Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis.

Porphyrin atropisomerism, which arises from restricted σ-bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20-tetrakis(o-hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry.

Antitumor Immunity Mediated by Photodynamic Therapy Using Injectable Chitosan Hydrogels for Intratumoral and Sustained Drug Delivery.

Photodynamic therapy (PDT) is an anticancer therapy with proven efficacy; however, its application is often limited by prolonged skin photosensitivity and solubility issues associated with the phototherapeutic agents. Injectable hydrogels which can effectively provide intratumoral delivery of photosensitizers with sustained release are attracting increased interest for photodynamic cancer therapies. However, most of the hydrogels for PDT applications are based on systems with high complexity, and often, preclinical validation is not provided. Herein, we provide a simple and reliable pH-sensitive hydrogel formulation that presents appropriate rheological properties for intratumoral injection. For this, Temoporfin (m-THPC), which is one of the most potent clinical photosensitizers, was chemically modified to introduce functional groups that act as cross-linkers in the formation of chitosan-based hydrogels. The introduction of -COOH groups resulted in a water-soluble derivative, named PS2, that was the most promising candidate. Although PS2 was not internalized by the target cells, its extracellular activation caused effective damage to the cancer cells, which was likely mediated by lipid peroxidation. The injection of the hydrogel containing PS2 in the tumors was monitored by high-frequency ultrasounds and in vivo fluorescence imaging which confirmed the sustained release of PS2 for at least 72 h. Following local administration, light exposure was conducted one (single irradiation protocol) or three (multiple irradiation protocols) times. The latter delivered the best therapeutic outcomes, which included complete tumor regression and systemic anticancer immune responses. Immunological memory was induced as ∼75% of the mice cured with our strategy rejected a second rechallenge with live cancer cells. Additionally, the failure of PDT to treat immunocompromised mice bearing tumors reinforces the relevance of the host immune system. Finally, our strategy promotes anticancer immune responses that lead to the abscopal protection against distant metastases.

Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

Novel Foscan®-derived ring-fused chlorins for photodynamic therapy of cancer.

Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, prostate and pancreatic cancers but is characterized by being photochemically unstable and associated with prolonged skin photosensitivity. Herein, we report the synthesis of new 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, having the meso-tetra(3-hydroxyphenyl)macrocycle core of mTHPC, by exploring the [8π + 2π] cycloaddition of a meso-tetra(3-hydroxyphenyl)porphyrin derivative with diazafulvenium methides. These chlorins have photochemical properties similar to Foscan® but are much more photostable. Among the novel compounds, two chlorins with a hydroxymethyl group and its azide derivative present in the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused system, are promising photodynamic agents with activity in the 100 nM range against triple-negative breast cancer cells and, in the case of azidomethyl chlorin, a safer phototherapeutic index compared to Foscan®.

Calibration Assessment of Low-Cost Carbon Dioxide Sensors Using the Extremely Randomized Trees Algorithm.

As the monitoring of carbon dioxide is an important proxy to estimate the air quality of indoor and outdoor environments, it is essential to obtain trustful data from CO2 sensors. However, the use of widely available low-cost sensors may imply lower data quality, especially regarding accuracy. This paper proposes a new approach for enhancing the accuracy of low-cost CO2 sensors using an extremely randomized trees algorithm. It also reports the results obtained from experimental data collected from sensors that were exposed to both indoor and outdoor environments. The indoor experimental set was composed of two metal oxide semiconductors (MOS) and two non-dispersive infrared (NDIR) sensors next to a reference sensor for carbon dioxide and independent sensors for air temperature and relative humidity. The outdoor experimental exposure analysis was performed using a third-party dataset which fit into our goals: the work consisted of fourteen stations using low-cost NDIR sensors geographically spread around reference stations. One calibration model was trained for each sensor unit separately, and, in the indoor experiment, it managed to reduce the mean absolute error (MAE) of NDIR sensors by up to 90%, reach very good linearity with MOS sensors in the indoor experiment (r2 value of 0.994), and reduce the MAE by up to 98% in the outdoor dataset. We have found in the outdoor dataset analysis that the exposure time of the sensor itself may be considered by the algorithm to achieve better accuracy. We also observed that even a relatively small amount of data may provide enough information to perform a useful calibration if they contain enough data variety. We conclude that the proper use of machine learning algorithms on sensor readings can be very effective to obtain higher data quality from low-cost gas sensors either indoors or outdoors, regardless of the sensor technology.

Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization.

The intrinsic challenge of large molecules to cross the cell membrane and reach intracellular targets is a major obstacle for the development of new medicines. We report how rotation along a single C-C bond, between atropisomers of a drug in clinical trials, improves cell uptake and therapeutic efficacy. The atropisomers of redaporfin (a fluorinated sulfonamide bacteriochlorin photosensitizer of 1135 Da) are separable and display orders of magnitude differences in photodynamic efficacy that are directly related to their differential cellular uptake. We show that redaporfin atropisomer uptake is passive and only marginally affected by ATP depletion, plasma proteins, or formulation in micelles. The α4 atropisomer, where meso-phenyl sulfonamide substituents are on the same side of the tetrapyrrole macrocycle, exhibits the highest cellular uptake and phototoxicity. This is the most amphipathic atropisomer with a conformation that optimizes hydrogen bonding (H-bonding) with polar head groups of membrane phospholipids. Consequently, α4 binds to the phospholipids on the surface of the membrane, flips into the membrane to adopt the orientation of a surfactant, and eventually diffuses to the interior of the cell (bind-flip mechanism). We observed increased α4 internalization by cells of the tumor microenvironment in vivo and correlated this to the response of photodynamic therapy when tumor illumination was performed 24 h after α4 administration. These results show that properly orientated aryl sulfonamide groups can be incorporated into drug design as efficient cell-penetrating motifs in vivo and reveal the unexpected biological consequences of atropisomerism.

Photodynamic therapy with redaporfin targets the endoplasmic reticulum and Golgi apparatus.

Preclinical evidence depicts the capacity of redaporfin (Redp) to act as potent photosensitizer, causing direct antineoplastic effects as well as indirect immune-dependent destruction of malignant lesions. Here, we investigated the mechanisms through which photodynamic therapy (PDT) with redaporfin kills cancer cells. Subcellular localization and fractionation studies based on the physicochemical properties of redaporfin revealed its selective tropism for the endoplasmic reticulum (ER) and the Golgi apparatus (GA). When activated, redaporfin caused rapid reactive oxygen species-dependent perturbation of ER/GA compartments, coupled to ER stress and an inhibition of the GA-dependent secretory pathway. This led to a general inhibition of protein secretion by PDT-treated cancer cells. The ER/GA play a role upstream of mitochondria in the lethal signaling pathway triggered by redaporfin-based PDT Pharmacological perturbation of GA function or homeostasis reduces mitochondrial permeabilization. In contrast, removal of the pro-apoptotic multidomain proteins BAX and BAK or pretreatment with protease inhibitors reduced cell killing, yet left the GA perturbation unaffected. Altogether, these results point to the capacity of redaporfin to kill tumor cells via destroying ER/GA function.

Steric Repulsion Induced Conformational Switch in Supramolecular Structures.

Inspired by the rigidified architecture of 'picket-fence' systems, we propose a strategy utilizing strain to impose intramolecular tension in already peripherally overcrowded structures leading to selective atropisomeric conversion. Employing this approach, tuneable shape-persistent porphyrin conformations were acquired exhibiting distinctive supramolecular nanostructures based on the orientation of the peripheral groups. The intrinsic assemblies driven by non-covalent bonding interactions form supramolecular polymers while encapsulating small molecules in parallel channels or solvent-accessible voids. The developed molecular strain engineering methodologies combined with synthetic approaches have allowed the introduction of the pivalate units creating a highly strained molecular skeleton. Changes in the absorption spectrum indicated the presence of severe steric repulsions between the peripheral groups which were confirmed by single crystal X-ray analysis. To release the steric strain introduced by the peripheral units, thermal equilibration strategies were used to selectively convert the most abundant atropisomer to the desirable minor one.

Ligand-Targeted Delivery of Photosensitizers for Cancer Treatment.

Photodynamic therapy (PDT) is a promising cancer treatment which involves a photosensitizer (PS), light at a specific wavelength for PS activation and oxygen, which combine to elicit cell death. While the illumination required to activate a PS imparts a certain amount of selectivity to PDT treatments, poor tumor accumulation and cell internalization are still inherent properties of most intravenously administered PSs. As a result, common consequences of PDT include skin photosensitivity. To overcome the mentioned issues, PSs may be tailored to specifically target overexpressed biomarkers of tumors. This active targeting can be achieved by direct conjugation of the PS to a ligand with enhanced affinity for a target overexpressed on cancer cells and/or other cells of the tumor microenvironment. Alternatively, PSs may be incorporated into ligand-targeted nanocarriers, which may also encompass multi-functionalities, including diagnosis and therapy. In this review, we highlight the major advances in active targeting of PSs, either by means of ligand-derived bioconjugates or by exploiting ligand-targeting nanocarriers.

Hydrogels: soft matters in photomedicine.

Photodynamic therapy (PDT), a shining beacon in the realm of photomedicine, is a non-invasive technique that utilizes dye-based photosensitizers (PSs) in conjunction with light and oxygen to produce reactive oxygen species to combat malignant tissues and infectious microorganisms. Yet, for PDT to become a common, routine therapy, it is still necessary to overcome limitations such as photosensitizer solubility, long-term side effects (e.g., photosensitivity) and to develop safe, biocompatible and target-specific formulations. Polymer based drug delivery platforms are an effective strategy for the delivery of PSs for PDT applications. Among them, hydrogels and 3D polymer scaffolds with the ability to swell in aqueous media have been deeply investigated. Particularly, hydrogel-based formulations present real potential to fulfill all requirements of an ideal PDT platform by overcoming the solubility issues, while improving the selectivity and targeting drawbacks of the PSs alone. In this perspective, we summarize the use of hydrogels as carrier systems of PSs to enhance the effectiveness of PDT against infections and cancer. Their potential in environmental and biomedical applications, such as tissue engineering photoremediation and photochemistry, is also discussed.

Impacts of low frequency noise exposure on well-being: a case-study from portugal.

INTRODUCTION: The aim of this article is to assess the impacts of low frequency noise, emitted by high-voltage lines and power poles, on the perception of discomfort, comparing two different groups of inhabitants (exposed and unexposed groups) in two areas in the Northwest of Portugal. It proposes a new oriented methodology to assess discomfort due to the low frequency noise. MATERIALS AND METHODS: Two predominantly urban areas were used to test the methodology: an "exposed" area with a high presence of the source under study and an "unexposed" area without records of power transmission lines. The research developed included measuring sound levels (in frequency bands from 10 to 160 Hz) with the help of a sound level meter in the two selected urban areas. RESULTS: The real sound coming from the source was recorded and reproduced in an audiometric testing booth to determine the hearing threshold and discomfort of the volunteers. Using the criteria curve developed by DEFRA (Department for Environment, Food & Rural Affairs/University of Salford) in 2011, the results reveal that the sound levels recorded for the "exposed" group were higher than that for the "unexposed" group. The first recording showed an average of 68.9 dB and the second 64.6 dB, resulting in a significant difference of 4.3 dB between the two groups. After an attempt to isolate the source, the difference was 5.6 dB. Regarding the adapted audiometric tests, the real sound was used, which was collected 5 m between the receiver and the source. CONCLUSION: These results provide support that at this distance the noise was considered annoying.

The spider tree of life: phylogeny of Araneae based on target-gene analyses from an extensive taxon sampling.

We present a phylogenetic analysis of spiders using a dataset of 932 spider species, representing 115 families (only the family Synaphridae is unrepresented), 700 known genera, and additional representatives of 26 unidentified or undescribed genera. Eleven genera of the orders Amblypygi, Palpigradi, Schizomida and Uropygi are included as outgroups. The dataset includes six markers from the mitochondrial (12S, 16S, COI) and nuclear (histone H3, 18S, 28S) genomes, and was analysed by multiple methods, including constrained analyses using a highly supported backbone tree from transcriptomic data. We recover most of the higher-level structure of the spider tree with good support, including Mesothelae, Opisthothelae, Mygalomorphae and Araneomorphae. Several of our analyses recover Hypochilidae and Filistatidae as sister groups, as suggested by previous transcriptomic analyses. The Synspermiata are robustly supported, and the families Trogloraptoridae and Caponiidae are found as sister to the Dysderoidea. Our results support the Lost Tracheae clade, including Pholcidae, Tetrablemmidae, Diguetidae, Plectreuridae and the family Pacullidae (restored status) separate from Tetrablemmidae. The Scytodoidea include Ochyroceratidae along with Sicariidae, Scytodidae, Drymusidae and Periegopidae; our results are inconclusive about the separation of these last two families. We did not recover monophyletic Austrochiloidea and Leptonetidae, but our data suggest that both groups are more closely related to the Cylindrical Gland Spigot clade rather than to Synspermiata. Palpimanoidea is not recovered by our analyses, but also not strongly contradicted. We find support for Entelegynae and Oecobioidea (Oecobiidae plus Hersiliidae), and ambiguous placement of cribellate orb-weavers, compatible with their non-monophyly. Nicodamoidea (Nicodamidae plus Megadictynidae) and Araneoidea composition and relationships are consistent with recent analyses. We did not obtain resolution for the titanoecoids (Titanoecidae and Phyxelididae), but the Retrolateral Tibial Apophysis clade is well supported. Penestomidae, and probably Homalonychidae, are part of Zodarioidea, although the latter family was set apart by recent transcriptomic analyses. Our data support a large group that we call the marronoid clade (including the families Amaurobiidae, Desidae, Dictynidae, Hahniidae, Stiphidiidae, Agelenidae and Toxopidae). The circumscription of most marronoid families is redefined here. Amaurobiidae include the Amaurobiinae and provisionally Macrobuninae. We transfer Malenellinae (Malenella, from Anyphaenidae), Chummidae (Chumma) (new syn.) and Tasmarubriinae (Tasmarubrius, Tasmabrochus and Teeatta, from Amphinectidae) to Macrobuninae. Cybaeidae are redefined to include Calymmaria, Cryphoeca, Ethobuella and Willisius (transferred from Hahniidae), and Blabomma and Yorima (transferred from Dictynidae). Cycloctenidae are redefined to include Orepukia (transferred from Agelenidae) and Pakeha and Paravoca (transferred from Amaurobiidae). Desidae are redefined to include five subfamilies: Amphinectinae, with Amphinecta, Mamoea, Maniho, Paramamoea and Rangitata (transferred from Amphinectidae); Ischaleinae, with Bakala and Manjala (transferred from Amaurobiidae) and Ischalea (transferred from Stiphidiidae); Metaltellinae, with Austmusia, Buyina, Calacadia, Cunnawarra, Jalkaraburra, Keera, Magua, Metaltella, Penaoola and Quemusia; Porteriinae (new rank), with Baiami, Cambridgea, Corasoides and Nanocambridgea (transferred from Stiphidiidae); and Desinae, with Desis, and provisionally Poaka (transferred from Amaurobiidae) and Barahna (transferred from Stiphidiidae). Argyroneta is transferred from Cybaeidae to Dictynidae. Cicurina is transferred from Dictynidae to Hahniidae. The genera Neoramia (from Agelenidae) and Aorangia, Marplesia and Neolana (from Amphinectidae) are transferred to Stiphidiidae. The family Toxopidae (restored status) includes two subfamilies: Myroinae, with Gasparia, Gohia, Hulua, Neomyro, Myro, Ommatauxesis and Otagoa (transferred from Desidae); and Toxopinae, with Midgee and Jamara, formerly Midgeeinae, new syn. (transferred from Amaurobiidae) and Hapona, Laestrygones, Lamina, Toxops and Toxopsoides (transferred from Desidae). We obtain a monophyletic Oval Calamistrum clade and Dionycha; Sparassidae, however, are not dionychans, but probably the sister group of those two clades. The composition of the Oval Calamistrum clade is confirmed (including Zoropsidae, Udubidae, Ctenidae, Oxyopidae, Senoculidae, Pisauridae, Trechaleidae, Lycosidae, Psechridae and Thomisidae), affirming previous findings on the uncertain relationships of the "ctenids" Ancylometes and Cupiennius, although a core group of Ctenidae are well supported. Our data were ambiguous as to the monophyly of Oxyopidae. In Dionycha, we found a first split of core Prodidomidae, excluding the Australian Molycriinae, which fall distantly from core prodidomids, among gnaphosoids. The rest of the dionychans form two main groups, Dionycha part A and part B. The former includes much of the Oblique Median Tapetum clade (Trochanteriidae, Gnaphosidae, Gallieniellidae, Phrurolithidae, Trachelidae, Gnaphosidae, Ammoxenidae, Lamponidae and the Molycriinae), and also Anyphaenidae and Clubionidae. Orthobula is transferred from Phrurolithidae to Trachelidae. Our data did not allow for complete resolution for the gnaphosoid families. Dionycha part B includes the families Salticidae, Eutichuridae, Miturgidae, Philodromidae, Viridasiidae, Selenopidae, Corinnidae and Xenoctenidae (new fam., including Xenoctenus, Paravulsor and Odo, transferred from Miturgidae, as well as Incasoctenus from Ctenidae). We confirm the inclusion of Zora (formerly Zoridae) within Miturgidae.

Pro-oxidant and Antioxidant Effects in Photodynamic Therapy: Cells Recognise that Not All Exogenous ROS Are Alike.

Photodynamic therapy (PDT) uses light, photosensitizer molecules and oxygen to generate reactive oxygen species (ROS) that kill cancer cells. Redaporfin, a new photosensitizer in clinical trials, generates both singlet oxygen and superoxide ions. We report the potentiation of redaporfin-PDT in combination with ascorbate and with the inhibition of antioxidant enzymes in A549 (human lung adenocarcinoma) and CT26 (mouse colon adenocarcinoma) cells. The addition of ascorbate and the inhibition of superoxide dismutase (SOD) strongly increased the phototoxicity of redaporfin towards A549 cells but not towards CT26 cells. The inhibition of catalase and the depletion of the glutathione pool also potentiate redaporfin-PDT towards A549 cells. The lower SOD activity of A549 cells might explain this difference. SOD activity levels may be explored to increase the selectivity and efficacy of PDT with photosensitizers that generate radical species.

Assessment and characterization of biofilm formation among human isolates of Streptococcus dysgalactiae subsp. equisimilis.

The capacity to form biofilm is considered a protective mechanism that allows the bacteria to survive and proliferate in hostile environments, facilitating the maintenance of the infectious process. Recently, biofilm has become a topic of interest in the study of the human pathogen group A Streptococcus (GAS). Although GAS has not been associated with infection on medical implants, the presence of microcolonies embedded in an extracellular matrix on infected tissues has been reported. Despite the similarity between GAS and Streptococcus dysgalactiae subspecies equisimilis (SDSE), there are no studies in the literature describing the production of biofilm by SDSE. In this work, we assessed and characterized biofilm development among SDSE human isolates of group C. The in vitro data showed that 59.3% of the 118 isolates tested were able to form acid-induced biofilm on glass, and 28% formed it on polystyrene surfaces. More importantly, biofilm was also formed in a foreign body model in mice. The biofilm structure was analyzed by confocal laser scanning microscopy, transmission electron microscopy, and scanning electron microscopy. Long fibrillar-like structures were observed by scanning electron microscopy. Additionally, the expression of a pilus associated gene of SDSE was increased for in vitro sessile cells compared with planktonics, and when sessile cells were collected from biofilms formed in the animal model compared with that of in vitro model. Results obtained from the immunofluorescence microscopy indicated the biofilm was immunogenic. Our data also suggested a role for proteins, exopolysaccharide and extracellular DNA in the formation and accumulation of biofilm by SDSE.

Challenging the future of siRNA therapeutics against cancer: the crucial role of nanotechnology.

The identification of numerous deregulated signaling pathways on cancer cells and supportive stromal cells has revealed several molecular targets whose downregulation can elicit significant benefits for cancer treatment. In this respect, gene downregulation can be efficiently achieved by exploiting the RNA interference mechanism, particularly by the delivery of chemical synthesized small-interfering RNAs (siRNAs), which have the ability to mediate, in a specific manner, the degradation of any mRNA with complementary nucleotide sequence. However, several concerns regarding off-target effects and immune stimulation have been raised. Depending on their sequence, siRNAs can trigger an innate immune response, which might mediate undesirable side effects that ultimately compromise their clinical utility. This is a very relevant effect that will be discussed in the present manuscript. Moreover, the major drawback in the translation of siRNAs into the clinical practice is undoubtedly their inability to accumulate in tumor sites, particularly in organs other than the liver. In fact, upon systemic administration, owing to siRNAs physico-chemical features, they are rapidly cleared from the blood stream. Therefore, the development of a proper drug delivery system is of utmost importance. In this review, some of the latest advances on different nanotechnological platforms for siRNA delivery under clinical evaluation will be discussed. Along with this, targeting approaches towards cancer and/or endothelial cells will also be addressed, as these are some of the most promising strategies to enhance specific tumor accumulation while avoiding healthy tissues. Finally, clinical information on ongoing studies in patients with advanced solid tumors will be also provided.

The genesis of collective health in Brazil.

During the 1970s in Brazil a social space directed towards health problems on the population level, called collective health, was created and institutionalised. To what extent did this Brazilian invention correspond to a specific socio-historical practice? The works published on this topic have considered social medicine as a homogeneous phenomenon without empirically studying the specificities of national experiences. To bridge this gap, a historical study on the genesis of collective health in Brazil was carried out based on Bourdieu's field theory. The interaction between the paths of the founders and the conditions of historical possibilities were researched through documentary and bibliographical sources, as well as through in-depth interviews of the founders. This social space originated from a meeting of agents with different social backgrounds but who interconnected, creating a structure that was independent of each agent considered individually. One of the components of this establishment was the joining of theoretical production and the implementation of health reforms that resulted in the organisation of a universal health system. This study attempts to show how the international political situation and the contradictions of the national crisis created a universe of possibilities, allowing for the genesis of this sui generis space in Brazil.

Quality of systematic reviews on the treatment of vesiculobullous skin diseases. A meta-epidemiological study.

BACKGROUND: Systematic reviews of Randomized Controlled Trials (RCTs) are considered high-level evidence to support a decision on therapeutic interventions, and their methodological quality is essential to provide reliable and applicable results. OBJECTIVE: This meta-epidemiological study aimed to map and critically appraise systematic reviews assessing treatments for vesiculobullous skin diseases. METHODS: We conducted a comprehensive search strategy on MEDLINE (via Pubmed) in December 2022 without restrictions to find systematic reviews evaluating pharmacological interventions for vesiculobullous skin diseases. The methodological quality was assessed using the AMSTAR-2 tool, and additional information was extracted. We identified nine systematic reviews published between 2002 and 2021, seven assessing pemphigus. RESULTS: According to the AMSTAR-2 tool, 55.6% were classified as critically low quality, 22.2% as moderate quality, 11.1% as low and 11.1% as high quality. No review assessed the certainty of the evidence (GRADE); 86% of pemphigus reviews had at least two overlapping RCTs. There were some limitations regarding methodological flaws and the AMSTAR-2 tool use CONCLUSIONS: These findings reveal a frail methodological quality of systematic reviews about vesiculobullous diseases treatment that may impact the results. Therefore, methodological rigor is mandatory for future systematic reviews to avoid duplication of effort and increase the certainty of the evidence supporting decision-making.

The Impact of Motherhood on Women's Career Progression: A Scoping Review of Evidence-Based Interventions.

(1) Background: Despite the progress made by women in the workplace, mothers still face systemic barriers that prevent them from advancing professionally. This "motherhood penalty" involves a variety of discriminatory practices and experiences that mothers can face at work, including being held to stricter standards regarding salary and recruitment. Despite ongoing research on the association between motherhood and career outcomes, few studies specifically explore how motherhood impacts career advancement and, consequently, access to leadership. This scoping review seeks to gain an understanding of how motherhood impacts women's career progression, and how interventions can address the underrepresentation of mothers in leadership. (2) Methods: Following the PRISMA-ScR framework, we analyzed 52 articles from 2010 to 2022, drawn from 10 databases. (3) Results: The results showed both negative and positive impacts of motherhood on career progression, affecting mothers' attitudes, feelings, and behaviors and yielding changes in interpersonal relationships and work conditions. Intersectionality is highlighted, urging a nuanced examination of challenges faced by mothers from a diversity of backgrounds. Recommendations for interventions include individual and institutional efforts, comprising societal support structures, organizational policy changes, and cultural shifts. (4) Conclusions: This scoping review offers an updated perspective on a classic challenge, providing practical insights for a more inclusive and structural understanding of the career trajectories of working mothers.

The respiratory oxygenation index for identifying the risk of orotracheal intubation in COVID-19 patients receiving high-flow nasal cannula oxygen.

OBJECTIVE: To assess whether the respiratory oxygenation index (ROX index) measured after the start of high-flow nasal cannula oxygen therapy can help identify the need for intubation in patients with acute respiratory failure due to coronavirus disease 2019. METHODS: This retrospective, observational, multicenter study was conducted at the intensive care units of six Brazilian hospitals from March to December 2020. The primary outcome was the need for intubation up to 7 days after starting the high-flow nasal cannula. RESULTS: A total of 444 patients were included in the study, and 261 (58.7%) were subjected to intubation. An analysis of the area under the receiver operating characteristic curve (AUROC) showed that the ability to discriminate between successful and failed high-flow nasal cannula oxygen therapy within 7 days was greater for the ROX index measured at 24 hours (AUROC 0.80; 95%CI 0.76 - 0.84). The median interval between high-flow nasal cannula initiation and intubation was 24 hours (24 - 72), and the most accurate predictor of intubation obtained before 24 hours was the ROX index measured at 12 hours (AUROC 0.75; 95%CI 0.70 - 0.79). Kaplan-Meier curves revealed a greater probability of intubation within 7 days in patients with a ROX index ≤ 5.54 at 12 hours (hazard ratio 3.07; 95%CI 2.24 - 4.20) and ≤ 5.96 at 24 hours (hazard ratio 5.15; 95%CI 3.65 - 7.27). CONCLUSION: The ROX index can aid in the early identification of patients with acute respiratory failure due to COVID-19 who will progress to the failure of high-flow nasal cannula supportive therapy and the need for intubation.

Lipid-based nanoparticles for siRNA delivery in cancer therapy: paradigms and challenges.

RNA interference (RNAi) is a specific gene-silencing mechanism that can be mediated by the delivery of chemical synthesized small-interfering RNA (siRNA). RNAi might constitute a novel therapeutic approach for cancer treatment because researchers can easily design siRNA molecules to inhibit, specifically and potently, the expression of any protein involved in tumor initiation and progression. Despite all the potential of siRNA as a novel class of drugs, the limited cellular uptake, low biological stability, and unfavorable pharmacokinetics of siRNAs have limited their application in the clinic. Indeed, blood nucleases easily degrade naked siRNAs, and the kidneys rapidly eliminate these molecules. Furthermore, at the level of target cells, the negative charge and hydrophilicity of siRNAs strongly impair their cellular internalization. Therefore, the translation of siRNA to the clinical setting is highly dependent on the development of an appropriate delivery system, able to ameliorate siRNA pharmacokinetic and biodistribution properties. In this regard, major advances have been achieved with lipid-based nanocarriers sterically stabilized by poly(ethylene glycol) (PEG), such as the stabilized nucleic acid lipid particles (SNALP). However, PEG has not solved all the major problems associated with siRNA delivery. In this Account, the major problems associated with PEGylated lipid-based nanoparticles, and the different strategies to overcome them are discussed. Although PEG has revolutionized the field of nanocarriers, cumulative experience has revealed that upon repeated administration, PEGylated liposomes lose their ability to circulate over long periods in the bloodstream, a phenomenon known as accelerated blood clearance. In addition, PEGylation impairs the internalization of the siRNA into the target cell and its subsequent escape from the endocytic pathway, which reduces biological activity. An interesting approach to overcome such limitations relies on the design of novel exchangeable PEG-derivatized lipids. After systemic administration, these lipids can be released from the nanoparticle surface. Moreover, the design and synthesis of novel cationic lipids that are more fusogenic and the use of internalizing targeting ligands have contributed to the emergence of novel lipid-based nanoparticles with remarkable transfection efficiency.