A growing number of oncology treatments, such as bevacizumab, are used across multiple indications. However, in health technology assessment (HTA), their clinical and cost-effectiveness are typically appraised within a single target indication. This approach excludes a broader evidence base across other indications. To address this, we explored multi-indication meta-analysis methods that share evidence across indications.

We conducted a simulation study to evaluate alternative multi-indication synthesis models. This included univariate (mixture and non-mixture) methods synthesizing overall survival (OS) data and bivariate surrogacy models jointly modeling treatment effects on progression-free survival (PFS) and OS, pooling surrogacy parameters across indications. Simulated datasets were generated using a multistate disease progression model under various scenarios, including different levels of heterogeneity within and between indications, outlier indications, and varying data on OS for the target indication. We evaluated the performance of the synthesis models applied to the simulated datasets in terms of their ability to predict OS in a target indication.

The results showed univariate multi-indication methods could reduce uncertainty without increasing bias, particularly when OS data were available in the target indication. Compared with univariate methods, mixture models did not significantly improve performance and are not recommended for HTA. In scenarios where OS data in the target indication is absent and there are also outlier indications, bivariate surrogacy models showed promise in correcting bias relative to univariate models, though further research under realistic conditions is needed.

Multi-indication methods are more complex than traditional approaches but can potentially reduce uncertainty in HTA decisions.

Sanitation Standard Operating Procedures (SSOP) are critical in key stages of food production and processing. After manufacturing, slicing process can serve as a point of contamination, potentially compromising the quality and shelf life of mozzarella. The objective of this study was to determine the effect of SSOP on the quantification and diversity of psychrotrophic bacteria with proteolytic and lipolytic potential in mozzarella before and after industrial slicing. Psychrotrophic bacteria were isolated, phenotypically assessed for spoilage potential under mesophilic and psychrotrophic conditions, analysed for diversity using dendrograms of genetic similarity and identified by partial sequencing of the 16S rRNA gene. The mean psychrotrophic counts were 3.77 (±0.83) log CFU/mL before slicing and 3.58 (±0.51) log CFU/mL in the sliced product, indicating a non-significant reduction (p < 0.05). Regarding spoilage potential, none of the 233 isolates evaluated exhibited proteolytic activity under psychrotrophic conditions. However, psychrotrophic lipolytic activity was predominant both before and after slicing. The species Lactobacillus delbrueckii, which is part of the saccharolytic inoculum used to reduce the pH of the curd during cheese production, was the main proteolytic bacteria under mesophilic conditions (35°C) in both before and after sliced samples. Although the bacterial counts indicated the full efficiency of the slicer’s SSOP, the microbial diversity analysis revealed the inclusion of Staphylococcus succinus, Staphylococcus hominis, Enterococcus faecalis and Klebsiella pneumoniae during the slicing process, albeit at low levels. Therefore, relying solely on psychrotrophic quantification may not be sufficient to attest the efficiency of the slicer’s SSOP. Even under controlled industrial conditions, spoilage bacteria from handling and environmental sources may be introduced into sliced mozzarella. Methods for improving the microbiological quality of the mozzarella pieces prior to slicing, as well as the intensification of sanitary procedures, must be reviewed and implemented to improve the shelf life and commercial potential of sliced mozzarella.

The developmental origins of health and disease hypothesis suggests that environmental exposures during critical developmental windows increase the risk of disease later in life. Among these, endocrine disruptors (EDs) are particularly concerning due to their ubiquitous presence. The kidneys are highly susceptible to EDs toxicity during the perinatal period; however, long-term effects of ED mixtures on renal structure in aging remain unclear. This study aimed to characterize the renal histoarchitecture of aged rats after perinatal exposure to an ED mixture. Pregnant Sprague-Dawley rats were assigned to two groups: Control (corn oil, 2 ml/kg) and ED Mix (32.11 mg/kg/day of 12 EDs, including phthalates, pesticides, UV filters, bisphenol A, and butylparaben, in corn oil). Exposure occurred from gestational day 7 to postnatal day 21. Offspring were euthanized at postnatal day 440. ED mixture exposure did not affect the organosomatic index. However, ED Mix offspring presented renal lesions, including necrosis and tubular fusion, with a trend toward increased pathological changes. Morphometric analysis revealed enlarged nuclei and increased nuclear perimeters in the cortex and medulla, along with altered cellular organization in glomerular and medullary regions. Collagen organization was disrupted, with increased fibrosis in cortical and medullary compartments and reduced collagen type I and III in glomeruli. These findings indicate that perinatal exposure to an ED mixture alters nuclear phenotype and promotes extracellular matrix remodeling in distinct renal compartments. Such changes suggest long-term impacts on renal structure and function, emphasizing the health risks associated with early-life exposure to complex ED mixtures.

Elephant grass [Cenchrus purpureus (Schum.) Morrone] is a tropical forage grass widely used in ruminant feeding in tropical and subtropical areas, mainly in cut-and-carry systems due to is high potential for herbage accumulation. However, most common genotypes (tall genotypes) generally show an early stem elongation, which contributes to a rapid decline in the forage nutritive value. Dwarf elephant grass types usually present less stem elongation and may be considered an option for the production of high nutritive value forage in cut-and-carry systems. The aims of this study were to evaluate and explain variations in herbage characteristics and kinetics of in vitro gas production of irrigated elephant grass genotypes (two tall-types – Elephant B and IRI-381 – and two dwarf-types genotypes – Mott and Taiwan A-146 2.37) under two harvest frequencies (60 and 90 days) in the dry and rainy seasons of two years. Herbage characteristics varied among genotypes, harvest frequency and seasons. Dwarf genotypes showed better in vitro fermentation parameters with the advancement of maturity compared to the tall size genotypes. Harvesting tall genotypes at a higher frequency (60-day) contributed to improving the fermentation, while dwarf elephant grass maintained greater fermentation when less frequent harvests were adopted (90-day).

The objective of the trial was to evaluate the effects of arginine supplementation in the feed of gestating sows on the variability of piglet birth weight. The weight of the piglets was evaluated using descriptive analysis, correlation analysis and analysis of variance with a 2 × 3 factorial arrangement. This arrangement included no supplementation or supplementation with 1.0 % L-arginine, combined in three periods. Period 1: from days 25 to 53 of gestation, providing 23 g/day from days 25 to 28 and 18 g/day from days 29 to 53 of gestation; period 2: from days 30 to 60 of gestation and from day 80 of gestation to farrowing, providing 18 g/day in the first period and 45 g/day in the second period and period 3: from day 85 of gestation to delivery, with 24 g/day was provided from day 85 until farrowing and 28 g/day from days 85 to 107, increasing to 56 g/day from day 108 until farrowing. Supplementation with 1.0 % of L-arginine reduced the percentage of total piglets born and piglets born alive with less than 800 g by 2.26 and 2.05 percentage points, respectively; and increased the percentage of total piglets born and piglets born alive between 1601 and 1800g by 5.89 and 6.08 percentage points, respectively. Supplementing with 1.0 % of L-arginine improves litter uniformity, with an average reduction of 4.06 percentage points in the piglet population of less than 1180 g and an increase in the piglet population of 1180 to 1890 g by 4.70 percentage points.

Medium to small petrels that mostly nest in burrows or crevices represent a large fraction of the world’s seabirds, yet their population trends are largely unknown. This lack of knowledge, which has implications for conservation planning, results mostly from methodological difficulties and from the approaches that have been used for their monitoring. Here, we present the surveying scheme created to monitor Cory’s Shearwater Calonectris borealis breeding numbers at their largest known colony, Selvagem Grande (Portugal). We defined 60 circular plots at fixed locations on this 2.45 km2 island and counted nests with eggs annually at the end of laying. Results show that the population increased at 1.45% (95% confidence interval [CI]: 0.72–2.01%) per year between 2009 and 2023. We estimate that the current population size is 38,830 pairs (95% quantile CIs = 34,373–43,713). To the best of our knowledge, this study provides the first systematic information (using fully repeatable methods and providing CIs for the estimates) on population trends of Cory’s Shearwaters, one of the most abundant seabirds in the warm temperate and subtropical North Atlantic and one of the most studied petrels globally. Monitoring using the approach detailed here requires two days of work (by 2–3 persons) per year. Our results and simulations indicate that this is a powerful methodology, with narrow confidence limits for estimated trends and an ability to detect small population changes over short time spans. We suggest that more monitoring protocols similar to this one (with necessary site-specific adaptations, particularly for potential colony expansion where suitable habitat exists) should be developed and implemented in a range of colonies with crevice and burrowing nesting petrels to improve our knowledge on the population status of a broad fraction of the world’s seabirds.

In this paper, we present a semi-empirical calibration between the oxygen abundance and the N2 emission-line ratio for low ionisation nuclear emission regions (LINERs). This relation was derived by comparing the optical spectroscopic data of 118 nuclear spaxels classified as LINERs using three different BPT diagrams from the Mapping Nearby Galaxies survey (MaNGA) and sub-classified as weak (wAGN, 84 objects) and strong (sAGN, 34 objects) active galactic nucleus (AGN) from the WHAN diagnostic diagram and photoionisation model results obtained with the cloudy code assuming gas accretion into a black hole (representing an AGN). We found that our wAGN LINERs exhibit an oxygen abundance in the range of $8.50 \lesssim \mathrm{12+\log(O/H)} \lesssim 8.90 $, with an average value of $\mathrm{12+\log(O/H)}=8.68$, while our sAGN LINERs exhibit an oxygen abundance in the range of $8.51 \lesssim \: \mathrm{12+\log(O/H)} \: \lesssim \: 8.81 $, with an average value of $\mathrm{12+\log(O/H)}=8.65$. Our abundance estimations are in good agreement with those derived for another two different samples one of them with 463 Seyfert 2 objects and the other with 43 LINERs galaxies ionised by post-AGB stars, showing that the assumptions of our models are likely suitable for wAGN and sAGN LINERs. A relation between the equivalent width of the observed H$\alpha$ emission-line and the estimated ionisation parameter provided by models was obtained. Our results also suggest that LINERs does not show a clear correlation between oxygen abundances and the stellar mass of the hosting galaxies.

This study hypothesized that the signal grass (Urochloa decumbens [Stapf] R. Webster) modifies its structural and productive characteristics under a silvopasture system with legume trees. The treatments were composed of (i) signal grass in monoculture and (ii) a silvopasture system intercropping signal grass + Mimosa caesalpiniifolia Benth. a legume tree, over two consecutive years. The experiment was set in a completely randomized block design with three replications. Grazing was carried out by cattle with an average body weight (BW) of 186 ± 26 kg. The type of system had no significant effect on the structural and productive characteristics of signal grass. In the first grazing season, the greatest canopy height (54 cm) and total forage mass (6473 kg DM/ha) occurred in the dry period. The leaf:stem ratio was greater in the rainy season. Forage accumulation (515 kg DM/ha/28 days) and forage accumulation rate (18 kg DM/ha/day) were greater in the rainy season. Higher total forage production (4583 kg DM/ha) occurred in the first grazing season. The silvopasture with double rows spaced 25 m apart and with a tree density of 600 plants/ha did not compromise the structural and productivity characteristics of the signal grass pasture. The legume M. caesalpiniifolia has the potential for use as an arboreal component in silvopasture systems with signal grass.

In this article, we consider some critical Brézis-Nirenberg problems in dimension $N \geq 3$ that do not have a solution. We prove that a supercritical perturbation can lead to the existence of a positive solution. More precisely, we consider the equation:

\begin{equation*}\left\{\begin{array}{rllll}-\Delta u & = & \lambda u^{q-1} + u^{2^*+ r^\alpha -1} & \mbox{in} & B, \\u & \gt & 0 & \mbox{in} & B, \\u&=&0 & \mbox{on} & \partial B,\\\end{array}\right.\end{equation*}

$B \subset \mathbb{R}^N$

$N\geq 3$

$r=\vert x \vert$

$\alpha \in (0,\min\{N/2,N-2\})$

$q\in [2,2^*]$

$r \in (0,1)$

From a neuroscientific point of view, one of the unique archetypes of substance use disorders is its road to relapse, in which the reward system plays a crucial role. Studies on the neurobiology of substance use disorders have highlighted the central role of a protein belonging to the Fos family of transcription factors, ΔFosB. Relying on the roles ΔFosB plays in the pathophysiology of substance use disorders, we endeavour to present some evidence demonstrating that N-acetylcysteine, a low-cost and well-tolerated over-the-counter medicine, may influence the downstream pathway of ΔFosB, thereby serving as a treatment strategy to mitigate the risk of relapse in cases of substance use.

Over the last few years, during the pandemic, the Brazilian population has suffered several problems, ranging from health to socioeconomic impacts. When we consider Brazilian science, there has been an undeniable scientific delay generated by the pandemic, especially in areas that are not related to the coronavirus. In this context, with the aim of fostering collaboration among researchers in the field of Developmental Origins of Health and Diseases (DOHaD) and enhancing the potential for implementing public health strategies to prevent noncommunicable chronic diseases, the Brazilian Association of Developmental Origins of Health and Diseases (DOHaD Brazil) was established in 2020. In this narrative, we explore the effects of the COVID-19 pandemic in Brazil, focusing on its impacts on scientific research conducted in universities. Additionally, we underscore the significance of the DOHaD Brazil Association, particularly from the perspective of young researchers engaged in DOHaD research in Brazil.

The symbiosis between microorganisms and host arthropods can cause biological, physiological, and reproductive changes in the host population. The present study aimed to survey facultative symbionts of the genera Wolbachia, Arsenophonus, Cardinium, Rickettsia, and Nosema in Cotesia flavipes (Cameron) (Hymenoptera: Braconidae) and Diatraea saccharalis (Fabricius) (Lepidoptera: Crambidae) in the laboratory and evaluate the influence of infection on the fitness of these hosts. For this purpose, 16S rDNA primers were used to detect these facultative symbionts in the host species, and the hosts' biological and morphological features were evaluated for changes resulting from the infection caused by these microorganisms. The bacterial symbionts studied herein were not detected in the D. saccharalis samples analysed, but the endosymbiont Wolbachia was detected in C. flavipes and altered the biological and morphological aspects of this parasitoid insect. The results of this study may help to elucidate the role of Wolbachia in maintaining the quality of populations/lineages of C. flavipes.

Maternal obesity may trigger long-term neurodevelopmental disorders in offspring. Considering the benefits of the Brazil nut (Bertholletia excelsa H.B.K.), a rich source of nutrients such as selenium, this study aimed to evaluate its effect on the behavior of obese rat offspring and its relationship with oxidative stress. From 60 days of age until weaning, female Wistar rats were fed a high-fat diet (mHF) or an HF diet supplemented with 5% Brazil nut (mHF/BN), while control mothers (mCTL) were fed a standard diet or a standard diet supplemented with 5% Brazil nut (mBN). Male pups received a standard diet throughout life and, at 30 and 90 days old, were subjected to behavioral tasks to evaluate anxiety and cognition. Biochemical evaluations were performed at 90 days of age. No alterations were observed in the anxiety behavior of the offspring. However, the offspring of the mHF group (oHF) exhibited impaired short-term memory at 30 and 90 days of age and impaired long-term memory at 30 days. Short-term memory impairment was prevented by Brazil nuts in young rats (30 days). While the serum selenium concentration was reduced in the oHF group, the serum catalase concentration was reduced in all groups, without changes in lipid peroxidation or protein carbonylation. Brazil nut maternal diet supplementation prevented short- and long-term cognitive impairment in the offspring, which may be related to the selenium levels.

Oocyte cytoplasmic evaluation is based on homogeneity and granular appearance. Our study investigated if a granular cytoplasm, highly heterogeneous, would affect oocyte competence in bovine. In two experiments, bovine cumulus–oocyte complexes (COCs) with homogeneous cytoplasm (control, CC) and granulated cytoplasm (granular, GC) were selected from a regular pool of COCs. Experiment 1 was performed with slaughterhouse ovaries, and Experiment 2 was carried out in Girolando COCs obtained from ovum pick-up. Granular oocytes had higher caspase 3 levels (66.17 ± 11.61 vs 172.08 ± 16.95, P < 0.01) and similar GAP junction activity (5.64 ± 0.45 vs 6.29 ± 0.29). ZAR1 relative mRNA amount was lower in granular oocytes (178.27 ± 151.63 vs 0.89 ± 0.89, P = 0.01) and no effect was detected for MATER, PPP2R1A, ENY2, IGF2R, and BMP15 genes. Despite molecular differences, no detrimental effect was detected on oocyte competence in GC oocytes. Cleavage (Experiment 1: 59.52 ± 7.21% vs 59.79 ± 6.10% and Experiment 2: 68.88 ± 4.82 vs 74.41 ± 5.89%) and blastocyst (Experiment 1: 29.28 ± 4.14% vs 23.15 ± 2.96% and Experiment 2: 21.11 ± 3.28% vs 21.02 ± 6.08%) rates were similar between CC and GC (Experiments 1 and 2, respectively). Post-transfer embryo development revealed that pregnancy (CC: 24.27 ± 9.70% vs GC: 26.31 ± 7.23%) and calving (23.68% vs 33.33%) rates and fetal growth were not affected by the presence of cytoplasmic granules. Our results demonstrated that oocytes with granular cytoplasm present equivalent efficiency for IVF and calf production compared with homogenous cytoplasm oocytes. This could be observed through similar cleavage, blastocyst rates, and fetal growth development. In addition to differences in oocyte gene expression related to oocyte quality, it seems not to affect oocyte developmental competence.