a seed orchard. The effects on growth and development of outcrossed and selfed progeny were studied across five progeny trials, after pedigree reconstruction of the open pollinated progeny based on SSR genotyping. An additive genetic mixed linear model was fitted to the data to evaluate the impact of inbreeding on height growth. The results showed a significant inbreeding depression, with a height growth reduction of 15% in selfed progeny, when compared with crosses from unrelated parents. These inbreeding depression values varied among families, ranging between 7% and 24%, evidencing the importance of genetic background. Contamination rates were on average 10% suggesting long distance pollen dispersal was present. A small number of abnormal phenotypes (less than 10%) was observed in the field. This was associated with specific, unrelated, crosses and not to high inbreeding rates such as found among selfed progeny. The relevance of these results for orchard management and parent selection is discussed.

The Phenobot platform is comprised by an autonomous robot, instrumentation, artificial intelligence, and digital twin diagnosis at the molecular level, marking the transition from pure data-driven to knowledge-driven agriculture 4.0, towards a physiology-based approach to precision viticulture. Such is achieved by measuring the plant metabolome ‘in vivo' and 'in situ', using spectroscopy and artificial intelligence for quantifying metabolites, e.g.: i. grapes: chlorophylls a and b, pheophytins a and b, anthocyanins, carotenoids, malic and tartaric acids, glucose and fructose; ii. foliage: chlorophylls a and b, pheophytins a and b, anthocyanins, carotenoids, nitrogen, phosphorous, potassium, sugars, and leaf water potential; and iii. soil nutrients (NPK). The geo-referenced metabolic information of each plant (organs and tissues) is the basis of multi-scaled analysis: i. geo-referenced metabolic maps of vineyards at the macroscopic field level, and ii. genome-scale 'in-silico' digital twin model for inferential physiology (phenotype state) and omics diagnosis at the molecular and cellular levels (transcription, enzyme efficiency, and metabolic fluxes). Genome-scale 'in-silico' Vitis vinifera numerical network relationships and fluxes comprise the scientific knowledge about the plant's physiological response to external stimuli, being the comparable mechanisms between laboratory and field experimentation - providing a causal and interpretable relationship to a complex system subjected to external spurious interactions (e.g., soil, climate, and ecosystem) scrambling pure data-driven approaches. This new approach identifies the molecular and cellular targets for managing plant physiology under different stress conditions, enabling new sustainable agricultural practices and bridging agriculture with plant biotechnology, towards faster innovations (e.g. biostimulants, anti-microbial compounds/mechanisms, nutrition, and water management). Phenobot is a project under the Portuguese emblematic initiative in Agriculture 4.0, part of the Recovery and Resilience Plan (Ref. PRR: 190 Ref. 09/C05-i03/2021 – PRR-C05-i03-I-000134).

A ampliação do conceito de saúde, historicamente acompanhado pelo contexto mundial de globalização da cultura de respeito e proteção dos direitos humanos, influenciou de forma significativa a criação e implementação de dispositivos jurídicos visando à garantia da seguridade social em todos os níveis como condição sine qua non para qualidade de vida e dignidade das pessoas. Nesse sentido, este trabalho tem como objetivo discutir as interfaces do direito que alicerçam a fluoretação das águas em território nacional como mecanismo básico essencial para a promoção de saúde bucal integral, universal e plena.

Ana Sofia Carvalho,1–3 Sandra Martins Pereira,1–3 António Jácomo,1–3 Susana Magalhães,1,2,4 Joana Araújo,1–3 Pablo Hernández-Marrero,1–3 Carlos Costa Gomes,1–3 Michael E Schatman5,6 1Instituto de Bioética, Universidade Católica Portuguesa, Porto, Portugal; 2UNESCO Chair in Bioethics, Universidade Católica Portuguesa, Porto, Portugal; 3CEGE: Centro de Estudos em Gestão e Economia (Research Centre in Management and Economics), Católica Porto Business School, Universidade Católica Portuguesa, Porto, Portugal; 4Universidade Fernando Pessoa, Porto, Portugal; 5Research and Network Development, Boston Pain Care, Waltham, MA, USA; 6Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA Introduction: The practice and study of pain management pose myriad ethical challenges. There is a consensual opinion that adequate management of pain is a medical obligation rooted in classical Greek practice. However, there is evidence that patients often suffer from uncontrolled and unnecessary pain. This is inconsistent with the leges artis, and its practical implications merit a bioethical analysis. Several factors have been identified as causes of uncontrolled and unnecessary pain, which deprive patients from receiving appropriate treatments that theoretically they have the right to access. Important factors include (with considerable regional, financial, and cultural differences) the following: 1) failure to identify pain as a priority in patient care; 2) failure to establish an adequate physician–patient relationship; 3) insufficient knowledge regarding adequate prescription of analgesics; 4) conflicting notions associated with drug-induced risk of tolerance and fear of addiction; 5) concerns regarding “last-ditch” treatments of severe pain; and 6) failure to be accountable and equitable.Objective: The aim of this article was to establish that bioethics can serve as a framework for addressing these challenging issues and, from theoretical to practical approaches, bioethical reflection can contextualize the problem of unrelieved pain.Methods: This article is organized into three parts. First, we illustrate that pain management and its undertreatment are indeed ethical issues. The second part describes possible ethical frameworks that can be combined and integrated to better define the ethical issues in pain management. Finally, we discuss possible directions forward to improve ethical decision making in pain management.Discussion: We argue that 1) the treatment of pain is an ethical obligation, 2) health science schools, especially medical training institutions, have the duty to teach pain management in a comprehensive fashion, and 3) regulatory measures, which prevent patients from access to opioid treatment as indicated in their cases, are unethical and should be reconsidered.Conclusion: Developing an ethical framework for pain management will result in enhanced quality of care, linking the epistemic domains of pain management to their anthropological foundations, thereby making them ethically sound. Keywords: bioethics, pain management, ethical decision making, ethics of care, narrative medicine, patient-centered care

Four new species of the genus Niveomyces are described from Thailand. They were found as mycoparasites on: Ophiocordyceps infecting flies (Diptera) for Niveomyces albus; ants (Hymenoptera) for N. formicidarum; and leafhoppers (Hemiptera) for N. hirsutellae and N. multisynnematus. A new genus, Pseudoniveomyces with two species: Pseudoniveo. blattae (type species), parasitic on Ophiocordyceps infecting cockroaches, and Pseudoniveo. arachnovorum, found on a spider egg sac, are also described. These fungi share a common feature which is a sporothrix-like asexual morph. Based on our molecular data, Sporothrix insectorum is shown to be affiliated to the genus Niveomyces, and thus a new combination N. insectorum comb. nov. is proposed. Niveomyces coronatus, N. formicidarum and N. insectorum formed the N. coronatus species complex found on ant-pathogenic Ophiocordyceps from different continents. Pseudoniveomyces species are distinguished from Niveomyces spp. based on the presence of fusoid macroconidia in culture and a red pigment diffused in the medium, resembling to Gibellula and Hevansia. The molecular phylogenetic analyses also confirmed its generic status. The host/substrates associated with the genera within Cordycipitaceae were mapped onto the phylogeny to demonstrate that mycoparasitism also evolved independently multiple times in this family. [ABSTRACT FROM AUTHOR]

Joana Araújo,1 João Tavares-Ferreira,1 Susana Penas,1,2 Luís Figueira,1,3 Flávio Prézia Paiva,1 Fernando Falcão-Reis1,2 1Ophthalmology Department, São João Hospital, 2Department of Sense Organs, 3Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal Abstract: We report one case of malignant hypertensive retinopathy as a presenting sign of fetal death in utero. Ophthalmic examination (including intravenous fluorescein angiography and optical coherence tomography) and obstetric and systemic evaluation were performed, providing a multidisciplinary approach. A 33-year-old overweight woman (body mass index 47 kg/m2) with no systemic or ocular known disease was admitted to our emergency department with a one-week history of bilateral vision loss and no systemic complaints. On examination, best corrected visual acuity was 1/10 in the right eye and 1/10 in the left eye. Anterior segment examination of both eyes was unremarkable. Ophthalmoscopic fundus findings included bilateral optic disc edema, diffuse cotton wool spots, intraretinal exudates, retinal hemorrhages, and multiple serous retinal detachments involving both maculae. Physical examination revealed a blood pressure of 220/ 110 mmHg. Further systemic workup revealed a previously unknown 35-week pregnancy with a dead fetus. An emergency cesarean section was performed. Pre-eclampsia is a life-threatening disorder for both mother and fetus. This case highlights the need to rule out pre-eclampsia in all women of childbearing age presenting with ocular signs of malignant hypertension, even without external signs of pregnancy. Keywords: hypertensive retinopathy, pre-eclampsia, vision loss

Ana Maria de Oliveira,1 Catarina Graça Rodrigues,1 Alexys Borges,2 Alexandra Martins,1 Sofia Loureiro dos Santos,3 Francisco Rocha Pires,4 João Mascarenhas Araújo,2 João Ramos de Deus1 1Department of Gastroenterology, 2Department of Internal Medicine, 3Department of Pathology and Anatomical Sciences, 4Department of Surgery, Pathology and Anatomical Sciences, Prof. Doutor Fernando Fonseca Hospital, Amadora, Portugal Background: Pseudomyxoma peritonei is an uncommon condition with an estimated incidence of one to two per million (worldwide) per year. It is characterized by the peritoneal deposition of mucinous tumors, most commonly of the appendix, and occasionally from the ovary, coupled by mucinous ascites. Case presentation: We report the case of a 76-year-old woman who presented with increased abdominal girth and dyspnea for 2 weeks. She was diagnosed as a case of pseudomyxoma peritonei. She was submitted to right oophorectomy, omentectomy, and pseudomyxoma debulking. The histology was compatible with a mucinous tumor of colorectal/appendicular origin. Chemotherapy was not administered because of her functional status. Two years and 8 months later, she refers with postprandial fullness and has moderate ascites. Keywords: pseudomyxoma peritonei, mucinous tumor, pseudomyxoma debulking

Nowadays, Ni@C nanostructured materials are attracting a great deal of attention due to their multiple catalytic or magnetic functionalities. In this article we report on the investigation of the correlation between the microstructure and magnetic properties of Ni nanoparticles embedded in a carbon matrix. The samples were obtained following a two-step procedure that ensures protection against nanoparticle oxidation, and was carried out in the following way: (i) the synthesis of a nickel-imidazole-based metal–organic framework (MOF) by a simple method in an aqueous medium at moderate temperature (95 °C); and (ii) carbonization of the MOF at different temperatures between 400 and 600 °C to obtain a carbon-supported hybrid material, containing Ni nanoparticles with an "artichoke-like" morphology, where a Ni-FCC core is surrounded by "bracts" of Ni-HCP and Ni3C. The average size of the nanoparticle slightly changes from 7 to 10 nm as the carbonization temperature is increased, but the Ni-FCC core diameter ranges from 3 to around 6 nm. We show how the information obtained on the evolution of the magnetic behaviour with carbonization temperature, using X-ray diffraction and electron microscopy, complements each other by providing consistent structural and magnetic characteristics of the investigated Ni@C nanoparticles. In fact, this joint analysis allows us to explain the formation and transformation of different Ni-based crystalline phases along the synthesis process, including Ni3C and Ni with both hexagonal and cubic crystalline structures. The amount of conventional Ni-FCC is below 10 wt% for the sample treated at 400 °C and it can reach up to 50 wt% for that treated at 600 °C. Finally, based on our current findings we propose an explanation for understanding the magnetic properties of Ni@C, in which the Ni-FCC core spins mainly govern the magnetic coupling of the whole system. [ABSTRACT FROM AUTHOR]

During surveys in central Florida of the zombie-ant fungus Ophiocordyceps camponoti-floridani, which manipulates the behavior of the carpenter ant Camponotus floridanus, two distinct fungal morphotypes were discovered associated with and purportedly parasitic on O. camponoti-floridani. Based on a combination of unique morphology, ecology and phylogenetic placement, we discovered that these morphotypes comprise two novel lineages of fungi. Here, we propose two new genera, Niveomyces and Torrubiellomyces, each including a single species within the families Cordycipitaceae and Ophiocordycipitaceae, respectively. We generated de novo draft genomes for both new species and performed morphological and multi-loci phylogenetic analyses. The macromorphology and incidence of both new species, Niveomyces coronatus and Torrubiellomyces zombiae, suggest that these fungi are mycoparasites since their growth is observed exclusively on O. camponoti-floridani mycelium, stalks and ascomata, causing evident degradation of their fungal hosts. This work provides a starting point for more studies into fungal interactions between mycopathogens and entomopathogens, which have the potential to contribute towards efforts to battle the global rise of plant and animal mycoses. [ABSTRACT FROM AUTHOR]

In this work, for a given oriented graph D, we study its interval and hull numbers, denoted by ⃗in (D) and ⃗hn (D), respectively, in the oriented geodetic, ⃗P 3 and ⃗ P* 3 convexities. This last one, we believe to be formally defined and first studied in this paper, although its undirected version is well-known in the literature. Concerning bounds, for a strongly oriented graph D and the oriented geodetic convexity, we prove that ⃗hn g (D) ≤ m(D)-n(D) + 2 and that there is at least one such that ⃗hn g (D) = m(D) - n(D). We also determine exact values for the hull numbers in these three convexities for tournaments, which imply polynomial-time algorithms to compute them. These results allow us to deduce polynomial-time algorithms to compute ⃗hn P3 (D) when the underlying graph of D is split or cobipartite. Moreover, we provide a meta-theorem by proving that if deciding whether ⃗in g (D) ≤ k or ⃗hn g (D) ≤ k is NP-hard or W[i]-hard parameterized by k, for some i ϵ Z * + , then the same holds even if the underlying graph of D is bipartite. Next, we prove that deciding whether ⃗hn P3 (D) ≤ k or ⃗hn P3 * (D) ≤ k is W[2]-hard parameterized by k, even if the underlying graph of D is bipartite; that deciding whether ⃗in P3 (D) ≤ k or whether ⃗in P3 *(D) ≤ k is NP-complete, and the same for ⃗hn P3 *(D) ≤ k even if D has no directed cycles and the underlying graph of D is a chordal bipartite graph; and that deciding whether ⃗in P3 (D) ≤ k or whether ⃗in P3 *(D) ≤ k is W[2]-hard parameterized by k, even if the underlying graph of D is split. Finally, we also argue that the interval and hull numbers in the ⃗ P 3 and ⃗ P* 3 convexities can be computed in polynomial time for directed graphs with underlying graph of bounded tree-width by using Courcelle's theorem. [ABSTRACT FROM AUTHOR]

We herein present the potentiality of a simple and desktop AC susceptometer to explore easily and in real time the influence of different alkaline agents on the coprecipitation reaction of Fe-oxide NPs. We have studied the aqueous coprecipitation reaction of Fe-oxide nanoparticles with three different chemical basis: NH3, NaOH and 1-amino-2propanol (MIPA). We conclude that ammonia leads to the fastest chemical reactions because the slope of the real time X(t) curves are the largest ones. On the other hand, the smallest NPs would be obtained with NaOH because the in-phase curve values are one order of magnitude smaller than those obtained with NH3 and MIPA and also, because there is no signal in the out-of-phase curves obtained with some concentrations of NaOH. Finally, we also corroborate that even though the NPs obtained with organic MIPA would be smaller than those found with traditional inorganic bases [q(t) θ(t) curves of MIPA exhibit lower values than those of NH3], the magnetic properties of the NPs synthesized with these new alkalonamines would be enhanced [X(t) curves of MIPA are one order of magnitude larger than those obtained with NaOH]. This work put on view the potentiality of our AC susceptometer to predict in situ and in less than 30 min how the dynamic of the chemical reaction together with the polydispersity and magnetic saturation of the NPs, are being influenced by the type of chemical base and its concentration. [ABSTRACT FROM AUTHOR]