Mechanochemical Synthesis of New Praziquantel Cocrystals: Solid-State Characterization and Solubility.

New cocrystals of praziquantel with suberic, 3-hydroxybenzoic, benzene-1,2,4,5-tetracarboxylic, trimesic, and 5-hydroxyisophthalic acids were obtained through ball milling experiments. The optimal conditions for the milling process were chosen by changing the solvent volume and the mechanical action time. Supramolecular interactions in the new cocrystals are detailed based on single-crystal X-ray diffraction analysis, confirming the expected formation of hydrogen bonds between the praziquantel carbonyl group and the carboxyl (or hydroxyl) moieties of the coformers. Different structural characterization techniques were performed for all samples, but the praziquantel:suberic acid cocrystal includes a wider range of investigations such as thermal analysis, infrared and X-ray photoelectron spectroscopies, and SEM microscopy. The stability for up to five months was established by keeping it under extreme conditions of temperature and humidity. Solubility studies were carried out for all the new forms disclosed herein and compared with the promising cocrystals previously reported with salicylic, 4-aminosalicylic, vanillic, and oxalic acids. HPLC analyses revealed a higher solubility for most of the new cocrystal forms, as compared to pure praziquantel.

First evidence of late-acting self-incompatibility in the Aristolochiaceae.

Most Aristolochiaceae species studied so far are from temperate regions, bearing self-compatible protogynous trap flowers. Although self-incompatibility has been suggested for tropical species, the causes of self-sterility in this family remain unknown. To fill this gap, we studied the pollination of the tropical Aristolochia esperanzae, including the physical and physiological anti-selfing mechanisms. Floral visitors trapped inside flowers were collected to determine the pollinators. Protogyny was characterized by observing the temporal expression of sexual phases and stigmatic receptivity tests. The breeding system was investigated using hand-pollination treatments. Pollen tube growth was observed using epifluorescence to identify the self-incompatibility mechanism. Flies were the most frequent visitors found inside A. esperanzae trap flowers, with individuals from the family Ulidiidae being potential pollinators since they carried pollen. The characteristic flower odour and presence of larvae indicate that A. esperanzae deceives flies through oviposition-site mimicry. Although this species showed incomplete protogyny, stigmatic receptivity decreased during the male phase, avoiding self-pollination. Fruits developed only after cross- and open pollination, indicating that the population is non-autonomous, non-apomictic, and self-sterile. This occurred through a delay in the growth of geitonogamous pollen tubes to the ovary and lower ovule penetration, indicating a late-acting self-incompatibility mechanism. Our findings expand the number of families in which late-acting self-incompatibility has been reported, demonstrating that it is more widespread than previously thought, especially when considering less-studied tropical species among the basal angiosperms.

A Review of Computational Modeling in Wastewater Treatment Processes.

Wastewater treatment companies are facing several challenges related to the optimization of energy efficiency, meeting more restricted water quality standards, and resource recovery potential. Over the past decades, computational models have gained recognition as effective tools for addressing some of these challenges, contributing to the economic and operational efficiencies of wastewater treatment plants (WWTPs). To predict the performance of WWTPs, numerous deterministic, stochastic, and time series-based models have been developed. Mechanistic models, incorporating physical and empirical knowledge, are dominant as predictive models. However, these models represent a simplification of reality, resulting in model structure uncertainty and a constant need for calibration. With the increasing amount of available data, data-driven models are becoming more attractive. The implementation of predictive models can revolutionize the way companies manage WWTPs by permitting the development of digital twins for process simulation in (near) real-time. In data-driven models, the structure is not explicitly specified but is instead determined by searching for relationships in the available data. Thus, the main objective of the present review is to discuss the implementation of machine learning models for the prediction of WWTP effluent characteristics and wastewater inflows as well as anomaly detection studies and energy consumption optimization in WWTPs. Furthermore, an overview considering the merging of both mechanistic and machine learning models resulting in hybrid models is presented as a promising approach. A critical assessment of the main gaps and future directions on the implementation of mathematical modeling in wastewater treatment processes is also presented, focusing on topics such as the explainability of data-driven models and the use of Transfer Learning processes.

Tesis doctorales españolas de ciencias de la salud en materia de género (1976-2022) / Spanish doctoral thesis in health sci-ences on gender subjects (1976-2022)

Objetivo principal: analizar cuantitativamente la producción de las tesis doctorales en materia sanitaria relacionadas con el género en España. Metodología: síntesis cuantitativa de indicadores de productividad de las tesis doctorales conseguidas en la base de datos española TESEO y defendidas en Universidades españolas entre 1976 y 2022. Los análisis empleados han sido descriptivos y el cálculo de predicción se basó en la metodología del modelo Holt-Winters. Resultados principales: el 18,75% de las tesis defendidas pertenecen a una Universidad de Madrid. El 75% de ellas son defendidas por graduados en Medicina. La temática de las tesis es en el 25% la violencia de género. El 87,5% son doctoras, pero solamente el 44% de las mujeres dirigen tesis. La predicción para los futuros 24 años indica que se generará alrededor de 1 tesis al año. Conclusión principal: la investigación española en tesis doctorales clínicas de género es escasa y masculinizada.(AU)

Main objective: to quantitatively analyze the production of gender-related doctoral theses in health in Spain. Methodology: quantitative synthesis of productivity indicators of the doctoral theses obtained in the Spanish TESEO database and defended in Spanish Universities between 1976 and 2022. The analyzes used have been descriptive and the prediction calculation was based on the methodology of the Holt- Winters. Main results: 18.75% of the theses defended belong to a University of Madrid. 75% of them are defended by graduates in Medicine. The theme of the theses is gender violence in 25%. 87.5% are doctors, but only 44% of women direct theses. The prediction for the future 24 years indicates that around 1 thesis will be generated per year. Main conclusion: Spanish research in gender clinical doctoral theses is scarce and masculinized.(AU)

Nerve block efficacy in breast augmentation: A systematic review and meta-analysis.

Breast augmentation is often performed as a day-case general anaesthetic operation, with postoperative, opioid-based analgesia regimens. However, it may also be performed using regional anaesthesia; a variety of nerve block techniques are available to reduce postoperative pain and analgesic requirements. This systematic review and meta-analysis were undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines comparing breast augmentation using regional anaesthesia with general anaesthesia, versus general anaesthesia alone or with local field infiltration. All randomised or quasi-randomised studies that recruited adult female patients undergoing breast augmentation using regional anaesthesia were considered. The primary outcome measures were postoperative pain and analgesic requirements. A randomised effects model was used, with standardised mean difference or mean difference outcomes used as appropriate. Thirteen studies were included for systematic review, out of which eight met the inclusion criteria for meta-analysis. Nerve blocks had statistically significant standardised mean difference reductions in postoperative pain scores across all time points: 0 h (-1.2 [-2.1 to -0.3], p = 0.01, I2 = 85%), 1 h (-1.3 [-2.1 to -0.5], p = 0.002, I2 = 89%), 2 h (-1.8 [-2.8 to -0.9], p = 0.0002, I2 = 88%), 4-6 h (-1.2 [-2.1 to -0.4], p = 0.006, I2 = 89%), 24 h (-1.4 [-2.5 to -0.2], p = 0.02, I2 = 94%). There was also a statistically significant reduction in postoperative opioid requirements: -150 mcg fentanyl (-259.2 to -40.9), p = 0.007. Although an element of study heterogeneity is noted, this systematic review and meta-analysis support the concept that regional anaesthesia using nerve blocks in breast augmentation surgery, reduces both postoperative pain and opioid requirements, compared with general anaesthesia.

Single-Particle Plasmon Sensor to Monitor Proteolytic Activity in Real Time.

We have established a label-free plasmonic platform that monitors proteolytic activity in real time. The sensor consists of a random array of gold nanorods that are functionalized with a design peptide that is specifically cleaved by thrombin, resulting in a blueshift of the longitudinal plasmon. By monitoring the plasmon of many individual nanorods, we determined thrombin's proteolytic activity in real time and inferred relevant kinetic parameters. Furthermore, a comparison to a kinetic model revealed that the plasmon shift is dictated by a competition between peptide cleavage and thrombin binding, which have opposing effects on the measured plasmon shift. The dynamic range of the sensor is greater than two orders of magnitude, and it is capable of detecting physiologically relevant levels of active thrombin down to 3 nM in buffered conditions. We expect these plasmon-mediated label-free sensors to open the window to a range of applications stretching from the diagnostic and characterization of bleeding disorders to fundamental proteolytic and pharmacological studies.

Structural Optimization of Antimycobacterial Azaaurones Towards Improved Solubility and Metabolic Stability.

While N-acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N-acetyl moiety for a N-carbamoyl group led to analogues with sub- and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug-susceptible and drug-resistant M. tuberculosis isolates. The new N-carbamoyl azaaurones exhibited improved microsomal stability, compared to their N-acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10-8 , a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.

Giant eagle syndrome with pseudoarthrosis and peripheral facial palsy. / Síndrome de Eagle con pseudoartrosis y parálisis facial periférica.

TITLE: Síndrome de Eagle con pseudoartrosis y parálisis facial periférica.

Subsistence swine farming: seroprevalence and risk factors associated with Lawsonia intracellularis infection in the state of Minas Gerais Brazil in 2016.

Although it is considered an economically relevant and prevalent disease, little information is available on the epidemiology and risk factors of porcine proliferative enteropathy (PPE) in commercial pigs, and no publication is available on subsistence pig farming. The objectives of this study were to estimate the seroprevalence of L. intracellularis and identify associated risk factors in backyard pigs in the 12 mesoregions of the state of Minas Gerais, Brazil. Blood from pigs between 2 months and 6 years of age were sampled; an epidemiological questionnaire was applied to 288 properties investigated in 2016. Serum samples were tested for the presence of anti-L. intracellularis antibodies using an immunoperoxidase monolayer assay. The seroprevalence of L. intracellularis was 97.7% (CI 95%: 96.7-98.4), and there was no statistical difference among the prevalence of the sampled mesoregions. Only 3 of the 12 risk factors were significant when samples were analyzed from strongly seropositive animals (≥ 1:120) in a Poisson multivariate regression model. There was an interaction between properties in peri-urban areas and extensive production systems. This interaction demonstrated an increase in prevalence rates by 3.7 times (95%CI: 2.4-5.8). Properties close to dumps demonstrated an increase in prevalence rates by 2.2 times (95%CI: 0.99-4.8). In conclusion, anti-L. intracellularis antibodies were widely dispersed in subsistence pig farming's in Minas Gerais, indicating a wide circulation of the agent in this type of production system. The interactions of animals raised close to peri-urban areas, extensively, and close to landfills are risk factors for spread of PPE.

Nutrient supplementation of beef female calves at pre-weaning enhances the commitment of fibro-adipogenic progenitor cells to preadipocytes.

We aimed to evaluate the impact of nutrient supplementation of beef female calves at pre-weaning on adipogenic determination. Thirty-four female calves were assigned to two experimental treatments: Control (CON, n = 17), where animals were supplemented only with mineral mixture; Supplemented (SUP, n = 17), where animals received energy-protein supplement containing minerals (5 g/kg of BW per day) of their body weight. Animals were supplemented from 100 to 250 days of age, and muscle samples were biopsied at the end of the supplementation period. Regarding the performance variables, there were no differences between treatments for initial body weight (P = 0.75). The final body weight (P = 0.07), average daily gain (P = 0.07), rib eye area (P = 0.03), and rib fat thickness (P = 0.08) were greater in SUP female calves compared with CON treatment. The number of fibro-adipogenic progenitor cells (P = 0.69) did not differ between treatments, while a greater number of intramuscular pre-adipocytes were observed in SUP than CON female calves (P = 0.01). The expression of miRNA-4429 (P = 0.20) did not differ between treatments, while the expression of miRNA-129-5p (P = 0.09) and miRNA-129-2-3p (P = 0.05) was greater in CON than SUP female calves. Our results suggest that nutrient supplementation at early postnatal stages of development enhances the commitment of fibro-adipogenic progenitor cells into the adipogenic lineages allowing to an increase in intramuscular fat deposition potential of the animals later in life.

SKELETAL MUSCLE SENSITIVITY TO WASTING INDUCED BY UROTHELIAL CARCINOMA.

BACKGROUND: Skeletal muscle wasting is a common phenotypic feature of several types of cancer, and it is associated with functional impairment, respiratory complications, and fatigue. However, equivocal evidence remains regarding the impact of cancer-induced muscle wasting on the different fiber types. AIM: The aim of this study was to investigate the impact of urothelial carcinoma induced in mice on the histomorphometric features and collagen deposition in different skeletal muscles. MATERIALS AND METHODS: Thirteen ICR (CD1) male mice were randomly assigned into two groups: exposed to 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in drinking water for 12 weeks, plus 8 weeks of tap water (BBN, n = 8) or with access to tap water for 20 weeks (CONT, n = 5). Tibialis anterior, soleus, and diaphragm muscles were collected from all animals. For cross-sectional area and myonuclear domain analysis, muscle sections were stained with hematoxylin and eosin, and for collagen deposition assessment, muscle sections were stained with picrosirius red. RESULTS: All animals from the BBN group developed urothelial preneoplastic and neoplastic lesions, and the tibialis anterior from these animals presented a reduced cross-sectional area (p < 0.001), with a decreased proportion of fibers with a higher cross-sectional area, increased collagen deposition (p = 0.017), and higher myonuclear domain (p = 0.031). BBN mice also showed a higher myonuclear domain in the diaphragm (p = 0.015). CONCLUSION: Urothelial carcinoma induced muscle wasting of the tibialis anterior, expressed by a decreased cross-sectional area, higher infiltration of fibrotic tissue, and increased myonuclear domain, which also increased in the diaphragm, suggesting that fast glycolytic muscle fibers are more susceptible to be affected by cancer development.

Effect of ultrasonic agitation on marginal adaptation, intratubular penetration and bonding strength of calcium-silicate-based endodontic sealers: A laboratory study.

The effect of ultrasonic activation (UA) on marginal adaptation, intratubular penetration and bond strength provided by three calcium silicate-based sealers was evaluated. Ninety-six distobuccal root canals of maxillary molars were randomly divided into 8 groups (n = 12) according to the sealer and UA application: EndoSequence BC sealer (ESBC), Sealer Plus BC (SPBC) and Bio-C Sealer (BCS), using AH Plus (AH) as a control group. The specimens were sectioned at 2, 4 and 6 mm from the apex. The data were statistically analysed using Kruskall-Wallis, Dunn, Mann-Whitney and chi-squared tests. UA improved the marginal adaptation of ESBC (6 mm), SPBC (all levels), BCS (2/4 mm) and AH (4 mm) (p < 0.05); the bond strength of SBPC (2 mm) and BCS (6 mm) were also improved (p < 0.05). The UA of endodontic silicate-based sealers improved the marginal adaptation in all levels and the bond strength of SBPC and BCS sealer.

Exploring the correlations between epi indicators of COVID-19 and the concentration of pharmaceutical compounds in wastewater treatment plants in Northern Portugal.

The COVID-19 pandemic caused by the SARS-CoV-2 virus led to changes in the lifestyle and human behaviour, which resulted in different consumption patterns of some classes of pharmaceuticals including curative, symptom-relieving, and psychotropic drugs. The trends in the consumption of these compounds are related to their concentrations in wastewater systems, since incompletely metabolised drugs (or their metabolites back transformed into the parental form) may be detected and quantified by analytical methods. Pharmaceuticals are highly recalcitrant compounds and conventional activated sludge processes implemented in wastewater treatment plants (WWTP) are ineffective at degrading these substances. As a results, these compounds end up in waterways or accumulate in the sludge, being a serious concern given their potential effects on ecosystems and public health. Therefore, it is crucial to evaluate the presence of pharmaceuticals in water and sludge to assist in the search for more effective processes. In this work, eight pharmaceuticals from five therapeutic classes were analysed in wastewater and sludge samples collected in two WWTP located in the Northern Portugal, during the third COVID-19 epidemic wave in Portugal. The two WWTP demonstrated a similar pattern with respect to the concentration levels in that period. However, the drugs loads reaching each WWTP were dissimilar when normalising the concentrations to the inlet flow rate. Acetaminophen (ACET) was the compound detected at highest concentrations in aqueous samples of both WWTP (98. 516 µg L - 1 in WWTP2 and 123. 506 µg L - 1in WWTP1), indicating that this drug is extensively used without the need of a prescription, known of general public knowledge as an antipyretic and analgesic agent to treat pain and fever. The concentrations determined in the sludge samples were below 1.65 µg g - 1 in both WWTP, the highest value being found for azithromycin (AZT). This result may be justified by the physico-chemical characteristics of the compound that favour its adsorption to the sludge surface through ionic interactions. It was not possible to establish a clear relationship between the incidence of COVID-19 cases in the sewer catchment and the concentration of drugs detected in the same period. However, looking at the data obtained, the high incidence of COVID-19 in January 2021 is in line with the high concentration of drugs detected in the aqueous and sludge samples but prediction of drug load from viral load data was unfeasible.

Cytosolic aldose metabolism contributes to progression from cirrhosis to hepatocarcinogenesis.

Oxidative stress modulates carcinogenesis in the liver; however, direct evidence for metabolic control of oxidative stress during pathogenesis, particularly, of progression from cirrhosis to hepatocellular carcinoma (HCC), has been lacking. Deficiency of transaldolase (TAL), a rate-limiting enzyme of the non-oxidative branch of the pentose phosphate pathway (PPP), restricts growth and predisposes to cirrhosis and HCC in mice and humans. Here, we show that mitochondrial oxidative stress and progression from cirrhosis to HCC and acetaminophen-induced liver necrosis are critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Both TAL and AR are confined to the cytosol; however, their inactivation distorts mitochondrial redox homeostasis in opposite directions. The results suggest that AR acts as a rheostat of carbon recycling and NADPH output of the PPP with broad implications for disease progression from cirrhosis to HCC.

The Impact of Different Surface Treatments on Topography and Bond Strength of Resin Cement to Lithium Disilicate Glass Ceramic.

OBJECTIVE: To evaluate the influence of different surface treatments on topography, surface roughness, surface energy, and microtensile bond strength stability of resin cement to lithium disilicate glass ceramic. METHODS AND MATERIALS: Seventy disc-shaped specimens of IPS e.max Press were divided into seven groups according to the surface treatment: NT - non-treated (control); FSil - hydrofluoric acid (HF) + silane; FPSil - HF + phosphoric acid (HP) + silane; FUSil - HF + ultrasonic bath (U) + silane; FPUSil - HF + HP + U + silane; MEP - Monobond Etch and Prime (MEP); and MEPH - MEP + heating. Topography and surface roughness were evaluated using a 3D laser confocal microscope (3DLCM) and scanning electron microscopy (SEM) and surface energy with a goniometer. The microtensile bond strength (µTBS) was evaluated after storage in distilled water at 37°C for 24 hours and after thermocycling (5,000 cycles, 5°-55° C, 30-second dwell time). Data were analyzed using one-way ANOVA (surface roughness and surface energy), two-way ANOVA (µTBS), Tukey's HSD post-hoc test, and Student t-test (α=0.05). RESULTS: FUSil, FPSil, and FSil presented similar and highest surface roughness, whereas NT, FPUSil, MEP, and MEPH showed similar, and lowest, roughness values (p<0.05). FPUSil, FPSil, FUSil, and FSil presented a similar and highest surface energy. NT, MEP, and MEPH showed similar and lowest surface energy. CONCLUSION: Only FSil, FPSil, and MEPH maintained bond strength stability after thermocycling, with FPSil leading to less bond strength reduction, suggesting this protocol is more reliable for bonding resin cements to lithium disilicate glass ceramics.