Ocular metastases profile in a tertiary hospital in São Paulo, Brazil.

OBJECTIVE: Ocular metastases are the most common intraocular tumours in adults. Data regarding the occurrence of these tumours in the Brazilian population is scarce. We aimed to investigate the profile of ocular metastases of patients referred to tertiary hospital service in São Paulo, Brazil. DESIGN: Retrospective study. PARTICIPANTS: Patients referred to the Ocular Oncology service of the Federal University of São Paulo with initial diagnostic hypothesis of ocular metastasis. METHODS: Data was retrospectively collected from medical records from June 2017 to June 2023. Age, sex, primary tumour site, previous knowledge of the systemic diagnosis, laterality, initial visual acuity (VA), local or systemic treatment and mean follow-up period were obtained. RESULTS: A total of 37 cases were referred to the ocular oncology division due to a suspected ocular metastasis, 15 (40.5%) were confirmed. Mean age at diagnosis was 53.47 ± 16.01 years old, the majority (86.7%) of patients already knew the systemic diagnosis. Breast cancer (66.7%) was the most common primary site, followed by Lung cancer (26.7%). Both eyes were affected in 66.67% of the cases, all patients had metastases at the choroid (100.0%), and the mean initial VA was 1.37 ± 1.04 logMAR. Chemotherapy was the main systemic treatment modality (73.3%), and most patients had no ocular treatment (53.3%). The mortality rate along the follow-up period was 30.0%. CONCLUSIONS: Considering the number of new patients absorbed by the Ocular Oncology service over the study period, the frequency of ocular metastases was relatively low. The patients' characteristics was comparable to data published in the international literature.

Correction: Gonçalves Vero et al. Transport of Pigs of Two Market Weights at Two Space Allowances: Effects on Behaviour, Blood Parameters, and Meat Quality under Summer and Winter Conditions. Animals 2023, 13, 2767.

In the original publication [...].

The Prolonged Activation of the p65 Subunit of the NF-Kappa-B Nuclear Factor Sustains the Persistent Effect of Advanced Glycation End Products on Inflammatory Sensitization in Macrophages.

Advanced glycation end products (AGEs) prime macrophages for lipopolysaccharide (LPS)-induced inflammation. We investigated the persistence of cellular AGE-sensitization to LPS, considering the nuclear content of p50 and p65 nuclear factor kappa B (NFKB) subunits and the expression of inflammatory genes. Macrophages treated with control (C) or AGE-albumin were rested for varying intervals in medium alone before being incubated with LPS. Comparisons were made using one-way ANOVA or Student t-test (n = 6). AGE-albumin primed macrophages for increased responsiveness to LPS, resulting in elevated levels of TNF, IL-6, and IL-1beta (1.5%, 9.4%, and 5.6%, respectively), compared to C-albumin. TNF, IL-6, and IL-1 beta secretion persisted for up to 24 h even after the removal of AGE-albumin (area under the curve greater by 1.6, 16, and 5.2 times, respectively). The expressions of Il6 and RelA were higher 8 h after albumin removal, and Il6 and Abca1 were higher 24 h after albumin removal. The nuclear content of p50 remained similar, but p65 showed a sustained increase (2.9 times) for up to 24 h in AGE-albumin-treated cells. The prolonged activation of the p65 subunit of NFKB contributes to the persistent effect of AGEs on macrophage inflammatory priming, which could be targeted for therapies to prevent complications based on the AGE-RAGE-NFKB axis.

Non-invasive meat quality assessment: Exploring the potential of ocular infrared thermography to predict ultimate pH in Nellore beef cattle.

This study investigated the use of infrared thermography (IRT) to identify the dark, firm, and dry (DFD) phenomenon in Brazilian beef, which is a significant concern for the industry because of its inferior quality and reduced shelf life. This study examined 113 Nellore bulls and analyzed their minimum and maximum ocular temperatures using IRT. The results highlight the efficacy of thermal images (IRTmax) as a significant predictor, with R2 values ranging from 0.84 to 0.88 for calibration models. The inclusion of parameters such as glucose and lactate further enhanced prediction accuracy. The models also revealed that the combination of features, such as lightness (L*), redness (a*), and yellowness (b*), contributed to the precise prediction of pHu, with an R2 of 0.88. In model validation, RMSEP ranged from 0.104 to 0.158, indicating good generalization capability. The RPD, ranging from 1.7 to 2.6, suggests satisfactory quantitative prediction. The statistical significance of all models, evidenced by P-values <0.001, strengthens the reliability of the results. In conclusion, the models support the use of IRT as a tool for identifying pHu alterations in carcasses. When combined with blood parameters, they may exhibit even greater efficiency in predicting pHu in Nelore cattle carcasses, highlighting the potential applicability of these methods in the beef industry.

Influence of occlusal appliances on the masticatory muscle function in individuals with sleep bruxism: A systematic review and meta-analysis.

This systematic review answers the question: "Does occlusal appliance use influence masticatory muscle function of dentate individuals with sleep bruxism?". The literature search included six databases, grey literature, and manual search for articles. Randomized and non-randomized clinical trials were included comparing muscle function of sleep bruxers before and after receiving occlusal appliances. Risk of bias was assessed with risk of bias assessment for randomized and non-randomized clinical trials tool. Twelve studies, three represent randomized clinical trials, were included. Risk of bias was considered low, moderate, or serious. Meta-analyses indicated that soft and hard appliances did not influence muscle activity and bite force of bruxers. Qualitative analysis showed that occlusal appliance use did not influence masticatory performance and muscle volume. However, it was effective in reducing tongue force. Certainty of evidence was considered very low for muscle activity when evaluated with hard appliances, and for bite force evaluated with both appliance materials. Low certainty of evidence was observed for muscle activity with soft appliances. Based on the findings of this meta-analysis, occlusal appliances do not affect masticatory muscle function of sleep bruxers. Regardless of appliance material, the activity of masseter and temporal, and bite force of sleep bruxers was not influenced.

Ecological modeling, biogeography, and phenotypic analyses setting the tiger cats' hyperdimensional niches reveal a new species.

Recently, the tiger-cat species complex was split into Leopardus tigrinus and Leopardus guttulus, along with other proposed schemes. We performed a detailed analysis integrating ecological modeling, biogeography, and phenotype of the four originally recognized subspecies-tigrinus, oncilla, pardinoides, guttulus-and presented a new multidimensional niche depiction of the species. Species distribution models used > 1400 records from museums and photographs, all checked for species accuracy. Morphological data were obtained from institutional/personal archives. Spotting patterns were established by integrating museum and photographic/camera-trap records. Principal component analysis showed three clearly distinct groups, with the Central American specimens (oncilla) clustering entirely within those of the Andes, namely the pardinoides group of the cloud forests of the southern Central-American and Andean mountain chains (clouded tiger-cat); the tigrinus group of the savannas of the Guiana Shield and central/northeastern Brazil (savanna tiger-cat); and the guttulus group in the lowland forests of the Atlantic Forest domain (Atlantic Forest tiger-cat). This scheme is supported by recent genetic analyses. All species displayed different spotting patterns, with some significant differences in body measurements/proportions. The new distribution presented alarming reductions from the historic range of - 50.4% to - 68.2%. This multidimensional approach revealed a new species of the elusive and threatened tiger-cat complex.

Sensory quality of beef with different ultimate pH values - A Brazilian perspective.

This study evaluated Brazilian consumer perceptions of beef with different pH values at 48 h post-mortem (pHu) through sensory analysis. A total of 138 consumers evaluated raw and grilled steaks. The steaks were divided according to their pHu (normal pH < 5.8, atypical darkness, firmness, and dryness [DFD] > 5.8 pH < 6, and typical DFD pH ≥ 6). There was no difference in the visual evaluation of raw steaks or purchase intention. Evaluation of the grilled steaks showed that consumers preferred typical DFD steaks in terms of tenderness, and there was a tendency for the same behavior in terms of juiciness. No differences were observed in other evaluated parameters. Cluster analysis identified three consumer segments for visual evaluation, indicating a preference for steaks with higher pHu in terms of freshness. Additionally, four segments were identified for evaluation, with some groups expressing a preference for higher pHu meat in terms of freshness appearance, tenderness liking, and overall liking. The developed regression models for overall liking and purchase intention exhibited favorable adjustment indices, with r2 values of 0.86 and 0.57, respectively, for raw steaks and 0.90 for grilled steaks for in overall liking. Regression models indicated a strong influence of color and freshness appearance, in addition to tenderness liking and juiciness liking, on the overall liking scores of consumers. These results indicate that Brazilian consumers do not dislike dark cutting and, despite differentiating their greater tenderness, do not show a preference between the different pHu values.

Transport of Pigs of Two Market Weights at Two Space Allowances: Effects on Behaviour, Blood Parameters, and Meat Quality under Summer and Winter Conditions.

This study was carried out through two separate experiments aiming at evaluating the effects of two space allowances (0.54 and 0.62 m2/pig in summer and 0.44 m2/pig and 0.50 m2/pig in winter) on the behavioural and physiological response, and meat quality of pigs of two slaughter weights (120 kg and 140 kg). In summer, higher blood haematocrit levels were found at slaughter in heavier pigs transported at a smaller space allowance (p = 0.04). During lairage, pigs transported at a smaller space allowance started fighting later (p = 0.04). Fighting behaviour was greater in heavier pigs (p ≤ 0.05), whilst their drinking activity was lower (p < 0.05). This resulted in greater exsanguination blood CK levels (p < 0.01) and drier hams (p = 0.05) in heavier pigs. In winter, only lower space allowance influenced some meat quality traits (p < 0.05), but these effects were minor. The effects of space allowance during summer transports on within-truck ambient conditions, post-transport pigs' welfare, and meat quality are similar. Mixing heavier pigs may result in greater aggressiveness and more fatigue-related meat quality variation during summer. Overall, winter transport results may have been biased by the short journey and within-truck load distribution.

Exploring microplastic contamination in Guiana dolphins (Sotalia guianensis): Insights into plastic pollution in the southwestern tropical Atlantic.

Marine mammals are considered sentinel species and may act as indicators of ocean health. Plastic residues are widely distributed in the oceans and are recognised as hazardous contaminants, and once ingested can cause several adverse effects on wildlife. This study aimed to identify and characterise plastic ingestion in the Guiana dolphins (Sotalia guianensis) from the Southwestern Tropical Atlantic by evaluating the stomach contents of stranded individuals through KOH digestion and identification of subsample of particles by LDIR Chemical Imaging System. Most of the individuals were contaminated, and the most common polymers identified were PU, PET and EVA. Microplastics were more prevalent than larger plastic particles (meso- and macroplastics). Smaller particles were detected during the rainy seasons. Moreover, there was a positive correlation between the stomach content mass and the number of microplastics, suggesting contamination through trophic transfer.

A fluidized-bed-riser adsorption system for continuous bioproduct recovery from crude feedstock.

In this work, a novel technique for continuous purification of biologics from a crude feedstock is demonstrated with equipment referred to as Fluidized Bed Adsorption System (FBRAS). The development and validation of such unit operations were performed utilizing lysozyme as a model protein and Relisorb™ SP405/EB as a carrier. The performance of FBRAS to carry out combined clarification and purification was evaluated by capturing of antifungal peptides directly from the lysed broth. The novel technique reduced the number of process unit operations from six to three without having an impact on purity. Overall productivity increased by 250% in comparison to the existing downstream processing routine.

Exploring microplastic contamination in reef-associated fishes of the Tropical Atlantic.

Microplastics (MPs) are ubiquitous in marine compartments, and their transboundary distribution favours the dispersion and accumulation of particles in ecosystems. This study investigated MP contamination in four coastal fish species (Haemulon squamipinna, Chaetodon ocellatus, Syacium micrurum, and Alphestes afer) from the southwestern Tropical Atlantic. An alkaline treatment was applied to extract MPs from the digestive tracts, and a Laser Direct Infrared (LDIR) system was used to identify polymers. All species analysed were contaminated with MPs, with Alphestes afer being the most contaminated (1.45 ± 1.09 MPs individual-1; frequency of occurrence 80 %). No significant differences were found in the number and size of detected particles among species. The most common shapes were fibres and films, and polyethylene was the most abundant polymer. This study provides important baseline data on MP contamination in coastal fish species inhabiting complex habitat areas relevant for conserving marine biodiversity.

High-resolution ultrasonography for early diagnosis of neural impairment in seropositive leprosy household contacts.

Leprosy household contacts (HC) represent a high-risk group for the development of the disease. Anti-PGL-I IgM seropositivity also increases the risk of illness. Despite significant advances in leprosy control, it remains a public health problem; and early diagnosis of this peripheral neuropathy represents one of the main goals of leprosy programs. The present study was performed to identify neural impairment in leprosy HC by analyzing differences in high-resolution ultrasonographic (US) measurements of peripheral nerves between leprosy HC and healthy volunteers (HV). Seventy-nine seropositive household contacts (SPHC) and 30 seronegative household contacts (SNHC) underwent dermato-neurological examination and molecular analysis, followed by high-resolution US evaluation of cross-sectional areas (CSAs) of the median, ulnar, common fibular and tibial nerves. In addition, 53 HV underwent similar US measurements. The US evaluation detected neural thickening in 26.5% (13/49) of the SPHC and only in 3.3% (1/30) among the SNHC (p = 0.0038). The CSA values of the common fibular and tibial nerves were significantly higher in SPHC. This group also had significantly greater asymmetry in the common fibular and tibial nerves (proximal to the tunnel). SPHC presented a 10.5-fold higher chance of neural impairment (p = 0.0311). On the contrary, the presence of at least one scar from the BCG vaccine conferred 5.2-fold greater protection against neural involvement detected by US (p = 0.0184). Our findings demonstrated a higher prevalence of neural thickening in SPHC and support the role of high-resolution US in the early diagnosis of leprosy neuropathy. The combination of positive anti-PGL-I serology and absence of a BCG scar can identify individuals with greater chances of developing leprosy neuropathy, who should be referred for US examination, reinforcing the importance of including serological and imaging methods in the epidemiological surveillance of leprosy HC.

Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs.

The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator's Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug's mechanism of action were included. The quality of IBs was assessed based on the presence of a rationale for the chosen animal model, completeness of pharmacokinetic (PK) results in reporting and internal validity information of the preclinical evidence. The IB-derisk tool was used to generate preclinical and early clinical data overviews data. For each compound, the overlap between pharmacologically active dose ranges and well-tolerated levels was calculated for three pharmacokinetic (PK) parameters: human equivalent dose (HED), maximum plasma concentration (Cmax) and area under the curve (AUC). Twenty-five IBs were included. In general, the quality of reporting in IBs was assessed as poor. About a third of studies did not explore the entire concentration-effect curve (pre)clinically. Single dose tolerability ranges were most accurately predicted by Cmax. Human equivalent dose and AUC were the best predictors of pharmacologically active ranges. Tolerable and pharmacologically active dose ranges in healthy volunteers can be reasonably well predicted from preclinical data with the IB-derisk tool. The translatability of preclinical studies can be improved by applying a higher reporting standard in IBs including comparable PK measurements across all preclinical and clinical studies.

Complexes of Charged-Neutral Block Copolymers and Surfactants: Process-Dependent Features and Long-Term Stability of Their Aqueous Dispersions.

Aqueous dispersions of charged-neutral block copolymers (poly(acrylamide)-b-poly(acrylate)) complexed with an oppositely charged surfactant (dodecyltrimethylammonium) have been prepared by different approaches: the simple mixing of two solutions (MS approach) containing the block copolymer and surfactant, with their respective simple counterions, and dispersion of a freeze-dried complex salt prepared in the absence of simple counterions (CS approach). The CS particles were investigated under different conditions: dispersion of a CS in salt-free water and dispersion of a CS in a dilute salt solution, the latter condition yielding dispersions with the same composition as the MS process. Additionally, aged dispersions (up to 6 months) and dispersed complexes of the polyacrylate homopolymer and dodecyltrimethylammonium surfactant were evaluated. By employing different characterization techniques, it was seen that dispersions prepared by the MS approach display nanometric spherical particles with disordered cores, and poor colloidal stability, partially caused by the absence of surface charge (ζ-potential close to zero). Oppositely, anisometric particles were formed in CS dispersions and were large enough to sustain micellar cubic cores. The CS particles presented long-time colloidal stability, partially due to a net negative surface charge, but the stability varied with the length of the neutral block composing the corona. Our results demonstrate that all dispersed particles are metastable structures, with physicochemical properties strongly dependent on the preparation procedure, thus making these particles suitable for fundamental studies and potential applications where accurate control of their properties, including size, shape, internal structure, and stability, is desired.

From prey to predators: Evidence of microplastic trophic transfer in tuna and large pelagic species in the southwestern Tropical Atlantic.

Plastic pollution is present in most marine environments; however, contamination in pelagic predators, including species of economic interest, is still poorly understood. This study aims to access the macro- and microplastic contamination in tuna and large pelagic species and verify whether a trophic transfer occurs from prey to tunas captured by two fleets in the Southwestern Tropical Atlantic (SWTA). We combined different methodological approaches to analyse the intake of macro- and microplastics. In addition to examining the plastics in the fish' stomachs, we investigated the contamination in the prey retrieved from the guts of predators. A low frequency of occurrence (3%) of macroplastic was detected in the tuna and large pelagic species; conversely, we observed a high frequency of microplastic in the tuna's stomachs (100%) and prey analysed (70%). We evinced the trophic transfer of microplastics by analysing the ingestion rate of particles in prey retrieved from the tuna stomachs. In the 34 analysed prey, we detected 355 microplastic particles. The most contaminated prey were cephalopods and fishes of the Bramidae family. The most frequent microplastic shapes in both prey and tuna stomachs were foams, pellets and fibres (<1 mm). A variety of polymers were identified; the most frequent were styrene-butadiene rubber (SBR), polyamide (PA), polyethylene terephthalate (PET) and polyethylene (PE). Our findings enhance scientific knowledge of how the ecological behaviour of marine species can affect microplastic intake.

Dietary Sodium and Nonalcoholic Fatty Liver Disease: A Systematic Review.

(1) Introduction: Restriction in sodium intake is an important strategy for reducing cardiovascular morbidity and mortality, considering the direct influence of high-sodium diet consumption on the development of hypertension and cardiovascular diseases. There are only a few studies dealing with the influence of dietary sodium on the development of nonalcoholic fatty liver disease (NAFLD). In this systematic review, evidence in humans and animal models was compiled in a critical view of the influence of dietary sodium intake patterns on NAFLD markers; (2) Methods: Systematic review of PubMed data. Clinical outcomes included the prevalence/incidence of NAFLD for human studies, and NAFLD markers (hepatic lipogenesis, and markers of steatosis, fibrosis, and inflammation) for animal studies. The protocol was registered at the International Prospective Register of Systematic Review (PROSPERO; CRD42023390447); (3) Results and Conclusion: Seven studies in humans and eight in animals were included. All studies in humans were observational and associated high-sodium intake with NAFLD. However, in animals, both the increased and reduced consumption of sodium negatively influenced markers of liver steatosis, inflammation, and fibrosis.

Influencing factors for microplastic intake in abundant deep-sea lanternfishes (Myctophidae).

Plastic debris is ubiquitous in the hydrosphere. Yet, we lack an understanding of contamination among deep-sea species and primarily how each trait can influence microplastic intake. We investigated microplastic contamination in the digestive tract of hyper-abundant mesopelagic lanternfishes (n = 364 individuals) from the Southwestern Tropical Atlantic, captured from 90 to 1000 m depth. Overall, microplastics were detected in most individuals analysed (frequency of occurrence = 68 %). Large microplastics, mostly of a filamentous shape were the most frequent, followed by smaller fragments and foams. Microplastics made of high-density polymers (PET, PVC, PA, SBR rubber) were more prevalent than low-density ones (PE, EVA and PBD rubber), especially under deeper layers. Larger microplastics were detected in lanternfishes captured off the northeastern Brazilian coast (mean 0.88 ± SE 0.06 mm) compared to those from around the Rocas Atoll and Fernando de Noronha Archipelago (0.70 ± 0.07 mm; p≤ 0.05), ∼350 km from the continent. Moreover, lanternfishes that migrate from the upper mesopelagic (200-500 m) to the epipelagic layers (<200 m) had simultaneously the highest intake and the smallest particles (1.65 ± 0.17 particles individual-1 and 0.55 ± 0.07 mm; p≤ 0.05). Biological mediated transport of microplastics from the epipelagic to the mesopelagic waters was evinced, but fishes foraging in shallower layers had the lowest intake (1.11 ± 0.10 part. ind.-1; p≤ 0.05). Furthermore, the jaw length was positively associated with an increment in microplastic intake (Incidence Rate Ratio = 1.1; p≤ 0.05). The lanternfishes that preferably prey upon fish larvae are more prone to microplastic intake than their counterparts, which forage mostly on crustaceans and gelatinous zooplankton (p≤ 0.05).

Is caffeine mouth rinsing an effective strategy to improve physical and cognitive performance? A systematic review.

The aim of this study was to perform a systematic review on the effects of caffeine mouth rinsing on physical and cognitive performance. Following a search through 4 databases, 18 studies were found meeting the inclusion criteria (15 for physical performance and 3 for cognitive performance). All selected studies found an improvement in cognitive performance with caffeine mouth rinse. Four studies found positive effects of caffeine mouthwash on physical performance when repeated during exercise, while one study detected a positive effect with a single mouthwash before exercise, but only in a fasted state. Among these studies that showed positive effects, however, three (2 for physical performance and 1 for cognitive performance) presented fair methodological quality. There was also a variety of methodological approaches in the studies that showed no improvement in physical performance with caffeine mouth rinse, which may have influenced the potential to detect the ergogenic effect of caffeine mouth rinse. Thus, the effects of caffeine mouth rinse on physical performance are mixed, but a potential ergogenic effect might be present in a fasted state and when mouthwash is repeated during exercise. Concerning cognitive performance, caffeine mouth rinse seems to be a beneficial strategy.

Anti-hyperglycemic potential and chemical constituents of Aristolochia triangularis Cham. leaves - A medicinal species native to Brazilian forests.

ETHNOPHARMACOLOGICAL RELEVANCE: Aristolochia triangularis Cham. has been used in Brazilian traditional medicine for various therapeutic purposes, including as a leaf-based infusion for diabetes management. AIM OF THE STUDY: This study was designed to chemically characterize an infusion of in natura A. triangularis leaves and evaluate the in vivo anti-hyperglycemic properties of this infusion. MATERIALS AND METHODS: Chemical composition was examined using liquid-liquid extraction procedure, chromatographic methods, NMR, and LC-MS/MS. The in vivo anti-hyperglycemic activity of the freeze-dried infusion of A. triangularis leaves (Inf-L-At) was assessed using oral glucose tolerance test (OGTT). Initially, normoglycemic male rats were pre-treated with orally administered Inf-L-At at doses of 62.5, 125, and 250 mg/kg for two consecutive days. On the day of the OGTT, fasting animals received a glucose load (4 g/kg) 30 min after treatment with Inf-L-At, and the blood glucose levels were verified at 15, 30, 60, and 180 min. Intestinal maltase, lactase, and sucrase activities and muscle and liver glycogen contents were also assessed after the OGTT. RESULTS: Inf-L-At extract led to glycemic reduction with no dose-response at 15, 30, and 60 min comparable to that of the antidiabetic drug glibenclamide and was accompanied by an increase in hepatic and muscle glycogen contents. Additionally, there was a significant statistically decrease in the in vitro activity of disaccharidases. Maltase and sucrase activities were inhibited at all doses, whereas lactase activity was inhibited only at 62.5 and 250 mg/kg. In total, 75 compounds were found in the infusion, including seven new ones, (7S*,8S*,7ꞌS*,8ꞌR*)-4,4ꞌ-dihydroxy-3,3ꞌ-dimethoxy-7,9ꞌ-epoxylignan-7ꞌ-ol; 4ꞌ-hydroxy-3ꞌ-methoxy-3,4-methylenedioxy-7,9ꞌ-epoxylignan-9,7ꞌ-diol; triangularisines A, B, and C; N-ethyl-N-methyl-affineine; and N-methyl pachyconfine, and one previously not described as a natural product, epi-secoisolariciresinol monomethyl ether. CONCLUSION: The results demonstrated the anti-hyperglycemic activity of the infusion from A. triangularis leaves and showed that it is a rich source of lignoids, alkaloids, and glycosylated flavonoids, which are known to exhibit antidiabetic effects and other biological properties that can be beneficial for patients with chronic hyperglycemia, thus certifying the popular use of this herbal drink.